Imaging Recommendations for Diagnosis, Staging, and Management of Testicular Cancer

Abstract

The common testicular tumors affect young males in the third and fourth decades and germ cell tumors especially have excellent post-treatment outcomes. Hence, guidelines for clinical, radiological, and tumor marker assessment for diagnosis, response assessment, and surveillance of these tumors have critical impact on the management of these tumors. This article aims to discuss the current recommendations and guidelines regarding the clinical and radiological assessment and treatment pathways of testicular tumors.

Keywords

guidelines - imaging - recommendations - testicular cancer

Introduction

Testicular malignancies constitute approximately 0.8% of newly diagnosed cases of malignancies in the male population.[1] While the incidence has been on the rise in the recent years, the mortality due to testicular malignancies has been on the decline.[2]

Classification

The World Health Organization (WHO) classification of testicular tumors is given in [Table 1].[3]

Table 1 The World Health Organization (WHO) 2016 classification of testicular tumors[3]

Germ cell tumors

Germ cell neoplasia in situ (GCNIS)

Derived from GCNIS

Seminoma

Embryonal carcinoma

Yolk sac tumor, postpubertal type

Trophoblastic tumors

Teratoma, postpubertal type

Teratoma with somatic malignant components

Mixed germ cell tumors

Germ cell tumors unrelated to GCNIS

Spermatocytic tumor

Yolk sac tumor, prepubertal type

Mixed germ cell tumor, prepubertal type

Sex cord/stromal tumors

Leydig cell tumor

Malignant Leydig cell tumor

Sertoli cell tumor

Malignant Sertoli cell tumor

Large cell calcifying Sertoli cell tumor

Intratubular large cell hyalinizing Sertoli cell neoplasia

Granulosa cell tumor

Adult type

Juvenile type

Thecoma/fibroma group of tumors

Other sex cord/gonadal stromal tumors

Mixed

Unclassified

Tumors containing both germ cell and sex cord/gonadal stromal—gonadoblastoma

Miscellaneous non-specific stromal tumors

Ovarian epithelial tumors

Tumors of the collecting ducts and rete testis

Adenoma

Carcinoma

Tumors of paratesticular structures

Adenomatoid tumor

Mesothelioma (epithelioid, biphasic)

Epididymal tumors

Cystadenoma of the epididymis

Papillary cystadenoma

Adenocarcinoma of the epididymis

Mesenchymal tumors of the spermatic cord and testicular adnexae

Testicular malignancies are classified into germ cell tumors (GCTs) and nongerm cell tumors. GCTs can further be divided into seminomatous and nonseminomatous (NSGCTs). A vast majority of nearly 98% of testicular cancers are GCTs.

Other testicular neoplasms include lymphoma, sarcoma, fibroma, leiomyoma, vascular tumors, and metastases.[4]

Risk Factors and Etiopathogenesis

The etiology of testicular GCTs is still poorly understood, but certain pre-existing medical conditions associated with testicular GCTs include cryptorchidism, radiation, impaired fertility, testicular dysgenesis, and family history or previous history of testicular cancer.[5]

Malignant postpubertal GCTs (type II GCTs) commonly originate from the germ cell neoplasia “in situ” (GCNIS) and are subdivided into seminomas and NSGCTs. The rarer nonrelated GCNIS tumors comprise pre-pubertal type teratoma and yolk sac tumors (Type I GCT) and spermatocytic tumors (Type III GCT) seen in the elderly.[6]

Epidemiology and Clinical Presentation

The highest incidence of testicular malignancy is in the twenties for NSGCT and in the thirties for seminomas.[7] The less common pre-pubertal type teratomas and yolk sac tumors, and the spermatocytic tumors are diagnosed in pre-puberty and elderly age group respectively. About 68% of these malignancies have organ-limited disease while 32% have nodal or distant metastases.[8]

Testicular swelling or pain, scrotal heaviness or lump, dull abdominal, flank or back pain and gynecomastia are common symptoms depending on testicular descent status, hormonal status and nodal or other metastatic disease.

Staging

The American Joint Commission on Cancer staging of testicular malignancy—TNM based on tumor (T), node (N) and metastases (M)—is given in [Table 2] ⁹.

