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Clinical manifestations, diagnosis, and staging of testicular germ cell tumors

Clinical manifestations, diagnosis, and staging of testicular germ cell tumors
Literature review current through: Jan 2024.
This topic last updated: Jun 13, 2023.

INTRODUCTION — Testicular cancer is the most common solid malignancy affecting males between the ages of 15 and 35, although it accounts for only 1 percent of all cancers in males [1]. Testicular cancer is also one of the most curable of solid neoplasms because of remarkable treatment advances, with five-year survival rates of approximately 95 percent [2].

Germ cell tumors (GCTs) account for 95 percent of testicular cancers (table 1). They may consist of one predominant histologic pattern or represent a mix of multiple histologic types. For treatment purposes, two broad categories of testis tumors are recognized: pure seminoma (no nonseminomatous elements present) and all others, which together are termed nonseminomatous germ cell tumors (NSGCTs). In most series, the ratio of seminoma to NSGCT is approximately one.

The clinical manifestations, diagnosis, and staging of testicular cancer will be presented here. Optimal therapy, which varies with the stage of disease, is discussed separately. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors".)

CLINICAL MANIFESTATIONS — Testicular tumors usually present as a nodule or painless swelling of one testicle, which may be noted incidentally by the patient or by his sexual partner [3]. Occasionally, a male with a previously small atrophic testis will note enlargement. Approximately 30 to 40 percent of patients complain of a dull ache or heavy sensation in the lower abdomen, perianal area, or scrotum, while acute pain is the presenting symptom in 10 percent.

The presenting manifestations of testicular cancer are attributable to metastatic disease in approximately 10 percent of patients. Symptoms vary with the site of metastasis:

A neck mass (supraclavicular lymph node metastasis)

Cough or dyspnea (pulmonary metastasis)

Anorexia, nausea, vomiting, or gastrointestinal hemorrhage (retroduodenal metastasis)

Lumbar back pain (bulky retroperitoneal disease involving the psoas muscle or nerve roots)

Bone pain (skeletal metastasis)

Central or peripheral nervous system symptoms (cerebral, spinal cord, or peripheral root involvement)

Unilateral or bilateral lower extremity swelling (iliac or caval venous obstruction or thrombosis)

Gynecomastia, which occurs in approximately 5 percent of males with testicular germ cell tumors, is a systemic endocrine manifestation of these neoplasms [4]. It also occurs in 20 to 30 percent of patients with the less common (2 percent of testicular tumors) Leydig cell tumors of the testes [5]. These tumors are found in 6- to 10-year-old boys who present with precocious puberty and in 26- to 35-year-old males who present with a testicular mass, gynecomastia, impotence, and loss of libido. (See "Testicular sex cord stromal tumors".)

Gynecomastia is usually associated with production of human chorionic gonadotropin (hCG) by foci of choriocarcinoma or trophoblastic cells in the tumor. However, the relationship between gynecomastia, testicular tumor morphology, and endocrine abnormalities remains incompletely defined. In individual patients, gynecomastia may or may not be associated with elevated serum concentrations of hCG, human chorionic somatomammotropin, prolactin, estrogens, or androgens. (See "Epidemiology, pathophysiology, and causes of gynecomastia" and "Clinical features, diagnosis, and evaluation of gynecomastia in adults".)

Patients with marked overproduction of hCG can develop another endocrine complication, paraneoplastic hyperthyroidism [6]. Thyroid-stimulating hormone and hCG have a common alpha subunit and a beta subunit with considerable homology. As a result, hCG has weak thyroid-stimulating activity. (See "Overview of thyroid disease and pregnancy", section on 'hCG and thyroid function' and "Disorders that cause hyperthyroidism", section on 'Trophoblastic disease and germ cell tumors'.)

Patients with testicular cancer may rarely develop a paraneoplastic limbic encephalitis. Most of these patients have anti-Ma2 (also called anti-Ta) antibodies [7]. The Ma2 antigen is selectively expressed in the neuronal nucleoli of normal brain tissue and the testicular tumor of the patient. (See "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis" and "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis", section on 'Ma2-associated encephalitis'.)

