Testicular Cancer

Shiva Jashwanth Gaddam; Gregory Chesnut

Testicular Cancer

Author: Shiva Jashwanth Gaddam Editor: Gregory T. Chesnut Updated: 5/27/2023 11:21:16 AM

Introduction

Testicular cancer is the most common malignancy in men aged 15 to 45 years and represents one of the most common curable malignancies when identified promptly and treated with a multimodal approach. It represents 1% of male tumors and 5% of urological malignancies.[1] The incidence of testicular cancer has been increasing over recent years, gaining increased significance due to the long impact both the disease and its treatment can have over the course of a patient's life. Testicular cancer incidence has doubled over the past 40 years.[2]

With effective management, the prognosis is excellent with >90% cure rate and >95% five-year survival rate.[3][4] Complex environmental and genetic factors are involved in the development of testicular cancer; common risk factors include cryptorchidism, family history of testicular cancer, personal history of testicular cancer in the contralateral testis, age, and ethnicity. Initial evaluation includes history and physical examination, tumor marker assessment, and scrotal ultrasound. Once a solid intratesticular tumor is identified, radical inguinal orchiectomy is performed both for diagnostic and therapeutic purposes. Tumor staging guides further management with options including active surveillance, chemotherapy, retroperitoneal lymph node dissection, and radiation therapy.

Etiology

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Etiology

Both genetic and environmental factors have been studied in the development of testicular cancers.

Epidemiological risk factors: They include cryptorchidism, decreased spermatogenesis evidenced by sub- or infertility, disorders of sexual development, familial history of testicular tumors among first-degree relatives, the presence of a contralateral tumor or germ-cell neoplasia in-situ (GCNIS), etc.[5][6][7][8][9]

The most common environmental risk factors for testicular cancers can be summarized as below:

Cryptorchidism —2–4 fold increase in risk.[10] As cryptorchidism is more common on the right side, a small increase in incidence in right-sided testicular cancer is observed.[11]

Family history—relative risk increased 6–10 fold in brothers or sons of affected man[12][13]

Infections - Human papillomavirus (HPV), Epstein-Barr virus (EBV), Cytomegalovirus (CMV), Parvovirus B-19, and Human immunodeficiency virus (HIV)[14]

Testicular trauma[15][16]

High maternal estrogen levels[17]

Carcinoma in situ (intratubular germ cell neoplasia)

Prior history of testis cancer or extragonadal germ cell tumor

Genetic risk factors: Multiple genetic changes have been described in the etiology of testicular cancer. The isochromosome of the short arm of chromosome 12 – (i12p) – is pathognomonic of all types of adult germ cell tumors (GCTs), as well as GCNIS. Alterations in p53 have been observed in about 66% of cases of GCNIS.[18][19] Genetic polymorphisms in the PTEN tumor suppressor gene and the risk of testicular cancer (TC) have also been described.[20] Dysregulation in the pluripotent program of fetal germ cells (identified by markers, M2A, C-KIT, and OCT4/NANOG) is thought to be responsible for the development of GCNIS and germ cell neoplasia. Along with this, genome-wide association studies (GWAS) showed evidence of several single nucleotide polymorphisms (SNPs) markers known to have an association with an increased risk of developing testicular cancer, in particular at 15q21.3.[21]

However, current genetic studies have not revealed any evidence for a major single high-penetrance gene known to cause increased testicular cancer susceptibility.[22] An overlap is observed between the development of seminoma and of embryonal carcinoma, as evidenced by genome-wide expression analysis and detection of alpha-fetoprotein (AFP) mRNA in some cases of atypical seminoma.[23]

Epidemiology

The highest incidence of testicular cancer is observed in Western and Northern Europe (8.7 and 7.2 per 100,000 men, respectively).[1] The highest mortality rates are reported in western Asia, with most countries showing a decrease in mortality, likely due to the combined impact of earlier detection through self-examination and integration of multimodal treatments.[1]

In the United States, testicular cancer is most frequently diagnosed among men aged 20 to 34 (51% of all cases). 22.9 % of the cases are diagnosed in the age group of 35 to 44, 12.9% between 45 to 54, and the rest in other age groups. The mean age of diagnosis is 33 years. It is more commonly seen in White race men with an incidence rate of 7.1 per 100,000 persons, compared to 5.4 in Hispanic men and 1.7 in African American men.[24]

