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 [44]. 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. Ultrasonography of the testes

High-frequency (>10 MHz) testicular US should be used to confirm a testicular tumour to:

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

It 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 [45].

5.2.2. Computerised tomography*

Contrast enhanced computerised tomography (CECT) is recommended in all patients for staging before orchidectomy [46]. This may be postponed until histopathological confirmation of malignancy. 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.

Cerebral imaging is recommended in GCT patients with either multiple lung metastases or poor-prognosis IGCCCG risk group (especially with hCG values > 5,000 UI/L), or clinical symptoms [47]. Contrast enhanced computerised tomography may be used if magnetic resonance imaging (MRI) is not available or contraindicated.

*For more information regarding CT, please see appendix 1, available online https://uroweb.org/guidelines/testicular-cancer/publications-appendices

5.2.3. Magnetic resonance imaging

Scrotal 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 [48], it should only be considered when US is inconclusive, as local staging for testis-sparing surgery (TSS), to differentiate between paratesticular and intratesticular lesions, and/or to characterise intratesticular masses (e.g., distinctive features of Leydig tumours) [48].

Magnetic resonance imaging of the abdomen may be used for staging where there are contra-indications to iodine-based contrast media with similar accuracy to CECT in the detection of retroperitoneal nodal enlargement [46].

Data from cerebral and spinal metastasis detection in other malignancies suggest that MRI is far more sensitive than CECT but requires specific expertise [49]. When available, MRI should be used to evaluate for both cerebral and spinal metastases in GCTs if there are clinical concerns [50].

5.2.4. Fluorodeoxyglucose-positron emission tomography

Evidence does not support the use of Fluorodeoxyglucose-positron emission tomography (FDG-PET) for initial staging of TC [51,52].

5.2.5. Bone scan

There is no evidence to support the routine use of bone scan for staging of TC unless clinically indicated.

5.3. Serum tumour markers

5.3.1. Pre-operative serum tumour markers

Serum alphafetoprotein (AFP), beta subunit of human Chorionic Gonadotropin (β-hCG) and LDH should be determined before and after 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 [44,53,54]. Pure seminomas may also have modestly elevated β-hCG level at diagnosis in up to 30% of cases [53,55]. Significant elevation of AFP in patients with seminomas should raise concerns of a non-seminoma component. Modest stable elevations may be considered a normal variant [41].

Tumour markers have limitations due to their low sensitivity as normal levels do not exclude the presence of disease [54].

5.3.2. Serum tumour markers after orchidectomy

Tumour markers need to be repeated following orchidectomy providing staging and prognostic information [41]. 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 [54,55]. If these remain elevated or increase metastatic disease is likely [53]. Marker normalisation after orchidectomy, however, does not exclude the possibility of metastatic disease.

In addition to staging, marker levels are used to define risk stratification and prognosis (Table 3). They are also used to monitor treatment response and detect disease relapse [53,55]. With follow-up the precise frequency of testing is not well defined [56].

5.3.3. Other tumour markers

Micro RNAs (miRNAs) are emerging as potential new biomarkers. A number of studies suggest higher discriminatory accuracy for miRNAs (particularly miR-371a-3p) compared to conventional GCT markers in diagnosis, treatment monitoring, and prediction of residual or recurrent viable disease [57-59]. Furthermore, they may differentiate between GCT and other (stromal/non-germ cell originating) tumours [59]. Issues which need to be resolved for use in routine clinical practice include laboratory standardisation, availability of the test and, importantly, prognostic validation [58].

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 TC. A scrotal approach should be avoided when TC is suspected as it results in a higher local recurrence rate [60].

5.4.2. Testis-sparing surgery

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.

In men with GCTs, orchidectomy represents the standard of care as pathological studies describe multifocal and/or adjacent GCNIS in 20-30% of patients [61,62]. Testis sparing surgery when feasible, is indicated in synchronous bilateral tumours or in tumours in solitary testis [63]. In this setting, at least two additional testicular biopsies should be taken to exclude GCNIS [64].

Testis-sparing surgery may be offered for 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 [63,65]. Patients should be informed that cancer can be present even in small (i.e., < 1 cm) masses [63,66,67].

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 [65,68,69]. In cases of discordance between FSE and final pathology, delayed orchidectomy 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 (up to 26.9%), when TC is present in the specimen [63,67,70], 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 [63,67,71], 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 [71]. The prosthesis can be inserted at orchidectomy, or subsequently, without adverse consequences, including infection [72].

5.4.4. Contralateral biopsy

Contralateral biopsy has been advocated to exclude GCNIS [73] and is routine policy in some countries [74]. 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) [75,76], the morbidity of GCNIS treatment (see section 7.1.1), and the fact that most metachronous tumours are low stage at presentation [77,78]. 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 [64,79,80]. Patients should be informed that a subsequent GCT may arise despite a negative biopsy [81]. When indicated, a two-site surgical testicular biopsy is the technical procedure recommended [64].

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) [37,82-84].

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 [82]:
  • Presence or absence of peri-tumoural 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 [83].
• If microscopic findings are not concordant with serum markers further block samples should be taken.
• pT category according to TNM 2016 [25]. 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
• Sex cord gonadal tumours: Inhibin, calretinin

The search for i12p (FISH or PCR) or gain in Ch9 (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 [85].

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) [84].

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 [84]. The dataset for handling pathological assessment of TC is shown in Table 4.

Table 4: Recommended dataset for reporting of neoplasia of the testis (modified from the International Collaboration on Cancer Reporting) [84].

* 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 [86,87]. In contrast, young males should be informed about the importance of physical self-examination, particularly those with risk factors including a history of cryptorchidism or a male relative with TC [88].

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 [89,90]. Up to 24% of TC patients are azoospermic and almost 50% have abnormal sperm counts (oligozo-ospemic) before treatment [90].

Treatment for TC, including orchidectomy, may have a negative impact on reproductive function [91]. Both chemotherapy and radiation treatment (RT) can impair fertility. Long-term infertility is rare after RT and dose-cumulative-dependent with chemotherapy [92-94]. Spermatogenesis usually recovers one to four years after chemotherapy [95]. Adjuvant treatment for CS I (BEP [Bleomycin, etoposide, cisplatin] x1; Carbo x1) does not appear to significantly affect testicular function compared to surveillance, with full recovery after one year [96].

All patients should be offered semen preservation as the most cost-effective strategy for fertility preservation. This should be offered before orchidectomy when feasible, maximising the chances of fertilisation, and avoiding the risk of a non-functioning remaining testicle. If not arranged before orchidectomy, it should be undertaken prior to chemotherapy or RT [92-94,97,98].

Chemotherapy and RT are both teratogenic. Therefore, contraception must be used during treatment and for at least six months after its completion [99].

For further information regarding management of hypogonadism and sub-fertility the reader is referred to the EAU Guidelines on Sexual Reproductive Health [100].

5.8. Guidelines for the diagnosis and staging of Testicular Cancer