Testicular examination — Physical examination of the testes should begin with bimanual examination of the scrotal contents, starting with the normal contralateral testis. This permits the examiner to appreciate the relative size, contour, and consistency of the normal testis as a baseline for comparison with the suspected gonad. The testis should be carefully palpated between the thumb and first two fingers of the examining hand.

The normal gonad is homogeneous in consistency, freely movable, and separable from the epididymis. Any firm, hard, or fixed area within the substance of the tunica albuginea should be considered suspicious until proven otherwise. Further evaluation of the affected side should be directed toward possible involvement of the spermatic cord, scrotal investments, or skin.

Testicular tumors tend to remain ovoid, being limited by the tough investing tunica albuginea. However, spread to the epididymis or spermatic cord occurs in 10 to 15 percent of patients. In general, a seminoma tends to expand within the testis as a painless, rubbery enlargement, while an embryonal carcinoma or teratocarcinoma forms an irregular mass with indiscrete borders. However, this distinction is not always easily appreciated.

A hydrocele may be present and can make evaluation of a suspected testicular tumor more difficult. In such cases, ultrasonography of the scrotum is a rapid, reliable technique to exclude a hydrocele or epididymitis; it is indicated in any male with a suspected testicular tumor. (See 'Scrotal ultrasound' below.)

Physical examination should also include palpation of the abdomen for evidence of nodal disease or visceral involvement. Routine assessment of the supraclavicular lymph nodes may reveal adenopathy in males with advanced disease. Examination of the chest may disclose gynecomastia or raise suspicion for thoracic involvement.

Cryptorchidism — Males with a history of cryptorchidism and prior orchiopexy are at increased risk for testicular cancer in both testes (greater in the undescended one), although the magnitude of increased risk compared with males in the general population is poorly quantified. Regardless, testicular self-examination is an important part of the routine evaluation. Because of the rarity of such tumors, surveillance scrotal ultrasound (in the absence of clinical exam findings) is not indicated. (See "Epidemiology and risk factors for testicular cancer", section on 'Cryptorchidism' and "Undescended testes (cryptorchidism) in children: Management", section on 'Long-term follow-up'.)

DIAGNOSTIC EVALUATION — In any male with a solid, firm mass within the testis, testicular cancer must be the considered diagnosis until proven otherwise. Prompt diagnosis and treatment of testicular cancer provides the best opportunity for cure. Nevertheless, both patient and clinician factors often contribute to a delay in diagnosis. Painless scrotal masses are sometimes ignored, while testicular cancers presenting with scrotal pain are often treated as epididymitis.

The differential diagnosis of a testicular mass includes testicular torsion, epididymitis, or epididymo-orchitis. Less common problems include hydrocele, varicocele, hernia, hematoma, spermatocele, or syphilitic gumma. In patients in whom the diagnosis is unclear or in whom a hydrocele precludes adequate examination, imaging studies are an important second step in determining the cause. (See "Acute scrotal pain in adults".)

The diagnostic evaluation of males with suspected testicular cancer includes scrotal ultrasound followed by radiographic testing, measurement of serum tumor markers, radical inguinal orchiectomy, and in some cases, retroperitoneal lymph node dissection (RPLND). The results are used to determine the histologic type and extent of disease, and to guide therapy. Testicular biopsy is not performed as part of the evaluation due to concern that it may result in tumor seeding into the scrotal sac or metastatic spread of tumor into the inguinal nodes.

In addition, since the vast majority of these patients are young males, consideration should be given to fertility issues and sperm cryopreservation during the initial diagnostic evaluation. If possible, a baseline sperm count and sperm banking should be performed prior to the radiographic diagnostic evaluation in order to avoid radiation exposure of the sperm. (See 'Cryopreservation of sperm' below.)

