38. Diagnosis, Staging and Management of Testis Cancer
KeywordsTestis cancerSeminonaNon-seminomaTestisGerm-cellRadical orchidectomyRPLNDChemotherapySurveillance
Testicular tumours may be benign or malignant. The latter present either with signs and symptoms of the primary tumour or with problems relating to metastatic spread. The eighth edition of the Union for International Cancer Control (UICC) TNM classification of testicular cancer is shown . Testis cancer is relatively rare, representing approximately 1% of all male cancers and 5% of all urological tumours. There are 3–10 new cases per 100,000 males per year in Western countries. However, the incidence is projected to rise in some of these to 10 cases/100,000 males by 2035 . Higher incidence rates are seen in developed countries compared to developing countries. Risk factors for testicular cancer include a previous or family history, with a higher risk if the affected male family member is a brother. Additional, clinical risk features include the presence of germ cell neoplasia in situ (GCNIS) and/or testicular dysgenesis syndrome (cryptorchidism, hypospadias and impaired spermatogenesis).
Germ-cell tumours are responsible for 90–95% of testis tumours. Pure seminoma has a peak incidence in the fourth decade, whilst non-seminomatous germ cell tumour (NSGCT) has a peak incidence in the third decade . Approximately 90% are localised to the testis at first presentation and 2–5% are extragonadal . Most are unilateral although 1–2% occur bilaterally, usually as a metachronous event. The different types of testicular tumour are set out below (Box 38.1). NSGCT’s have a tendency to spread more commonly via haematogeneous as well as lymph node routes and stage III metastasis occurs more common in these. By contrast, approximately 80% of seminoma patients have stage I disease at diagnosis, with only 15% having stage II disease and <5% presenting with advanced disease.
Most testicular germ cell tumours are confined to the scrotum at first presentation: these are usually cured by local surgery using inguinal orchidectomy. When patients present with metastases or develop distal spread after primary orchidectomy, the disease is usually chemo-sensitive, particularly to regimens involving cisplatin. This renders the condition curable in the majority, but not all cases. High risk NSCGT is still lethal in approximately 50% of patients. In light of this, preservation of reproductive function, quality of life and avoidance of delayed treatment effects are important concerns for testis cancer patients who survive long-term.
Presentation and Diagnosis
The commonest presentation is with a painless unilateral testicular mass. However a significant number of men may present with pain and are misdiagnosed with epididymitis or orchitis, leading to a delay in essential treatment. GCT’s can also present with a secondary hydrocele or more rarely, a para-neoplastic syndrome. One rare example of this is hCG induced hyperthyroidism, seen in GCTs containing high levels of hCG. This can activate the TSH receptor as both TSH and hCG have similar alpha subunits.
An uncommon but well-recognised acute presentation is with symptoms and signs arising from disseminated disease. When patients present in this way it is an oncological emergency and urgent referral to a specialist oncology team is required. Such cases need immediate chemotherapy without orchidectomy. Patients with disease of this type must be referred within 24 h of presentation.
Examination of the patient should include inspection for and documentation of the condition of both testicles, noting the size of both the affected and contra-lateral testicle. The abdomen and thorax should be examined for nodal or visceral disease and gynaecomastia (present in 7% of men and associated with elevated hCG levels). In men with an unexplained retroperitoneal, pulmonary/mediastinal or mass, testis cancer should always be considered as a primary cause.
US scanning of the testis is the standard imaging modality, with a sensitivity of almost 100%. Difficulty can arise differentiating between orchitis and tumour. In addition, small intra-testicular lesions may produce considerable diagnostic uncertainty. Further imaging with contrast enhanced US or MRI can help clarify the diagnosis. MRI has a higher sensitively and specificity than US but in the main it is not necessary. PET scanning is not recommended for the initial staging of testicular cancer but it can be used for assessment of residual metastatic masses post chemotherapy .
Staging investigations include computed tomography (CT) of the thorax, abdomen and pelvis with IV and oral contrast. Cranial imaging should also be performed if there are neurological symptoms or if there is widespread metastatic disease with high marker levels at first presentation .
Where precise clinical diagnosis is impossible and a lesion is suspicious, biopsy or orchidectomy may be needed for definitive verification. In these circumstances, surgical exploration should always be through the groin: testis conservation should be attempted in the first instance where possible. Percutaneous needle biopsy or testicular biopsy via the scrotum is only indicated in exceptional circumstances.
It is inevitable that following orchidectomy some lesions will ultimately prove to be benign: this should be explained to the patient pre-operatively.
