Testicular Cancer

5. DIAGNOSTIC EVALUATION

5.1. Physical examination

Testicular cancer usually presents as a painless testicular mass or incidental finding on ultrasound (US). Pain, either scrotal or abdominal/back, may occur and result in delayed diagnosis [48]. Gynaecomastia may be present in a small number of patients. Clinical assessment should thus include abdominal, chest and supraclavicular examination.

5.2. Imaging

5.2.1. Primary tumour

The primary tumour and contralateral testis need to be assessed radiologically to

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

High-frequency (>10 MHz) testicular US is recommended. Scrotal US is also recommended for all men with retroperitoneal or visceral masses with/or without elevated serum β-hCG or Alpha-fetoprotein (AFP) in the absence of a palpable testicular mass [49].

Small, usually non-palpable masses may be incidental findings on scrotal US which may be benign. Of lesions with small diameter virtually all < 3mm, 87% of those < 5mm and 70% < 10mm are benign [50-52]. With small masses US features may assist in discriminating between benign and malignant tumours although none are completely reliable [50].

Scrotal magnetic resonance imaging (MRI) provides higher sensitivity and specificity than US in the diagnosis of TC, but its high cost does not justify its routine use for this purpose [53]. It should only be considered when US is inconclusive as local staging for potential testis-sparing surgery (TSS), to differentiate between paratesticular and intratesticular lesions, and/or to characterise intratesticular masses (e.g., distinctive features of Leydig tumours) [53].

5.2.2. Staging

Cross-sectional imaging of the chest, abdomen and pelvis is recommended in patients with elevated markers or clinical suspicion of metastases for staging before orchidectomy and remains standard practice. This may be postponed in patients with small or indeterminant masses until histopathological confirmation of malignancy. Contrast enhanced CT scan (CECT) and MRI are the imaging modalities used. Evidence does not support the use of Fluorodeoxyglucose-positron emission tomography (FDG-PET) for initial staging of TC [54,55].

a. Abdomen and Pelvis

Contrast enhanced CT scan is the long-established imaging modality used to assess the abdomen and pelvis to identify nodal and visceral metastases. The size of metastases should be described in three dimensions, or at least by the greatest diameter. The expected patterns of nodal spread in TC should be considered when evaluating small and borderline nodes.

A SR of a number of small studies, with a total of 102 evaluable patients, has suggested that MRI appears comparable to CECT in detecting nodal metastases [56]. It is significantly more expensive and less available than CECT for routine use. It clearly has utility in patients who have contra-indications to iodine-based contrast media or likely to require numerous subsequent scans.

b. Thorax

The chest and supraclavicular fossa should also be imaged with CECT to assess for nodal and pulmonary disease. Magnetic resonance imaging appears equivalent to CT in detecting supra-diaphragmatic lymph nodes but less sensitive in detecting pulmonary nodules. Thus, it is not recommended as a routine alternative to CT [57].

c. Other Sites

Cerebral and spinal imaging is recommended in GCT patients with either multiple lung metastases or poor-prognosis IGCCCG risk group (especially with β-hCG values > 5,000 UI/L), or clinical symptoms [58]. Data from cerebral and spinal metastasis detection in other malignancies suggest that MRI is far more sensitive than CECT but requires specific expertise [59,60]. When available, MRI should be used to evaluate for both cerebral and spinal metastases in GCTs if there are clinical concerns. Contrast enhanced computerised tomography may be used if MRI is not available or contraindicated.

5.3. Serum tumour markers

5.3.1. Pre-operative serum tumour markers

Serum AFP, beta subunit of human Chorionic Gonadotropin (β-hCG) and LDH should be determined before orchidectomy as they support the diagnosis of TC and may be indicative of GCT histology.

Up to 90% of NSGCT’s have elevated AFP or β-hCG at diagnosis with 39% having an increased level of both [48,61]. Pure seminomas may also have elevated β-hCG level at diagnosis in up to 30% of cases [61]. Significant elevation of AFP in patients with seminomas should raise concerns of a NSGCT component. Modest stable marker elevations may be considered ‘normal’ and of no clinical significance [45].

Thus, current tumour markers have limitations due to their low sensitivity as normal levels do not exclude the presence of disease.

5.3.2. Serum tumour markers after orchidectomy

Tumour markers need to be repeated following orchidectomy providing staging and prognostic information [45]. If elevated pre-operatively normalisation may take several weeks as the serum half-lives of AFP and β-hCG are five to seven days and one to three days respectively. If these remain elevated or increase metastatic disease is likely [61]. Marker normalisation after orchiectomy however does not exclude the possibility of metastatic disease.

In addition to staging marker levels are used to define risk stratification and prognosis (Table 4). They are also used to monitor treatment response and detect disease relapse [61]. With follow-up the precise frequency of testing is not well defined [62].