The overall incidence in the United States increased gradually over the last 4 decades (6.3 per 100,000 persons in 2017 compared to 3.7 per 100,000 in 1975). Testicular cancer incidence is higher in industrialized countries than in developing countries and, while higher incidences are seen in Caucasian men, the incidence of testicular cancer among non-white and immigrant men within the United States is increasing for unknown reasons.[25] Synchronous contralateral tumors are seen in 0.6% of cases and metachronous contralateral tumors are identified in 1.9% of cases.[26]

Pathophysiology

Germ-cell tumors are observed to develop secondary to a tumorigenic event in utero that leads to intratubular germ-cell neoplasia.[27] Intratubular germ-cell neoplasia is derived from gonocytes that have failed to differentiate into spermatogonia.[28] These cells do not attain invasive potential until after hormonal changes occur during puberty. Seminomas consist of transformed germ cells that are blocked in their differentiation. Embryonal carcinoma cells resemble undifferentiated stem cells, and their gene expression is similar to those of stem cells and intratubular germ-cell neoplasms.[29][30] Choriocarcinomas and yolk-sac tumors have extraembryonic differentiation, and teratomas have somatic differentiation.

Several genetic loci that confer a predisposition to testicular cancer have been identified.[31][32] The variant with the highest impact was detected at 12q21, the genes encoding the proteins involved in KITLG–KIT signaling.[33] The development of intratubular germ-cell neoplasia may involve aberrantly activated KITLG–KIT in utero, which induces arrest of embryonic germ cells at the gonocyte stage; subsequently, overexpression of embryonic transcription factors such as NANOG, sex-determining-region Y–box 17 (SOX17), and octamer-binding transcription factor 3–4 (OCT3/4, also known as POU domain, class 5, transcription factor 1 [POU5F1]) leading to suppression of apoptosis, increased proliferation, and accumulation of mutations in gonocytes.[34]

The genes related to the pathogenesis and their respective chromosomes as outlined below:[35]

UCK1: Chromosome 1
HPGDS: Chromosome 4
CENPE: Chromosome 4
TERT: Chromosome 5
TERT/CLPTM1L: Chromosome 5
SPRY4: Chromosome 5
BAK-1: Chromosome 6
MAD1L1: Chromosome 7
DMRT1: Chromosome 9
AFT7IP: Chromosome 12
KITLG: Chromosome 12
RFWD3: Chromosome 16
TEX14: Chromosome 17
PPM1E: Chromosome 17

Distinct gene expression through epigenetic regulation, including DNA methylation, may result in the formation of the different histologic subtypes, as outlined in the flowchart.[36]

Histopathology

Testicular cancers are defined based on their cell type. 2016 updated WHO histopathological classification characterizes testicular cancers with the following classifications:[37]

1. Germ Cell Tumors

Germ cell neoplasia in situ(GCNIS)

2. Derived from Germ Cell Neoplasia In Situ (GCNIS)

Seminoma

Embryonal carcinoma

Yolk sac tumor, post-pubertal type

Trophoblastic tumor

Teratoma, post-pubertal type

Teratoma with somatic-type malignancies

Mixed germ cell tumors

3. Germ Cell Tumors Unrelated to GCNIS

Spermatocytic tumor

Yolk sac tumor, pre-pubertal type

Mixed germ cell tumor, pre-pubertal type

4. Sex Cord/Stromal Cell 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

5. Miscellaneous Non-specific Stromal Cell Tumors

Ovarian epithelial tumors

Tumors of collecting ducts and rete testes

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 the testicular adnexa

History and Physical

Testicular malignancy usually presents as a unilateral lump or painless swelling as an incidental finding. Less commonly, testicular cancer presents with pain, with about one-third of the patients having dull pain. Acute pain is noted in about 10% of the individuals. While testicular cancer is not associated with trauma, antecedent trauma may elicit examination or imaging of the testes and result in an ultimate diagnosis. A careful physical examination will reveal a firm intratesticular lesion. Each testis should be gently held and rolled between the fingers to identify a firm intratesticular mass and differentiate intratesticular from extratesticular lesions. It is important to completely examine the contralateral testis as 0.6% of patients have a synchronous contralateral testis tumor. Occasionally, the testis is unable to be completely palpated due to the presence of a hydrocele, and the presence of a testicular lesion should be confirmed with ultrasonography, which is an extension of the physical examination. Patients uncommonly present with symptoms or signs of metastatic disease.[38] These are summarised below:

Clinical manifestations of testis cancer from metastatic disease

Systemic symptoms: anorexia, malaise, weight loss
Pulmonary metastasis: cough or shortness of breath
Lymphatic metastasis: cervical or supraclavicular lymphadenopathy
Retroperitoneal disease: Bulky retroperitoneal disease can present as back pain or may lead to compression on the gonadal veins leading to findings of varicocele
Vascular obstruction or thrombosis leading to lower extremity edema
Nausea, vomiting, or gastrointestinal hemorrhage from retroduodenal metastases
Central or peripheral nervous system symptoms from the cerebral, spinal cord, or peripheral nerve root involvement

Prompt diagnosis and treatment are crucial since testicular malignancy has excellent cure rates due to high chemo-sensitivity with modern cisplatin-based chemotherapy, radio-sensitivity, and surgical excision with orchiectomy or retroperitoneal lymph node dissection.

Evaluation

Evaluation of testicular cancer begins with obtaining a thorough history and performing a detailed physical examination. History includes inquiry regarding clinical features, as discussed above. It is important to ask specifically about the history of cryptorchidism, orchiopexy, or inguinal hernia repair as an infant. A family history of testicular cancer in father or brother should be elicited. Physical examination findings of any solid intratesticular mass should be considered to be testicular cancer until proven otherwise. Examination findings related to metastatic disease, described previously, may also be identified.

Testicular imaging with trans-scrotal ultrasound is the primary imaging modality to identify testicular cancer when suspected on physical examination.[39][40][41] Ultrasound imaging, when combined with a physical examination, provides nearly 100% sensitivity in the diagnosis of testicular cancer.[42] Testicular cancer is suspected when an ultrasound reveals a hypoechoic, solid, vascularized intratesticular lesion, and different testicular cancer types show subtle morphologic differences in imaging.[43] Further evaluation should include serum tumor markers (AFP, HCG, and LDH) before any intervention, including orchiectomy. Adequate counseling should be given regarding the possibility of infertility and placement of the testicular prosthesis if desired. Sperm banking should be considered in patients with bilateral testicular pathology.[39][40]

Radical inguinal orchiectomy is both therapeutic and provides tissue for histopathological diagnosis. Trans-scrotal biopsy should not be undertaken due to the risk of local dissemination due to the manipulation of established lymphatic drainage pathways. A retrospective analysis study showed a small but statistically significant increase in the incidence of local recurrence with trans-scrotal biopsy when compared to orchiectomy (2.9% vs. 0.4%).[44]

Testicular germ cell tumors spread along well-described and predictable lymphatic channels.[45][46] For tumors arising in the right testis, the primary landing zone is the infrarenal inter-aortocaval lymph nodes, followed by paracaval lymph nodes and para-aortic lymph nodes. Tumors arising from the left testis spread primarily to the para-aortic lymph nodes, followed by inter-aortocaval lymph nodes. Retroperitoneal spread from the right side to the left side can be seen in tumors arising from the right testis, but left-to-right spread within the retroperitoneum is rarely seen unless it is associated with bulky lymph node disease.[47] Abdominopelvic cross-sectional imaging is important to identify retroperitoneal lymph node disease arising from primary testis cancer and to inform multimodal treatment.

All patients with testicular germ cell tumors should undergo abdominopelvic imaging with computed tomography (CT). Patients with elevated serum tumor markers (AFP, α-fetoprotein; β-hCG, β-subunit of human chorionic gonadotropin; LDH, lactate dehydrogenase) should be evaluated further with computed tomography (CT) of the chest, abdomen, and pelvis for staging.[39] If testicular tumor markers are within the normal range, the rate of metastasis almost outside of the retroperitoneum is very low; therefore, the addition of a chest CT-scan to cross-sectional imaging of the abdomen and pelvis is highly unlikely to alter the treatment plan, and a chest radiograph suffices when combined with abdominopelvic CT imaging. Choriocarcinoma has been shown to spread via hematogenous routes, and patients with high levels of β-hCG should undergo cross-sectional imaging of the brain to identify metastatic lesions due to choriocarcinoma hematogenously spreading to the brain.