Serum Tumour Markers
These include beta human chorionic gonadotrophin, (β-hCG), alpha- fetoprotein (AFP) and lactate dehydrogenase (LDH). AFP is raised in the presence of embryonal and/or yolk sac elements and has a half-life of 5–7 days after treatment. β-hCG is raised in the presence of syncytiotrophoblastic elements and has a half-life of 24–36 h. It is raised in all choriocarcinomas. Elevations of AFP are seen in 50–70% of NSGCTs. AFP is not elevated in pure seminomas. Seminoma with elevated AFP is treated as a NSGCT.
β-hCG is raised in 40–60% of men with NSGCTs and <30% of men with seminomas. LDH is a non-specific marker of tumour bulk but it is raised in 80% of patients with advanced disease . Tumour markers are essential in the diagnosis and disease stratification for treatment in all patients with testicular cancer. New molecular markers are in development; there is evidence that micro-RNAs may be more accurate in detecting recurrent or residual disease. Further validation studies of these are required .
Testis Preserving Surgery
This may be considered in specific circumstances, namely, when there is a high degree of confidence that a lesion is benign, when there are synchronous bilateral tumours, following development of a metachronous contralateral tumour, or in patients with a single testis and normal pre-operative testosterone levels. Organ sparing surgery can be performed when tumour volume is <30% of total testicular volume  although it may be possible to undertake local excision of larger tumours in the polar areas. Germ cell neoplasia in situ (GCNIS) is present in up to 80% of patients undergoing testis preservation. Sperm storage issues should be discussed prior to surgery and the patient should be counselled about the long-term risks of tumour recurrence, long term endocrine failure and the requirement for subsequent radiotherapy or completion orchidectomy if GCNIS is detected.
Contra-Lateral Testicular Biopsy & GCNIS
GCNIS is present in 4–8% of men presenting with testicular cancer: the risk of a contralateral metachronous tumour is approximately 2.5% . When present there is a higher chance of progression to invasive disease as it is a malignant precursor lesion. GCNIS is now the WHO recommended term for all precursor lesions of invasive germ cell tumour . This condition has previously been known either as carcinoma in situ or intratubular germ cell neoplasia unclassified (IGCNU).Treatment by low dose irradiation of the affected testis after preliminary storage of semen has been used previously but more recently, surveillance strategies using self-examination and interval US scanning have now been adopted almost universally. If low-dose radiotherapy has to be used, treatment comprises scrotal radiotherapy (16–20 Gy in fractions of 2 Gy ). If this treatment is used, the patient needs counselling that it will lead to irreversible infertility and that future Leydig cell insufficiency requiring testosterone substitution will occur in about 30% of patients.
In the case of primary orchidectomy, there is uncertainty about routine synchronous contra-lateral testicular biopsy to identify GCNIS. Because of this, the policy of contra-lateral biopsy at the time of primary surgery varies. High-risk cases can be identified, limiting the need for contra-lateral sampling to those whose risk is greatest. Risk factors include cryptorchidism, younger age (<40 years), testicular microlithiasis, infertility and testicular atrophy (≤12 mL) [3, 4]. If biopsy is done, a two-site biopsy technique will improve detection by 18% compared to single-site biopsy methods .
Post Orchidectomy Management
This is predicated on the histological classification and clinical staging after primary orchidectomy. The disease stage is classified into two basic groups: clinical stage I (low and high risk) or stage IIA/IIB/III. (Sub-categorised for the 3 International Germ Cell Collaborative Consensus Group (IGCCCG) types: see below ). These sub-types are based on the findings of cross-sectional imaging and post-orchidectomy tumour marker levels.
If the disease is Stage II or more, the standard treatment for most tumours utilises combination platinum based chemotherapy with bleomycin, etoposide and cisplatin (BEP) followed by surgical removal of post-chemotherapy residual masses when they are present and resectable. The combination of chemotherapy with post-chemo resection of surgical masses is undertaken for most NSGCT whilst chemotherapy is used alone for most seminomas, surgery being indicated only for highly selected cases.
Staging is by CT of the chest, abdomen and pelvis and assay of tumour markers (Box 38.2). The first order lymph nodes in the retroperitoneum are usually the initial site of metastatic spread although primary distal haematogenous dissemination can occur in up to 15% of men. CT scanning has its limitations: up to 30% of patients with negative CT scans will have microscopically positive lymph nodes detected subsequently at surgical staging. By contrast, up to 25% of patients may be radiologically over-staged, having abnormal nodes on CT staging which are subsequently shown to be negative following surgical exploration. MR imaging has been used in this scenario although it has not proved to be more effective or reliable than CT scanning. PET scanning has significant problems with false negativity and therefore has no role in primary tumour staging. In the case of seminoma, PET does have role in assessing the post-chemotherapy residual retroperitoneal mass; a negative scan in this circumstance has a very strong association with post-chemotherapy fibrosis in residual masses. However, a positive scan does not indicate active disease: most post-chemotherapy PET positive seminoma masses contain only fibrous tissue and great care should be taken to avoid over-interpretation of the scan in this circumstance.