5.3.3. Other tumour markers

Micro RNAs (miRNAs) are emerging as potential new biomarkers. Pre-operative elevation has been reported in 80-90% of both SGCT and NSGCT with higher levels in metastatic compared to localised disease [63]. A number of studies suggest higher discriminatory accuracy for micro-RNA (miRNAs) (particularly miR-371a-3p) compared to conventional GCT markers in diagnosis, clinical staging, treatment monitoring, and predicting of residual or recurrent viable disease [63-65]. Furthermore, they may differentiate between GCT and other (stromal/non-germ cell originated) tumours [65]. Issues which need to be resolved for use in routine clinical practice include laboratory standardisation, availability of the test and, importantly, prognostic validation [66]. As with both AFP and β-hCG miRNA is not expressed in teratoma which will limit its use in NSGCT.

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 for patients with a TGTC. A scrotal approach should be avoided when TC is suspected as it results in a higher local recurrence rate [67].

5.4.2. Testis-sparing surgery

In men with GCTs, orchidectomy represents the standard of care as pathological studies describe multifocal and/or adjacent GCNIS in 20-30% of patients [68]. Testis sparing surgery when feasible, may be considered in synchronous bilateral tumours or in tumours in solitary testis [69]. In these settings, at least two additional testicular biopsies should be taken to exclude GCNIS [70].

Testis-sparing surgery (TSS) is a valid treatment option in men with interstitial cell or benign testicular tumours and may prevent hypogonadism and infertility in young men. These tumours are often small although larger lesions may be difficult to differentiate from GCT.

Thus, TSS may be considered in patients with small or indeterminate testicular masses, negative tumour markers and a normal contralateral testis to avoid over-treatment of potentially benign lesions and preserve testicular function [69,71]. Patients should be informed that cancer may be present even in small (i.e., < 1 cm) masses [69,72,73].

In both settings, TSS should be offered together with frozen section examination (FSE). Frozen section examination has shown to be reliable and highly concordant with final histopathology in expert hands, with a 99% and 96% of sensitivity and specificity respectively and 98% and 97% of PPV and NPV, respectively [71]. In cases of discordance between FSE and final pathology delayed orchiectomy may be required.

In cases of a history of GCT or indeterminate small testicular lesion, patients should be made aware of the following issues regarding TSS practice: that limited data exists regarding oncological safety of TSS; that local recurrence rates have been reported (up to 26.9%), when TC is present in the specimen [69,74] 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, potential infertility, the need for hormonal supplementation despite parenchyma preservation [69,75] and that discordance between FSE and final pathology requiring a delayed orchidectomy.

5.4.3. Insertion of testicular prosthesis

Testicular prosthesis should be offered to all patients receiving unilateral or bilateral orchidectomy [76]. The prosthesis can be inserted at orchidectomy or subsequently without adverse consequences, including infection [77].

5.4.4. Contralateral biopsy

Contralateral biopsy has been advocated to exclude GCNIS [78] and routine policy in some countries [79]. It is, however, controversial to recommend routine contralateral biopsy in all patients due to the low incidence of GCNIS and metachronous contralateral testicular tumours (up to 9% and approximately 2.5%, respectively) [80,81], the morbidity of GCNIS treatment (see section 6.1.1), and the fact that most metachronous tumours are low stage at presentation [82,83]. 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 > 40 years without risk factors [70,84,85]. Patients should be informed that a subsequent GCT may arise despite a negative biopsy [86]. When indicated, a two-site surgical testicular biopsy is the technical procedure recommended [70].

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) [39,44,87,88].

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 2022 [27]:
  • Presence or absence of peri-tumoral lymph and/or blood vessel 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 [44].
• If microscopic findings are not concordant with serum markers further block samples should be taken.
• Pathological tumour (pT) category according to TNM 2016 [28]. 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
• Syncytiotrophoblastic: β-hCG
• Embryonal carcinoma: CD30
• Yolk sac tumour: Glypican 3, AFP.
• Sex cord gonadal tumours: Inhibin, calretinin steroidogenic factor 1.

The search for i12p (FISH or PCR) or gain in Chr9 (spermatocytic tumour) are additional molecular techniques which are only rarely required. Confirmation of the utility of other molecular markers such as P53, MDM2, KRAS and HRAS is awaited [89].

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) [88].

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 [88]. The dataset for handling pathological assessment of TC is shown in Table 5.

Table 5: Recommended dataset for reporting of neoplasia of the testis (modified from the International Collaboration on Cancer Reporting) [88]

* 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

No high-level evidence studies supporting screening programs exists [90,91]. In contrast young males should be informed about the importance of testicular self-examination. Testicular self-examination is recommended in high-risk groups which include a history of cryptorchidism, as well as those with a personal or family history of TC [90,92].

5.7. Summary of evidence and recommendations for the diagnosis and staging of Testicular Cancer