Scrotal ultrasound — Bilateral scrotal ultrasound can distinguish intrinsic from extrinsic testicular lesions with a high degree of accuracy and can detect intratesticular lesions as small as 1 to 2 mm in diameter. In males with testicular masses, scrotal ultrasound has become an extension of the physical examination, but it should never be considered a substitute for the latter.

A cystic or fluid-filled mass is unlikely to represent malignancy. By comparison, seminomas appear as well-defined hypoechoic lesions without cystic areas, while nonseminomatous germ cell tumors (NSGCTs) are typically inhomogeneous with calcifications, cystic areas, and indistinct margins [8,9]. However, this distinction is not always apparent; in one series for example, the radiologist's interpretation of the type of tumor was correct in only 70 percent of cases [9]. Even magnetic resonance imaging (MRI) does not improve the specificity [10].

Another limitation is that because the tunica albuginea is difficult to discern by ultrasonography, local tumor staging has proved to be unreliable with this technique [8,9]. In the above report, tumor staging was accurate in 44 percent of seminomas and only 8 percent of nonseminomatous tumors [9]. For these reasons, scrotal ultrasound cannot replace radical inguinal orchiectomy for the determination of histology and stage.

The widespread use of scrotal ultrasound in the evaluation of male infertility occasionally leads to the diagnosis of an incidental nonpalpable testicular mass [11,12]. (See "Approach to the male with infertility".)

In the largest series, 46 asymptomatic lesions smaller than 10 mm were identified in 4418 males evaluated for infertility [11]. The majority of the males did not undergo surgery and were followed with active surveillance and serial ultrasound. Among the eight patients who either chose surgery or who had surgery because of progressive enlargement of the lesion, one seminoma and two Leydig cell tumors were identified. The remaining five patients had benign lesions. The authors concluded that ultrasound surveillance for small, incidentally discovered testicular masses is a safe and appropriate alternative to surgery. For those males with an incidentally detected testicular mass (and normal serum tumor markers) who choose to undergo surgery, less-radical surgery (ie, excisional biopsy), rather than orchiectomy, is appropriate [13,14].

Microlithiasis — Testicular ultrasonography identifies patients with microlithiasis, defined as five or more echogenic 1 to 3 mm foci in a single cross-sectional ultrasound image. Retrospective cohort studies have demonstrated a strong association between microlithiasis and testicular cancer, both in adult and pediatric populations [15,16]. However, a causal link is unlikely as ultrasound surveillance of patients with microlithiasis with no clinical risk factors has not shown an increased incidence of cancer [17]. Consequently, patients with microlithiasis and otherwise normal ultrasound findings do not require further imaging, although they should be instructed in testicular self-examination [18].

Imaging studies

CT scan — A high-resolution computed tomography (CT) scan of the abdomen and pelvis, and a chest radiograph are generally performed [3]. Chest CT is recommended if the chest radiograph is abnormal or if metastatic disease involving the thorax is strongly suspected.

Regional metastases first appear in the retroperitoneal lymph nodes. Although CT is the imaging modality of choice to evaluate the retroperitoneum, false-negative rates as high as 44 percent have been described [19]. Occult micrometastases are responsible for most of these false negatives, as evidenced by a retroperitoneal relapse rate of 20 to 25 percent in males with clinical stage I disease who do not undergo RPLND [20-22].

The utility of the staging CT scan is also dependent on the cutoff value used to define an abnormal node. Most institutions use a 10 mm cutoff (measurement based upon the short axis in the transverse plane) to define pathologic adenopathy. Higher cutoffs (greater than 15 mm) yield higher false-negative rates, while lower cutoffs (less than 5 mm) may result in some patients undergoing unnecessary therapeutic RPLND [23] (see "Retroperitoneal lymph node dissection for early-stage testicular germ cell tumors"). A more exacting method to evaluate lymph node enlargement utilizes craniocaudal measurement of lymph nodes in the suspected landing site. Above 10 mm, for every 3 mm increase in craniocaudal length in patients with nonseminomatous tumors, the risk of relapse increased by 52 percent [24].

