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Multimodality Radiological Pictorial Review of Testicular Carcinoma: From Initial Staging to Restaging

Abstract With an overall 5-year survival rate >95%, patients with testicular cancer have a great prognosis. Although initial diagnosis is based on clinical examination, imaging does play a significant role in the diagnosis and prognosis of testicular cancer, which are dependent on tumor burden and staging. Successful treatment requires appropriate disease assessment throughout a patient’s treatment: evaluating treatment response, restaging, and monitoring for disease recurrence after treatment completion. Ultrasound is usually the initial screening modality for painless testicular masses, and computedtomography (CT) the most commonly used for staging and restaging. However, with regard to seminomas, positron-emission tomography (PET) combined with CT is slowly taking priority. With regard to nonseminomatous germ-cell tumors, PET-CT has not proven to be completely effective, due to a high number of false-negative results. The purpose of this paper is to provide radiologists with a pictorial review of testicular carcinoma from initial staging through posttreatment follow-up.


Introduction
Testicular cancer is the most common tumor among young adult males, and accounts for 8.2% of all cancer in men aged 15-39 years. 1,2 In 2017, a National Cancer Institute Physician Data Query cancer-information summary about testicular cancer reported the incidence of new cases to be 8,850, and the lifetime risk of developing testicular cancer is a reported 0.4%. 3,4 Risk factors for testicular cancer include cryptorchidism (Figure 1), family or personal history of testicular cancer, ethnicity, infertility, testicular dysgenesis. and prenatal exposure. 5,6 Such factors as marijuana exposure, vasectomy, trauma, mumps, and HIV infection continue to be investigated. With the advent of improved management, survival and life expectancy of patients with testicular cancer is quite good, with reported life expectancy nearly equal to those without a diagnosis of testicular cancer. 4 Particularly, survival rates for testicular germ-cell tumors (GCTs) are nearly 100% for seminomas and 91% for nonseminomas. 4,7 Pathologically, GCTs are broadly divided into seminomas, which resemble primordial GCs, and nonseminomas, which are either undifferentiated or differentiated, exhibiting a degree of embryonic or extraembryonic patterning (including yolk-sac tumors, teratomas, embryonal cell tumors, and choriocarcinoma). Testicular cancer is classified as per the 2016 World Health Organization (WHO) guidelines (Table 1). 8 A complete description of the pathogenesis of testicular tumors is beyond the scope of this radiological review. Rather, the purpose of this manuscript is to provide an updated overview of the staging of testicular cancer with an emphasis on the radiological perspective.

Diagnosis
Although clinical history and examination of testicular masses remain the cornerstone of diagnosis, imaging using ultrasound (US) examination of the scrotum plays a crucial role in initial diagnosis of tumors. Testicular sonography is also helpful in assessing patients presenting with metastatic disease in whom an occult primary tumor of the testis is suspected or for synchronous tumors in the contralateral testis. 8,9 Heller et al observed an eightfoldincreased prevalence of primary testicular neoplasms in patients with microlithiasis over those without, as well as an increased prevalence of GCTs, particularly pure seminomas ( Figure 2). 10 However, US follow-up is of questionable significance, and some studies have clearly expressed doubts that follow-up US screening for patients with testicular microlithiasis would substantially change outcomes. 11 Figure 1 Testicular mass in cryptorchid testis: homogeneous diffuse intratesticular mass lesion with surrounding internal vascularity.