Table 2 TNM Classification for testicular cancer[28]

pT—Primary tumor

pTX—Primary tumor cannot be assessed

pT0—No evidence of primary tumor

pTis—Intratubular germ cell neoplasia (carcinoma in situ)

pT1—Tumor limited to testis and epididymis without vascular/lymphatic invasion; tumor may invade tunica albuginea but not tunica vaginalis

pT2—Tumor limited to testis and epididymis without vascular/lymphatic invasion, or tumor extending through tunica albuginea with involvement of tunica vaginalis

pT3—Tumor invades spermatic cord with or without vascular/lymphatic invasion

pT4—Tumor invades scrotum with or without vascular/lymphatic invasion

N—Regional Lymph Nodes: Clinical

Nx—Regional lymph nodes cannot be assessed

N0—No regional lymph node metastasis

N1—Metastasis with a lymph node mass 2cm or less in greatest dimension or multiple lymph nodes, none more than 2cm in greatest dimension

N2—Metastasis with a lymph node mass more than 2 cm but not more than 5cm in greatest dimension; or more than 5 nodes positive, none more than 5cm; or evidence of extranodal extension of tumor

N3—Metastasis with a lymph node mass more than 5 cm in greatest dimension

Pn—Regional Lymph Nodes: Pathological

pNx—Regional lymph nodes cannot be assessed

pN0—No regional lymph node metastasis

pN1—Metastasis with a lymph node mass 2 cm or less in greatest dimension and 5 or fewer positive nodes, none more than 2cm in greatest dimension

pN2—Metastasis with a lymph node mass more than 2cm but not more than 5cm in greatest dimension; or more than 5 nodes positive, none more than 5cm; or evidence of extranodal extension of tumor

pN3—Metastasis with a lymph node mass more than 5cm in greatest dimension

M—Distant metastases

Mx—Distant metastasis cannot be assessed

M0—No distant metastasis

M1—Distant metastasis cannot be assessed

M1a Nonregional lymph node(s) or lung metastasis

M1b Distant metastasis other than nonregional lymph nodes or lung

In addition, a unique marker for testicular malignancies is the tumor marker level (α fetoprotein [AFP], β human chorionic gonadotrophin [β-hCG] and lactate dehydrogenase [LDH]), which is included into the International Germ Cell Cancer Collaborative Group (IGCCCG) system of classification of testicular tumors given in [Table 3]; this system classifies patients into good, intermediate, and poor risk, taking into account location of tumor and metastases as well as post-orchidectomy tumor markers.[9] [10]

Table 3 Prognostic-based staging system for metastatic germ cell cancer (IGCCCG)[10]

Good prognosis group
Nonseminoma 5-year PFS 90% 5-year survival 96%	All of the following criteria:  • Testis/retroperitoneal primary  • No nonpulmonary visceral metastases  • AFP < 1,000 ng/mL  • β-hCG < 5,000 IU/L (1000 ng/mL)  • LDH < 1.5 x ULN
Seminoma 5-year PFS 89% 5-year survival 95%	All of the following criteria:  • Any primary site  • No nonpulmonary visceral metastases  • Normal AFP  • Any β-hCG  • Any LDH
Intermediate prognosis group
Nonseminoma 5-year PFS 78% 5-year survival 89%	Any of the following criteria:  • Testis/retroperitoneal primary  • No nonpulmonary visceral metastases  • AFP 1,000–10,000 ng/mL  • β-hCG 5,000–50,000 IU/L (1,000 ng/mL)  • LDH 1.5–10 x ULN
Seminoma 5-year PFS 79% 5-year survival 88%	All of the following criteria:  • Any primary site  • Nonpulmonary visceral metastases  • Normal AFP  • Any β-hCG  • Any LDH
Poor prognosis group
Nonseminoma 5-year PFS 54% 5-year survival 67%	Any of the following criteria:  • Mediastinal primary  • Nonpulmonary visceral metastases  • AFP > 10,000 ng/mL  • β-hCG > 50,000 IU/L (10,000 ng/mL)  • LDH > 10 x ULN
Seminoma	No patients classified as “poor-prognosis”

Abbreviations: AFP, α fetoprotein; β-hCG, β-human chorionic gonadotrophin; IGCCCG, International Germ Cell Cancer Collaborative Group; LDH, lactate dehydrogenase; PFS, progression-free survival; ULN, upper limit of normal.

Clinical Workup

Clinical History

This should include present symptoms and any history of previous testicular cancer and treatment.

Physical Examination

This includes local site examination and chest, abdominal, and supraclavicular examination.[11]

Hormonal Levels

AFP, β-hCG, and LDH levels are assessed post-orchidectomy. Maintained or rising levels can point to presence of metastases. Normalizing levels post-orchidectomy, although a favorable indicator, do not definitively exclude metastases. Tumor markers are also used for surveillance as indicators of recurrence.[11] Micro-RNAs are promising new biomarkers for diagnosis and monitoring and also for differentiating GCTs from non-GCTs, but not yet included in routine practice and are awaiting standardisation.[12]

Imaging Guidelines

Imaging in testicular malignancies plays an important role in diagnosis, staging, post-treatment disease response assessment, and surveillance.