Management of Clinical Stage 1 Disease (CS1)
CSI Non-Seminomatous Germ Cell Tumour (NSGCT)
Approximately 30% of patients with CS1 NSGCT will have occult micrometastatic disease. A number of histopathological risk factors in the primary tumour predict for this in CS1, including lymphovascular invasion (LVI), the presence of embryonal carcinoma (undifferentiated cells) and the absence of yolk sac elements. The presence of lymphovascular invasion (LVI) is associated with a 44% relapse rate compared to 14% without LVI . LVI is an important validated risk factor and if present with embryonal carcinoma and rete testis invasion is associated with a relapse risk of 50% compared to a relapse rate of 12% when these features are absent .
Active treatment schedules for CS1 NSGCT involve the use of low dose adjuvant chemotherapy with one or two cycles of BEP. However, surveillance with serial imaging and tumour marker assay is used more commonly. Retroperitoneal Lymph Node Dissection (RPLND) has largely been discontinued in this setting, although some centres in the USA still use this approach. It is rarely used elsewhere, apart from in patients with a contraindication to adjuvant chemotherapy or where there are patient compliance issues.
Surveillance in Clinical Stage 1 NSGCT
Using stratification profiles based on histology and markers, it is possible to predict with accuracy of approximately 80% that low risk cases will not relapse and furthermore, if they do, they can then undergo systemic treatment with chemotherapy with excellent long-term survival. Patients relapsing on surveillance are successfully treated with standard chemotherapy and have long-term cure rates of 98%, which is the same as that for primary surgery. In addition, >95% of patients who relapse will do so within the first 2 years of diagnosis of their original cancer . Prolonged and intensive follow up beyond 5 years is therefore not required in most cases.
Adjuvant Treatment for High Risk
Surveillance is the standard of care in most high volume centres for low and high-risk CS1 disease. More recently some groups have advocated adjuvant chemotherapy using one or 2 cycles of BEP when high risk features are present. Concerns about this approach are that 50% of cases who would not have relapsed are exposed to the significant long-term effects of platinum based chemotherapy. Long term studies have also shown that the survival of the 50% of high-risk patients who do relapse and require full dose systemic treatment have an excellent long-term survival . However, there is debate and variation in practice amongst clinicians in this area.
In the presence of risk factors, 50% of patients with CS1 NSGCTs managed by surveillance will relapse. One cycle of adjuvant BEP chemotherapy will reduce this risk of relapse by over 90% whilst a two course regimen is even more effective. In 2015 the SWENOTECA group demonstrated that adjuvant treatment can safely be reduced to one cycle of BEP. A reduction in the relapse rate of >90% was seen with the benefit of reduced toxicity and decreased need for salvage therapy thus ensuring relapsing patients avoid the potential toxicity associated with salvage chemotherapy involving 3–4 cycles of BEP  However, this adjuvant intervention with chemotherapy is associated with measurable short-term toxicity and in the long term, BEP is known to have long-term adverse consequences. Whilst there seems to be benefit for those who will definitely relapse, there is clear and potentially avoidable toxicity for those who would not.
Compared to NSCGTs, seminomas have a more favourable prognosis: they remain localised for longer and approximately 75–80% have CS1 disease at initial diagnosis. Seminoma tends to metastasise to the retroperitoneal lymph nodes initially with a lower rate of haematogenous metastasis than NSGCTs. They are sensitive to radiotherapy and platinum-based chemotherapy. Adjuvant radiotherapy to the retroperitoneum is no longer used in CS1 due to the long-term risks associated with treatment. Single cycle AUC7 carboplatin chemotherapy is now the main intervention if surveillance is not adopted. This has less neurotoxicity, ototoxicity and nephrotoxicity compared to cisplatin. Overall only about 15% of patients with stage I will relapse without adjuvant therapy, although the relapse rate is higher in men with high risk features. Most recurrences occur in the retroperitoneal lymph nodes and are treated effectively with BEP.
Rationale for Surveillance in Clinical Stage 1 Seminoma
Since 2007, strategies have emerged using a similar approach to those adopted as standard practice in CS1 NSGCT. Approximately 16% of CS1 seminoma patients are at risk for recurrent disease: the median time to relapse is 12–15 months with 96% of these occurring in the retroperitoneal or inguinal regions.
Tumour size >4 cm.
Stromal invasion of the rete testis.
Lymphovascular Invasion (LVI).