MRI — Magnetic resonance imaging (MRI) of the abdomen and pelvis or scrotum usually adds little to the information obtained by CT scan and ultrasound [10]. MRI of the brain is performed if brain metastases are suspected. Bone radionuclide scan is rarely indicated.

Is there a role for PET imaging? — Positron emission tomography (PET) scan is of limited utility in the initial staging of patients with testicular germ cell tumors (GCTs) [25,26] because of the frequent occurrence of false-negative results:

The utility of PET as compared with CT as an initial staging modality for the retroperitoneum was studied in a German study of 72 males, all of whom underwent subsequent RPLND for clinical stage I or II NSGCT [25]. In this study, correct nodal staging was achieved in more patients by PET compared to CT (83 versus 71 percent), and the positive predictive value was also higher with PET (95 versus 87 percent). However, false-negative results with PET-CT were still a problem, with a negative predictive value that was only modestly higher than that achieved by CT (78 versus 67 percent).

Similar results were seen in a subsequent study in 111 patients with clinical stage I NSGCT that used the negative results of PET to select patients for surveillance [26]. Of the 87 patients with a negative PET who were managed with surveillance, 33 (38 percent) relapsed within one year.

PET scanning is more commonly used for the evaluation of posttherapy residual masses than for initial diagnostic evaluation. (See "Treatment of stage II seminoma", section on 'Posttherapy residual masses'.)

Serum tumor markers — In a male suspected of having testicular cancer, blood should be obtained for a chemistry profile, a complete blood count, and serum tumor markers. Three serum tumor markers have established roles in testicular cancer: alpha-fetoprotein (AFP), the beta subunit of human chorionic gonadotropin (beta-hCG; since the alpha subunit is common to several pituitary hormones), and lactate dehydrogenase (LDH). Serum levels of AFP and/or beta-hCG are elevated in 80 to 85 percent of males with NSGCTs, even when nonmetastatic. By contrast, serum beta-hCG is elevated in less than 20 percent of testicular seminomas, and AFP is not elevated in pure seminomas. (See "Serum tumor markers in testicular germ cell tumors".)

Neither serum beta-hCG nor AFP, alone or in combination, is sufficiently sensitive or specific to establish the diagnosis of testicular cancer in the absence of histologic confirmation. Marked elevations in these markers are rarely found in males, except in GCTs.

Serum beta-hCG concentrations above 10,000 milli-international units/mL occur only in GCTs, the rare patient with trophoblastic differentiation of a primary lung or gastric cancer, or in females, pregnancy or gestational trophoblastic disease [27]. (See "Hyperthyroidism during pregnancy: Clinical manifestations, diagnosis, and causes" and "Hydatidiform mole: Epidemiology, clinical features, and diagnosis".)

Serum AFP concentrations above 10,000 ng/mL occur almost exclusively in GCTs and hepatocellular carcinoma. (See "Clinical features and diagnosis of hepatocellular carcinoma".)

These observations are especially pertinent for the patient with a suspected extragonadal GCT. Elevated serum tumor markers can be used to make the diagnosis if a biopsy is not feasible or will compromise a patient with compatible clinical features or if biopsy reveals poorly differentiated carcinoma. (See "Poorly differentiated cancer from an unknown primary site", section on 'Extragonadal germ cell tumors' and "Poorly differentiated cancer from an unknown primary site", section on 'Clinical evaluation'.)

Although serum tumor markers are helpful at the time of initial diagnosis of testicular cancer and for prognostication, their main utility is for subsequent follow-up of disease status after primary treatment. (See "Serum tumor markers in testicular germ cell tumors".)

Studies have identified noncoding micro RNAs, the miR-371-373 cluster in particular, as a potential emerging tumor marker for both seminomas and NSGCTs [28].