Diagnosis and Staging

Ultrasound (US)

Ultrasound (US) of testis is done by a high frequency linear transducer (>10 MHz). The objective of US is to localize the scrotal mass (whether testicular or extratesticular), characterize the mass based on morphology, estimate size and volume, look for testicular lesions in known metastatic disease as well as for screening the contralateral testis. US has greater than 90% sensitivity and specificity in diagnosing testicular lesions.[13] Testicular microlithiasis, defined as 5 or more hyperechoic microliths in one US image, is currently not included as an independent risk factor for testicular cancer.[14] [15] Contrast-enhanced US is not used routinely, while elastography that reveals increased stiffness in testicular tumors as compared with benign lesions cannot yet be used as a substitute for histopathological evidence in suspicious lesions.[16] [17]

Computed Tomography (CT)

CT is recommended for staging retroperitoneal nodal metastases and for diagnosing pulmonary metastases and mediastinal lymphadenopathy. For retroperitoneal nodal metastases, the left-sided malignancies have propensity for paraaortic nodal involvement and right-sided malignancies for aortocaval nodal involvement due to the drainage of the left-sided and right-sided gonadal veins into the left renal vein and inferior vena cava, respectively.[8] Contrast-enhanced CT study is helpful in better delineation of the nodal size, morphology, and vascular relations. N-staging employs the greatest dimension of the node and the short axis dimension is used for distinguishing between benign and metastatic nodes. While there is no clear consensus for the cutoff value for the short axis diameter, 8 mm or larger can be considered suspicious.[8] In masses up to 2 cm in the retroperitoneum or thorax and negative tumor markers, restaging scan after 6 to 8 weeks is advisable instead of starting treatment immediately.[11] CT brain is a recommendation in patients with NSGCT having pulmonary metastases and poor prognosis IGCCCG risk group (beta hCG values > 5,000 UI/L), or in the presence of clinical symptoms,[18] but magnetic resonance imaging (MRI) can be preferred.

Magnetic Resonance Imaging (MRI)

MRI can help in scenarios where US cannot definitively characterize testicular lesions,[4] but is not universally used. Its use is limited to defining location of scrotal lesions (if intra- or extra- testicular), for planning of testis-sparing surgery, and to characterize intratesticular masses when US is inconclusive. Retroperitoneal nodes can also be assessed by MRI if patient is allergic to iodinated contrast of CT. Brain MRI is particularly useful in aggressive tumors such as choriocarcinomas that have propensity for brain metastases. The National Comprehensive Cancer Network (NCCN) recommends brain MRI in seminoma patients with pulmonary metastasis or β-hCG more than 5,000 IU/L. In NSGCTs, brain MRI is recommended when serum AFP is more than 10,000 ng/mL, β-hCG is more than 5,000 IU/L, and in the presence of visceral or extra-pulmonary metastases or neurological symptoms.[19]

Bone Scan and Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography /CT (18F-FDG-PET/CT)

These are not recommended in initial staging studies.

Response Assessment and Surveillance

Computed Tomography

CT is the modality of choice to evaluate treatment response and diagnose disease recurrence. The standardized Response Evaluation Criteria in Solid Tumors (RECIST 1.1) is used to label response as complete response, partial response, stable disease, and progressive disease. The National Comprehensive Cancer Network (NCCN) guidelines recommend surveillance by CT for 3 to 5 years or beyond after treatment, the frequency of scan depending on tumor histology, stage, treatment, and risk factors.[19]

Magnetic Resonance Imaging

In patients with allergy to iodinated contrast, MRI can be used for restaging instead of CT.

18F-FDG-PET/CT study

PET/CT study is not a part of guidelines for initial staging, but in the restaging scenario, especially in seminomas, 18F-FDG-PET/CT study is of value to differentiate between viable and nonviable residual lesions based on FDG avidity and CT morphology characteristics; indeed, it has shown decrease in overtreatment of seminomas.[20] [21] Various studies have shown positive predictive values ranging from 30 to 69%.[22] [23] [24] Current recommendations include using 18F-FDG-PET/CT study in post-treatment seminomas with residual mass more than 3 cm. It should be delayed until at least 2 months post last chemotherapy cycle, to prevent false positive findings as a result of inflammation and desmoplastic reaction induced by chemotherapy.[25] 18F-FDG PET/CT in the surveillance setting can be used in certain patients with advanced stage seminoma. 18F-FDG-PET/CT is not recommended in response assessment or surveillance in other testicular tumor subtypes.[19]