Germ-cell tumors
• Intratubular germ-cell neoplasia, unclassified (IGCNU) • Seminoma (including cases with syncytiotrophoblastic cells) • Spermatocytic seminoma (mention if there is sarcomatous component)  Magnetic resonance imaging (MRI) may be a valuable problem-solving modality for the morphological evaluation and characterization of scrotal masses in patients with inconclusive and inconsistent sonographic features, and may improve differentiation between intratesticular and extratesticular masses. 12 Dynamic contrast-enhanced subtraction MRI may be used to differentiate benign from malignant intratesticular mass lesions by analyzing contrast enhancement. 13 At present, the role of positron-emission tomography (PET) is limited in the initial evaluation of testicular tumors. Current testicular cancer-staging algorithms rely primarily on anatomic features of primary and metastatic disease (eg, enlarged lymph nodes, pulmonary nodules, bone lesions), as opposed to the functional information provided by PET. A few studies have demonstrated a potential benefit of PET to alter a patient's initial testicular cancer staging -upstage or downstagewhich could mean that one day this modality will have a more active role in initial staging. 14 Initial Tumor-Node-Metastasis Staging and Serology The diagnosis of testicular cancer is commonly based on histopathology after radical orchiectomy. Use of noninvasive imaging allows for clinical staging of testicular cancer before orchiectomy (Table 2). Staging is crucial, as the treatment approach is based on the staging/clinical classification of the malignancy. 15 Serum tumor markers can assist in appropriate diagnosis, most notably a histopathologically reported pure seminoma in the presence of elevated serum AFP: as AFP should not be elevated in a pure seminoma, the diagnosis is more likely a nonseminomatous GCT with at least some component of yolk-sac tumor. In addition to tumor markers, staging also involves assessment of metastatic disease: nodal and distant metastatic sites, including the chest, abdomen, and pelvis. With normal tumor markers and no evidence of metastases on imaging, patients are classified as having clinical stage I disease. Bone and brain metastatic evaluation are considered if related symptoms are present. 16 TNM international classification criteria are used for staging of the tumor. 17,18 Using TNM classification (Tables 3 and 4), patients can be staged based on the AJCC classification (Tables 5 and 6). 19 AJCC classification is often used to determine prognosis and patient survival, which is also provided by the International Germ Cell Cancer Collaborative Group classification (Table 7). 20

Tumor Staging (T Stage)
In sum, 70%-80% will present with disease confined to the testis (stage I). The primary imaging modality is US scanning of the scrotum, which has sensitivity approaching 100% in experienced hands. Recently, use of US elastography in providing additional information to differentiate between malignant and benign lesions has been evaluated by many studies. 21 However, this technique can only be complementary to conventional US, but not an imaging modality of choice, because of overlapping imaging findings in lesions <10 mm in size. The majority (>95%) of intratesticular lesions are malignant, typically present as a painless mass, and usually result in orchiectomy. 22 On US, seminomas are typically round, homogeneous, hypoechoic tumors with increased vascularity compared to background testicular parenchyma ( Figure 3). In certain cases, seminoma can replace testicular parenchyma, which can make it difficult to differentiate from other infiltrative masses of the testis, such as leukemia and lymphoma. This appearance is in contrast to the heterogeneity of nonseminomatous GCTs (NSGCTs) related to hemorrhage and necrosis with cystic degeneration and calcifications ( Figure 4). 23,24 Two factors associated with poor prognosis include rete-testis invasion and tumors ≥4 cm. 25 Color Doppler US may be helpful in prepubertal boys when the gray-scale findings of the mass are subtle, and may help identify an isoechoic mass. 26 US elastography typically demonstrates increased parenchymal "stiffness"; however, the role of US elastography is still questionable in characterization of testicular lesions. 27 Difficulties may arise in differentiating orchitis from tumors and in establishing definitive diagnoses for small lesions on regular US. Usually, surgical exploration through the groin and open biopsy of the testis using the Chevassu technique along with intraoperative US localization is necessary to diagnose and stage the tumor appropriately.   MRI is an efficient diagnostic tool for the evaluation of testicular masses. It is accurate in the preoperative differentiation of benign and malignant intratesticular masses. MRI of the testes seems to be more efficient than US for detecting local extent of the tumor: involvement of the tunica albuginea, epididymis, and spermatic cord. 28 MRI may also be helpful in differentiating seminomas from NSGCTs, showing better characterization of NSGCTs demonstrating heterogeneous signal and enhancement characteristics caused by necrosis and hemorrhage. However, there may be overlap in the imaging characteristics of seminomas and NSGCTs. 29 Lymph-Node Metastases (N Stage) About 15%-20% will present with disease that has metastasized to abdominal lymph nodes, constituting stage II disease. CT scans of the chest, abdomen, and pelvis are the   recommended method for staging for infradiaphragmatic lymph nodes ( Figure 5). Lymphatics are a major route of cancer spread for testicular malignancies, because the tunica albuginea forms a barrier against local extension. Retroperitoneal spread is felt to be the result of embryological migration of the testis through the retroperitoneum, where it acquires drainage from the lymphatics adjacent to the aorta and inferior vena cava. 30 As per the literature, about 15%-20% of patients with stage I seminoma can have subclinical metastatic disease, usually in the retroperitoneum, and relapse after orchiectomy alone. 31 While CT is the standard of care for locating the presence of lymphadenopathy or retroperitoneal masses, its false-negative rates have been reported to be as high as 30%-59%. 32,33 A pitfall of CT is that inflammatory reactive lymph nodes cannot be differentiated from those that are enlarged secondarily to malignant disease. 34 Lymph-node involvement is usually limited to the site of the primary tumor, and contralateral nodal involvement is usually present only in the presence of advanced disease. 35 Lymph nodes >1 cm are suspicious for metastasis, especially if they are located in the renal hilar regions or the aortocaval areas. Various studies have established the accuracy of CT in detecting metastatic retroperitoneal lymph nodes, with sensitivity of 65%-96% and specificity of 81%-100%. 36,37 On CT,