Serum tumor markers play an important role in the evaluation and management of testicular cancer. Post-orchiectomy markers are part of the tumor staging and risk categorization of testicular cancer and are part of any evaluation of treatment response or of disease relapse. LDH is found in diverse tissues throughout the body, and LDH-1 is expressed on chromosome 12p, which is over-expressed in germ cell tumors. Higher LDH levels can correspond to higher tumor burden. AFP and β-hCG evaluations are seen in many germ cell tumors.[48] β-hCG is produced by syncytiotrophoblasts within germ cell tumors and is seen in both non-seminomatous and seminomatous germ cell tumors. Choriocarcinomas commonly express β-hCG, as do approximately 15% of seminomas. AFP derives from the yolk sac, embryonal, and some teratomas within germ cell tumors and is never elevated in pure seminoma or pure choriocarcinoma.[49]

AFP and β-hCG are expressed not only in germ cell tumors but also in other neoplasms. β-hCG levels are increased in neuroendocrine tumors, cancers of kidney, lung, head, and neck, bladder, and GI tract.[50][51] AFP levels have been found to be elevated in liver diseases.[52][53] LDH is fairly nonspecific and is observed to be elevated in multiple different conditions. Recent studies have evaluated levels of circulating microRNAs, especially miR-371a-3p, in the evaluation of germ cell tumors, though their precise role in testicular cancer management remains to be fully defined.[54][55]

Multiple new immunohistochemical markers have been studied for diagnostic purposes.[2] They include PLAP, OCT3/4 (POU5F1), NANOG, HMGA1, HMGA2, PATZ1, RNF4, Aurora-B, AP-2γ (TFAP2C), and LIN28.[56] The table represents the types of tumors and respective immunohistochemical markers.[57][58][59][60][61][60]

Note --> E: Expressed; NE: Not Expressed; E(c): Expressed with cytoplasmic localization; NO: Not observed.

Treatment / Management

The International Germ Cell Cancer Collaborative Group (IGCCCG)-based clinical staging is used to tailor management strategies in patients with testicular malignancies. All patients are classified as Clinical Stage 0, I, II, or III after imaging and quantification of tumor markers. Stage 0 includes patients with germ cell neoplasia in-situ, stage I includes patients with tumor limited to the testis, stage II patients have lymph node involvement, and stage III patients have distant metastases.

Stage 0: If untreated, GCNIS has a risk of developing into TGCT after 7 years in 70% of cases.[62] Management of GCNIS should involve shared decision-making, and options include close surveillance with ultrasonography, orchiectomy, and radiotherapy. Though low-dose radiotherapy (at least 20 cGy) has similar cure rates as orchiectomy, scatter to contralateral testis can result in up to 40% of men treated by radiotherapy requiring testosterone replacement therapy or experiencing subfertility.[63] Contralateral GCNIS screening is recommended for patients with high-risk factors such as contralateral cryptorchid testis with testicular volume <12ml and age <40 years (30% risk of developing GCNIS). In such patients, screening for GCNIS in the contralateral testis should be offered with biopsy, and radiotherapy/orchiectomy can be given as required. However, regular ultrasonography is preferable for male individuals who desire to maintain fertility.

Stage I: Orchiectomy is the initial management strategy. The risk of relapse differs between seminoma and non-seminomatous tumors, and management differs accordingly, as discussed below.

Seminoma: Approximately 15% to 18% of patients with stage I disease will relapse after orchiectomy without adjuvant treatment.[64] While surveillance is recommended, two strategies may be considered: single-agent carboplatin chemotherapy for high-risk patients (rete-testis invasion and tumor size >4cm) or surveillance. In the absence of high volume(>4cm) and rete-testis invasion, the risk of relapse is <5%, and no adjuvant therapy is indicated. Invasion of both rete-testis and lymphovascular tissue yields a 25% risk of relapse, while the risk of relapse is only 4% if neither of them is involved.[65] Primary radiotherapy to the retroperitoneum and ipsilateral pelvis with 20 to 30 Gy has been the historic standard therapy for patients not agreeable to surveillance, and this treatment results in a 1% in-field recurrence rate, though longer-term cardiovascular side effects of such treatment now limit its common use.[66][67] (B2)