Screening

There is no evidence of screening of asymptomatic patients having any utility in detecting testicular carcinoma at a more curable stage.[26]

Management Principles

Orchidectomy, by dividing the spermatic cord at the internal inguinal ring, is the initial diagnostic and partially therapeutic step in patients with testicular cancer. Prosthesis may be offered at the time of surgery or later. Contralateral testicular biopsy is not done routinely but can be considered in patients with high risk for contralateral tumor, such as volume of testis less than 12 mL with or without cryptorchidism.[11] All patients should be offered semen preservation and fertility assessment prior to treatment by estimation of testosterone, follicle-stimulating hormone, and luteinizing hormone levels.[27] Histopathological evaluation of testicular cancer can be supplemented with specific immunohistochemical markers with comment on the presence of lymphovascular infiltration, rete testis involvement, tumor size, and proportion of each histological component in mixed NSGCTs.[11]

The European Association of Urology (EAU) recommends tailoring of treatment according to patient risk profile in testicular tumors post-orchidectomy after discussing all options. Some broad principles of the recommendations are described below.[11]

Local radiotherapy can be considered for GCNIS. Seminomas clinical stage 1 can have subclinical retroperitoneal metastases in up to 15% patients; hence treatment options including surveillance, adjuvant chemotherapy, and adjuvant radiotherapy have to be tailored to each patient. In NSGCT clinical stage 1, options comprise surveillance, adjuvant chemotherapy, or retroperitoneal lymph node dissection (RPLND).

For stage IIA/B seminomas, radiotherapy or alternatively chemotherapy is considered standard of care. In stage II NSGCTs, with elevated tumor marker levels and retroperitoneal nodal disease with elevated tumor levels, primary chemotherapy is the initial treatment of choice, while in retroperitoneal nodal disease without tumor marker elevation, RPLND can be the first-line treatment. For stage IIC/III seminomas as well as NSGCTs, chemotherapy is the initial line of treatment.

Post-treatment residual seminomas are monitored by tumor marker levels and imaging. If residual lesion is less than 3 cm, then observation and follow-up can be considered. If residual lesion is more than 3 cm, a PET/CT is recommended that is usually done 10 to 12 weeks after treatment completion. In patients with residual NSGCTs, if size of residual lesion is more than 1 cm, then it should be resected and if less than 1 cm, then it can be observed on follow-up with imaging and tumor marker levels.

Follow-Up Timelines

The EAU recommends follow-up protocols for different patient subsets as described below.[11]

For seminoma stage 1 on active surveillance or after adjuvant treatment, abdominopelvic CT is recommended at 6 months interval for the initial 2 years, once in the 3rd year and once at 5 years. Tumor markers are assessed at 6 monthly intervals for the initial 3 years and once at 5 years.

For NSGCT stage 1 on active surveillance, abdominopelvic CT is recommended at 6 monthly intervals in the 1st year, annually for the next 2 years, and once at 5 years. Chest radiograph is recommended at 6 monthly intervals in the first 2 years for all patients and once after 3rd and 5th year in case of lymphovascular infiltration. Tumor markers are assessed four times a year in the first 2 years and two times a year for the next 3 years.

For advanced disease after adjuvant treatment or complete remission, thoracoabdominopelvic CT is recommended at 6 monthly intervals in the 1st year, annually in the second and 3rd year and once at 5 years. Chest radiograph is recommended at 6 monthly intervals in the 1st year, annually in the next 2 years and once at 5 years. Tumor markers are assessed four times a year in the first 2 years and twice a year for the next 3 years.

Summary of Recommendations

• - US is used for evaluation of scrotal/testicular masses including screening of contralateral testis.

• - CT is the primary modality for staging for metastatic disease and for post-treatment restaging and surveillance.

• - MRI can be done in patients with iodinated contrast allergy. Brain MRI is used in advanced disease to look for metastases.

• - PET/CT study is not recommended for initial staging, but can be useful in restaging of seminomas to distinguish between viable and nonviable residual lesions.

• - Tumor markers are useful in conjunction with imaging for initial risk stratification and in follow-up and surveillance.

Conclusion

Management of testicular malignancies needs multidisciplinary approach by radiologists, pathologists, and treating physicians. Imaging along with tumor marker levels is crucial in staging, risk stratification, assessing treatment response, and for surveillance. Decision-making regarding treatment algorithms and surgical planning is aided by imaging. Since these are potentially curable malignancies in young males, all efforts must be invested by the treating physician team for optimum treatment planning in these patients.

Conflict of Interest

None declared.

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Publication History

Article published online:
04 May 2023