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Research and Reports in Urology 2020:12 retroperitoneal spread will present as enlarged lymph nodes, which could be homogeneous or heterogeneous, depending on cystic or necrotic degeneration. These lymph nodes can be bulky and lobulated, showing conglomeration, and can be encasing the retroperitoneal vasculature.
A recent meta-analysis study by Zhao et al concluded that PET-CT may be an accurate noninvasive and useful diagnostic tool for patients with testicular cancer (Figure 6). 38 A negative PET-CT result eliminates viability in large lesions and helps to avoid unnecessary surgery. In addition, PET-CT demonstrates good specificity, being a potentially useful tool if combined with other imaging methods. Another study by the National Cancer Research Institute Testis Cancer Clinical Studies Group evaluated the performance of PET-CT in nodal staging of testicular cancers with good prognosis, chemotherapy being offered to PET-CT-positive patients, and monitoring of PET-CT-negative patients. 39 The sensitivity of PET-CT does not at present seem to be sufficient to detect lymph-node micrometastases or single out patients

Revels et al
Research and Reports in Urology 2020:12 submit your manuscript | www.dovepress.com DovePress with a low risk of recurrence, and additional evidence is needed in order to support its use in initial staging of testicular cancer. 40 However, PET-CT may still play a role in deciding between chemotherapy or surgery for the initial management of retroperitoneal masses by using metabolic activity as one additional criterion. 41

Distant Metastases (M Stage)
The M1 stage consists of visceral metastatic and supradiaphragmatic lymph-node involvement. In testicular malignancies, nodal involvement of the inguinal, external iliac, and pelvic nodes is usually considered distant spread. Hematogeneous metastasis usually includes pulmonary metastases (can show a "cannonball" appearance as well), and can also metastasize to the liver, brain, or bone to a lesser extent. Other rare sites of metastasis include the peritoneum, kidneys, and spleen, and are more frequently observed at the time of relapse. CT of the chest, abdomen, and pelvis is currently the most precise and rapid imaging method for exploring the entire trunk, looking for metastases in the lungs and other target organs. 42 CT of the thorax is most often preferred over chest X-rays. 43 It is uncommon to observe metastases in the lung and posterior mediastinum without concomitant retroperitoneal disease (Figures 8 and 9). 44 Brain MRI may be advocated in addition to the chest/ abdomen/pelvis CT scan if the patient has pertinent clinical symptoms or for testicular tumors with a poor prognosis ( Figure 10). Brain metastases are most common with choriocarcinoma, which is also the most common cause of hemorrhagic pulmonary metastases. 45 GCT metastases may have histological characteristics that are different from those of the primary testicular tumor, indicating the totipotential nature of the GCs. 46 Spinal MRI may also be proposed when vertebral metastasis has been shown on the CT scan. Bone scintigraphy using technetium-99mlabelled phosphate derivatives can be recommended in patients when bone metastasis is suspected. 18 Evaluation by PET-CT is again not currently indicated in any initial staging of testicular cancer. 40 MRI has also been recommended in the staging of testicular tumors in special circumstances: patients with iodinated contrast is contraindicated or in cases where radiation exposure should be limited. In these instances, MRI sensitivity and specificity results have been shown to be similar to CT. 47 The disadvantages of MRI are longer examination times, high cost, artifacts, and low availability   Figure 7). MRI with lymphotrophic nanoparticles has been shown to be an effective method for evaluating lymph nodes in different cancers. 48 The role of MRI with lymphotrophic nanoparticles still needs larger study designs to be able to be accommodated in regular clinical practice.