Surveillance of seminoma, however, relies heavily on cross-sectional imaging, as serum tumor markers are elevated only in approximately 15% of pure seminoma, and longer-term surveillance is required.[68] Though not routinely performed for clinical Stage I seminoma, RPLND is increasingly advocated by some due to high surgical cure rates and avoidance of late toxicities associated with chemotherapy, radiotherapy, or the cumulative effect of multiple surveillance CT scans in young men.[69]

Non-seminomatous tumors: There is a 14% to 22% risk of relapse without adjuvant treatment in tumors without lymphovascular invasion. The risk of occult metastatic disease is greater if the lymphovascular invasion or embryonal predominance is seen in the primary tumor. If the lymphatic or vascular invasion is involved, there is an approximately 50% risk of developing metastasis without adjuvant treatment.[70] The chemotherapy regimens used commonly are BEP (bleomycin, etoposide, and cisplatin) or EP (etoposide and cisplatin). Active surveillance without adjuvant therapy is proposed due to the 70%-80% cure rates seen by orchiectomy alone.[71] Such a strategy avoids long-term effects of chemotherapy and surgical recovery from primary retroperitoneal lymph node dissection, though it relies upon regular laboratory and cross-sectional imaging evaluation. Though most relapses occur within the first two years after diagnosis, longer-term surveillance is required due to the risk of late relapse. For patients who decline to undergo surveillance, one or two cycles of BEP chemotherapy can be considered.[72] (A1)

A single cycle of BEP is found to reduce the risk of relapse from 50% to 3%.[72][73] While relapse rates after primary chemotherapy are low, those patients who do recur following BEP are commonly chemoresistant. In select patients, at dedicated referral centers with experienced surgeons, nerve-sparing retroperitoneal lymph node detection(RPLND) offers cure rates comparable to chemotherapy and also results in a decreased need for surveillance cross-sectional imaging.[72] (A1)

The rationale for surgery is that modern nerve-sparing techniques can result in an excellent cure rate without diminishing fertility. Retroperitoneal lymph node dissection also treats occult metastatic teratoma, which is not sensitive to any chemotherapy regimens, and which is present in up to 25% of men with occult metastatic disease. Studies have shown that between 19% and 28% of men with clinical Stage I disease harbor pathologic Stage II disease in the retroperitoneum and that over 80% of these patients can be cured by RPLND alone, sparing chemotherapy and its side effects.[74][75] Additionally, the long-term cancer-specific survival following RPLND (with or without adjuvant chemotherapy) is nearly 100%, and the risk of difficult-to-cure late relapse is less than 2%.[76](B2)

Stage IIA and IIB: Orchiectomy is the initial management strategy. Further management depends on the histopathological type as below.

Seminoma: Radiotherapy has been the historical standard for Stage IIA seminomas, though induction chemotherapy with three cycles of BEP or four cycles of EP is increasingly used. The standard radiation field should be extended from the ipsilateral iliac region to the para-aortic region (also called as 'hockey-stick field'). The relapse rate is 5% after radiotherapy, and overall survival is approximately 100%.[77][78] IIB seminomas warrant three cycles of BEP or four cycles of EP.[79] The PRIMETEST and SEMS trials are currently investigating the role of primary RPLND in clinical Stage IIa and IIb seminoma.[80](A1)

Non-seminomatous tumors: All IIA and IIB non-seminomatous tumors are treated with IGCCCG risk group-directed chemotherapy and can be treated with three cycles of BEP, four cycles of EP, or primary RPLND.[81][82] In patients with residual retroperitoneal disease of >1cm after chemotherapy, salvage resection is recommended.[83] Nerve-sparing surgical techniques can be undertaken to preserve ejaculation and to conserve fertility. For N1 disease, surveillance is generally preferred after RPLND since the rate of relapse is <20%. For N2 or N3 disease, recurrence rates are higher, and hence chemotherapy with two cycles of BEP or EP is justified. For N2 and N3 teratomas, surveillance after RPLND is adequate, as teratoma is chemoresistant.[81][82] (A1)

When imaging data is insufficient to determine the stage, RPLND can be performed, or surveillance with imaging six weeks later to evaluate disease status is also an acceptable alternative. Rapidly growing lesions with rising tumor marker levels should be treated with primary chemotherapy according to IGCCCG risk-group classification, as shown in the figure below. Following chemotherapy, if there are any residual lesions ≥, 1 cm, RPLND should be performed. If patients undergoing chemotherapy have growing tumors and normal or declining tumor markers, teratoma or an undifferentiated malignant tumor should be suspected, and RPLND is indicated.