Radical inguinal orchiectomy — A radical inguinal orchiectomy should be performed to permit histologic evaluation of the primary tumor and to provide local tumor control. Neither scrotal ultrasound, as mentioned above, nor serum tumor markers are sufficiently accurate to replace radical inguinal orchiectomy. (See "Radical inguinal orchiectomy for testicular germ cell tumors", section on 'Scrotal violation'.)

Contralateral testicular biopsy — The role of contralateral testicular biopsy at the time of radical orchiectomy in a clinically normal testis is controversial. Testicular germ cell neoplasia in situ (GCNIS), a precursor for GCT, is present in 2 to 5 percent of males with GCTs [29-31]. (See "Testicular germ cell neoplasia in situ".)

In North America, biopsy is not recommended, but instead, careful surveillance of the contralateral testis is advocated. By contrast, many European groups suggest biopsy, particularly in patients considered at increased risk of GCNIS (eg, cryptorchidism) [32].

Retroperitoneal lymph node dissection — RPLND is the only reliable method to identify nodal micrometastases given the high false-negative rate with CT scan (see 'CT scan' above). It is also the gold standard for providing accurate pathologic staging of the retroperitoneum. Both the number and size of involved retroperitoneal lymph nodes have prognostic importance. (See "Retroperitoneal lymph node dissection for early-stage testicular germ cell tumors".)

Following radiographic evaluation of the retroperitoneum and radical inguinal orchiectomy, a subset of patients with low-stage NSGCT (T1-3,N0-2,M0, see below) should be considered candidates for a surgical staging RPLND. By comparison, primary chemotherapy is the treatment of choice for patients with stage III disease or high-volume stage II disease; in such patients, RPLND is reserved for those with postchemotherapy residual disease (see "Initial risk-stratified treatment for advanced testicular germ cell tumors"). Surveillance is an appropriate option for males with clinical stage I testicular cancer, especially those with limited risk factors, such as a minimal embryonal cell component and the absence of lymphovascular invasion. (See "Surveillance for stage I testicular germ cell tumors following orchiectomy".)

STAGING — The results of clinical and radiographic evaluation are used to assign a clinical stage in order to estimate prognosis and guide therapy. Testicular cancer is staged using the eighth (2017) tumor, node, metastasis (TNM) staging system developed jointly by the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC), which applies to both seminomas and nonseminomatous germ cell tumors (NSGCTs) [33]. In the TNM system, assessments of the primary tumor (T), lymph nodes (N), and distant metastases (M) are combined with serum tumor marker values (S) for the beta subunit of human chorionic gonadotropin (beta-hCG), alpha-fetoprotein (AFP), and lactate dehydrogenase (LDH) to define prognostic stage groups from I to III (table 2A-B).

It is important to note that for the purposes of TNM staging, the serum tumor markers should be assessed as S0 to S3 only after orchiectomy has been completed. (See "Radical inguinal orchiectomy for testicular germ cell tumors", section on 'Serum tumor markers'.)

Compared with NSGCTs, pure seminomas are more likely to be localized to the testis at presentation. Approximately 80 percent of males with seminomas present with stage I disease (limited to the testicle), while 15 percent have stage II disease (limited to the retroperitoneal nodes). (See "Treatment of stage I seminoma".)

For males who present with advanced disease, numerous staging and prognostic systems have been proposed to separate different prognostic subgroups, based primarily on single-institution experience [34-38]. In 1997, consensus was reached on a uniform, validated prognostic model by the International Germ Cell Cancer Collaborative Group (IGCCCG). The classification system is discussed separately [39]. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors", section on 'Definition of risk'.)

Because of the availability of serum tumor markers and the predictable metastatic pattern of testicular cancer, most experts do not require a confirmatory biopsy of suspected disease as part of the staging procedure. Biopsies of suspected disease should only be performed in unusual situations, such as in patients who present with imaging-detected masses without elevated tumor markers, or the presence of disease in atypical locations (eg, bone [40]). If patients have evidence of advanced disease suggested by imaging and/or elevated tumor markers, definitive treatment is recommended. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors".)