Serological Tumor Markers
In testicular GCTs, serum concentrations of α-fetoprotein (AFP), human chorionic gonadotrophin (hCG), and lactate dehydrogenase (LDH) are imperative in screening, diagnosis, staging, treatment monitoring, and surveillance. However, different types of GCT have different tumormarker profiles, as well as pure form or mixed type. Patients with testicular GCT will have elevated tumor markers in 51% of cases: increased levels of AFP are associated with yolk-sac tumors, and elevated β-hCG is found in cases of choriocarcinoma. LDH is reportedly a less informative tumor marker. 49,51 Tumor markers also offer a means of patient follow-up and continue to yield information regarding response and ongoing prognosis. 52 In cases of seminomatous testicular tumors, LDH may be elevated in 80% of patients, but this tumor marker can also be elevated in up to 60% of NSGCTs. 53 Elevated LDH may be seen, and correlates with tumor burden, growth rate, cellular proliferation, and advanced disease. Placental alkaline phosphatase is another tumor marker that may be elevated in seminomas, but may also be falsely elevated in smokers. 25 Elevated β-hCG can be seen in up to 20% of cases of advanced seminomatous disease. 54 Testicular choriocarcinoma very often has elevated serum β-hCG levels that are produced by tumor syncytiotrophoblasts. Therefore, β-hCG is important in monitoring treatment response and recurrence. 54 Yolk-sac tumors have elevated AFP levels in 90% of cases, which usually decrease 5 days after orchiectomy. 54 If AFP levels do not decrease, this raises concern for possible residual primary disease or metastases that were not detected on the initial staging evaluation. 54 Testicular embryonal-cell tumors demonstrate elevated AFP and β-hCG; however, in pure embryonal cell tumors these tumor markers are elevated to a lesser extent. Levels of these tumor markers are proportional to tumor burden, and elevation is a sign of poor prognosis. 54 Pure testicular teratomas do not have APF elevation; however, elevated AFP can be seen in tumors with mucinous or hepatoid differentiation. The lack of tumor-marker elevation at initial staging can pose a challenge in treatment monitoring/surveillance, as confidence in a disease-free state becomes exclusively reliant on radiological changes: new or growing soft tissue at the site of resection, lymphadenopathy, or new distant lesions suggestive of metastases.