Stage IIC and III: Standard treatment regimens for advanced tumors include chemotherapy with BEP, EP, or Cisplatin-based chemotherapy regimens such as VIP (etoposide, ifosfamide, cisplatin) or VeIP (vinblastine, ifosfamide, cisplatin), according to the IGCCCG risk classification. In an IGCCCG analysis, the 5-year overall survival rate for patients with intermediate prognosis was 80% and for patients with poor prognosis was 48%.[84] For patients with good prognosis according to the IGCCCG risk stratification, three cycles of BEP or four cycles of EP are recommended. For patients with intermediate or poor prognosis, four cycles of BEP are recommended. Several other studies did not show more effective or less toxic chemotherapy regimens.[85] (A1)

Tumor marker levels should be assessed at the end of the first cycle of chemotherapy. For patients with unsatisfactory tumor marker decline, dose-intensified chemotherapy should be considered. High dose chemotherapy regimens are not indicated as the initial treatment itself since trials have failed to prove a survival benefit when compared to standard doses.[81][82] Rarely, in a few patients, the levels of tumor markers decline but the tumor mass increases, indicating growing teratoma syndrome. In such cases, immediate tumor resection should be completed.(A1)

Approximately 1 to 2% of patients present with brain metastasis. The overall survival in such patients at initial diagnosis is poor (30% to 40%), but it is worse in patients in whom brain metastasis occurs as relapsed disease (2% to 5%).[81][82] Currently, an optimal management protocol for patients with brain metastasis is not defined. Chemotherapy is necessary for all patients with brain metastasis. An analysis from the Global Germ Cell Cancer Group showed that primary chemotherapy is an adequate treatment modality in patients with brain metastasis discovered at the initial diagnosis of TGCT. In patients with brain metastasis at relapse, cranial radiotherapy in combination with systemic chemotherapy improved the overall prognosis.[86] (A1)

Concurrent whole-brain radiotherapy and chemotherapy strategy is found to cause central nervous system toxicity (progressive multifocal leukoencephalopathy or cerebral atrophy), and hence should be avoided.[87] There is an increasing interest in the use of stereotactic radiosurgery to treat oligometastases or solitary brain metastasis when radiation is required. The role of neurosurgical interventions in such cases is unclear. Further trials are needed to clearly define the utility of neurosurgery in such cases.(B3)

Treatment of Residual Lesions

Seminoma

Usually, seminoma responds well to chemotherapy (approximately 95% of patients) and does not need residual tumor resection. If serum βHCG levels are increased, salvage chemotherapy is indicated.[81][82] Over half of patients with seminoma have residual tumor masses after primary chemotherapy, and studies have found that residual masses under 3cm in size after risk group-directed chemotherapy are comprised of fibrosis with rare findings of the viable disease, while residual masses over 3cm in size may harbor viable tumor in approximately a third of cases.[88][89] For tumor masses over 3cm in size after induction chemotherapy, a PET scan should be performed, and any PET-avid mass should be surgically excised, while patients with non-avid masses may be observed.[90] There is no role for radiotherapy in residual masses following induction chemotherapy. (A1)

Nonseminomatous Tumors

When residual radiographic abnormalities (classed as lesions >1 cm) are present after chemotherapy, residual tumor resection is warranted. Among residual masses over 1cm in size following chemotherapy, approximately 10% can harbor vital cancer, 40% may harbor chemotherapy-resistant teratoma, and 50% can be expected to harbor necrotic tissue and/or fibrosis.[91][92] Patients with disseminated disease, who, following chemotherapy, have serological remission and radiographic residual tumors of <1 cm can be safely observed without residual tumor resection.[93][94] (B2)