CRYOPRESERVATION OF SPERM — Semen cryopreservation should be made available to all males diagnosed with testicular cancer prior to instituting therapy if they wish to preserve fertility. If possible, a baseline sperm count and sperm banking should be performed prior to the radiographic diagnostic evaluation in order to avoid radiation exposure of the sperm. (See "Effects of cytotoxic agents on gonadal function in adult men".)

However, a number of issues need to be considered:

Testicular tumors are associated with gonadal dysgenesis, and approximately 50 percent of males have some degree of underlying impairment of spermatogenesis [41-47] (see "Effects of cytotoxic agents on gonadal function in adult men", section on 'Testicular cancer'). Semen quality may further deteriorate following removal of the affected testis [47], although others have shown no impact of orchiectomy [48]. The cause of gonadal dysgenesis is unknown in these males; it has been suggested that common etiologic factors are responsible for both low semen quality and testicular cancer [49].

Despite this abnormality, sperm from males with testicular cancer does not appear to be more sensitive to the effects of cryopreservation and thawing than normal donors [45]. Males with seminoma may have better sperm quality both before and after cryopreservation than those with nonseminomatous germ cell tumors (NSGCTs) [50].

Newer assisted reproductive techniques and improvements in cryopreservation techniques may permit successful future pregnancy in 30 to 60 percent of males who undergo treatment for testicular cancer [51-53] (see "Treatments for male infertility"). Congenital abnormalities have not been noted in these children.

Not all males are willing to undergo sperm testing or banking.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Testicular cancer".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Beyond the Basics topic (see "Patient education: Testicular cancer (Beyond the Basics)")

SUMMARY

Clinical manifestations

Testicular germ cell tumors (GCTs) are the most common malignancies affecting adult males between the ages 15 and 35 years. Testicular GCTs are highly curable cancers.

A majority of patients present with a painless testicular mass. Other less common clinical manifestations include local symptoms (such as pain or a heaviness in the lower abdomen), gynecomastia, or symptoms due to metastases. (See 'Clinical manifestations' above.)

Diagnostic evaluation – The initial diagnostic evaluation of the patient with a suspected testicular tumor should include (see 'Diagnostic evaluation' above):

Physical exam and scrotal ultrasound – Physical examination of the scrotum supplemented by ultrasound to differentiate tumor from a hydrocele or epididymitis. (See 'Scrotal ultrasound' above.)

Serum tumor markers – These include the beta subunit of human chorionic gonadotropin [beta-hCG], alpha-fetoprotein [AFP], and lactate dehydrogenase [LDH]). (See 'Serum tumor markers' above.)

Imaging studies – Imaging studies should include chest radiograph as well as computed tomography (CT) or magnetic resonance imaging (MRI) of the pelvis and abdomen to look for evidence of regional lymph node metastases. (See 'Imaging studies' above.)

Sperm cryopreservation – Prior to definitive treatment, cryopreservation of sperm should be made available to all males who wish to preserve fertility. (See 'Cryopreservation of sperm' above.)

Diagnosis – Radical inguinal orchiectomy is used both to provide the histologic diagnosis and for local tumor control. Lesser surgical procedures, such as biopsy of the testicle, are generally contraindicated. (See 'Radical inguinal orchiectomy' above.)

Staging – Tumor staging (table 2A-B) is determined from pathology of the primary tumor, lymphatic spread, the presence or absence of metastases, and the levels of serum beta-hCG, AFP, and LDH. (See 'Staging' above.)

Risk stratification – For males with metastatic testicular cancer, males are stratified into separate prognostic groups using the International Germ Cell Cancer Collaborative Group (IGCCCG) stratification system. (See "Initial risk-stratified treatment for advanced testicular germ cell tumors", section on 'Definition of risk'.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges William K Oh, MD, who contributed to earlier versions of this topic review.

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Topic 2980 Version 50.0

References

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