Restaging and Surveillance
Of all seminomas, 75% are confined to the testicle at the time of clinical presentation, and a complete cure is thus achieved with a thorough radical orchiectomy. In patients with nonmetastatic stage I seminoma, the risk of subsequent paraaortic lymp-node relapse is 15%-20%, but adjuvant use of either chemotherapy or radiotherapy reduces the risk of recurrence to <1%. 55 Patients declining primary chemotherapy may be offered primary nerve-sparing retroperitoneal lymph-node dissection with adjuvant chemotherapy. Primary chemotherapy and primary retroperitoneal lymphnode dissection have comparable outcomes and a cure rate of almost 90% for stage II disease. 56 Chemotherapy with radiotherapy appears to reduce the relapse rate in stage II seminoma with minimal additional toxicity. 57 Imaging and tumor markers are the two import aspects of restaging and surveillance of testicular tumors.  (Tables 8-, 10). 58 The European Consensus Conference on Diagnosis and Treatment of GC Cancer guidelines state that radiological restaging must be performed after completion of first-line chemotherapy; however, in patients with slow tumor-marker decline or clinical evidence of progression, restaging should be performed earlier, because immediate modification of the first-line treatment strategy may be required. 59 CT of chest/abdomen/pelvis is the usual method for assessing response of disease to treatment. Size reduction of metastases is the primary criterion for assessing tumor response to therapy, though institutional preferences may vary based on clinical trial guidelines. In addition to size change, CT can help assess residual postchemotherapy tissue characteristics, eg, development of cystic and fatty features at sites of previous metastases have been associated with mature differentiated teratomas and may indicate the need for surgical removal. 60,62 Seminoma primary  and metastatic sites may demonstrate necrosis, fibrosis, and/or calcifications. 63 Treated lung metastases may demonstrate cavitation that may initially appear ominous, then subsequently progress to more benign-appearing fibrosis. 64 Patients with large-volume post-neoadjuvant therapy disease may benefit from the use of CT and MRI for planning an operative approach. 65 Follow-up of metastatic lymphadenopathy with CT demonstrates similar features to response and recurrence at primary and other metastatic sites, eg, treatment response of decreased size and necrosis/fibrosis, and progression or recurrence of lymphadenopathy growth. Studies have emphasized the usefulness of PET-CT in the follow-up evaluation of metastatic lymphadenopathy based on maximum systemic uptake values. 41 In patients with pure seminomas and postchemotherapy residual disease >3 cm, PET-CT can be considered (Figures 11 and  12), and PET-positive masses should be considered for biopsy, selective surgical resection, or close    surveillance. 66 It should be noted that FDG-PET is suboptimal at distinguishing fibrosis from teratomas, as both have low uptake values; however, Sugawara et alsuggested the utility of PET kinetic-rate constants to differentiate mature teratomas from fibrosis and necrosis. 67 PET-CT may also demonstrate false-positive (nonmalignant) hypermetabolic activity as a result of posttreatment inflammation. 38,68 For this reason, it might be prudent to perform PET-CT before chemotherapy or have an interval of no sooner than 4 weeks after chemotherapy. 69

Treatment and Treatment Complications
Standard-of-care medical therapy for patients with low-risk GCTs includes three cycles of bleomycin, etoposide, and cisplatin (BEP) or four cycles of EP. 70 Patients with advanced disease typically receive four cycles of BEP or etoposide, ifosfamide, and cisplatin. 71,72 Toxicities associated with these chemotherapeutic agents have been well described in the literature. 70,73,76 Bleomycin is associated with immunomediated pulmonary toxicity, eventually leading to fibrosis. With dose as the sole risk factor, bleomycin-induced  pulmonary toxicity has an incidence of 8.5%. 73 Poor renal function and high cumulative dose are the best-established risk factors, and their presence increases the probability of developing pulmonary toxicity. In fact, incidence of fatal pulmonary fibrosis has been reported as high as 10% for patients receiving high cumulative doses. 70,73 High-resolution CT findings of bleomycin-induced pulmonary toxicity vary by histological patterns of lung injury. Injury patterns vary from aspecific interstitial pneumonia, cryptogenic organizing pneumonia, and diffuse alveolar damage patterns. Cisplatininduced venous thromboembolism and cardiovascular disease is another common chemotherapy-induced toxicity encountered in the treatment of testicular cancer. 70,76 Endothelial injury and increased circulating prothrombotic factors can lead to thrombosis. 76 On cardiovascular or abdominopelvic imaging, the presence of new or increasing calcified or uncalcified atherosclerotic plaques can suggest the presence of cisplatin-induced vascular toxicity.

Conclusion
Testicular cancer is considered almost curable in low tumorburden stages. In addition to tumormarkers, multimodalityimaging evaluation plays a pivotal role in patient management. While US and CT are mainly used as imaging modalities for initial staging, PET-CT and MRI can be used in restaging in special circumstances. Imaging is necessary for tumor response to treatment, restaging, and surveillance. It is essential that the clinical team has thorough knowledge of imaging modalities to be used in each stage of the disease, and radiologists should also guide clinicians to order a study depending on the circumstancs of the patient.