However, some centers prefer to perform RPLND to decrease the risk of late relapse, particularly in the case of teratoma and secondary somatic malignancy. Patients in whom the levels of serum tumor markers (especially AFP) plateau after chemotherapy need residual tumor resection rather than salvage chemotherapy. Even in patients with localized disease and plateauing levels of βHCG, surgery may offer a superior cure rate, and in these cases, the treatment decision should be made by specialized centers for testicular tumors.[95] After the resection of residual tumors with necrosis or the complete resection of teratomas, no further treatment is warranted.[81][82](A1)

Treatment of Relapsed or Refractory Disease

Standard treatment of patients with tumor marker-positive relapse after first-line chemotherapy, refractory disease, and tumor progression during chemotherapy, or within 3 months thereafter, is salvage chemotherapy followed by surgical resection of residual disease. Standard salvage regimens include four cycles of paclitaxel, ifosfamide, and cisplatin (TIP), four cycles of vinblastine, ifosfamide, and cisplatin (VIP), and two or three courses of carboplatin and etoposide high-dose chemotherapy (HDCT).[96][97] To date, no randomized trial has been done to evaluate the superiority of HDCT over conventional-dose chemotherapy. The TIGER trial (a randomized phase III trial) is currently ongoing comparing these two strategies.[98] (A1)

The residual disease of any size should be resected since resection is known to be superior to salvage therapy in preventing relapse. Unresectable disease warrants salvage chemotherapy. Late relapse (defined as disease recurrence >2 years after completion of first-line therapy) tumors are more likely to be chemoresistant, and surgery is the first choice of treatment in patients with resectable disease, irrespective of tumor marker levels.[99] In the case of unresectable tumors, salvage chemotherapy should be undertaken.[100][101] TGCTs that progressed after cisplatin-based combination chemotherapy may be treated with HDCT or peripheral blood stem cell transplantation (PBSCT). The 2-year progression-free and overall survival values were found to be 60% and 66% with HDCT and PBSCT, respectively.[102](B2)

Differential Diagnosis

A hard intratesticular mass is a diagnostic of testicular cancer unless proven otherwise. However, some other diagnoses to consider while evaluating a testicular mass include:

Epididymo-orchitis
Hematoma
Inguinal hernia
Hydrocele
Spermatocele or epididymal head cyst
Varicocele
Lymphoma (the most common finding in bilateral testis lesions in older men)
Metastasis from other cancers (eg, lung cancer, melanoma, prostate cancer)
Syphilitic gumma
Tuberculoma

Ultrasonography helps further narrow down the diagnosis and radical inguinal orchiectomy is the definitive modality for diagnosis.

Surgical Oncology

When a diagnosis of testicular cancer is suspected based on physical examination and/or ultrasound findings, radical inguinal orchiectomy is performed, which removes the testicle, epididymis, and spermatic cord up to the level of the internal inguinal ring. In this procedure, these structures are delivered through an inguinal incision made along Langer's lines in the groin. If the mass is too large to pass through a standard 3 to 5 cm inguinal incision, the incision can be carried inferiorly to the anterior scrotum to allow for removal of the testis in its tunics along with the spermatic cord. Trans-scrotal orchiectomy or biopsy is contraindicated, as doing so alters the lymphatic drainage patterns and impacts further management. Partial orchiectomy is contraindicated in the presence of normal contralateral testis and can be considered in small polar lesions in solitary testicles only after biopsy of the adjoining testicles are confirmed on frozen sectioning to be clear of GCNIS or malignancy. Such a procedure should be performed through an inguinal incision and should not be routinely considered.

Predictable lymph node drainage patterns contribute to high success rates of retroperitoneal lymph node dissection. A full RPLND removes all lymphatic tissue within a template whose superior border is the renal vessels and whose lateral borders are the ureters and with an inferior border of where the ureter crosses the iliac vessels. Lymphatic tissue is removed from the great vessels using the "split and roll" technique, whereby para-aortic, pre-aortic, interaortocaval, para-caval, and pre-caval node packets are removed. The ipsilateral gonadal vein is removed and the stump of the spermatic cord is removed. The postganglionic sympathetic nerve fibers can be prospectively identified and spared in nerve-sparing RPLNDs.[103]

Radiation Oncology

Though radiotherapy to the retroperitoneum and ipsilateral pelvic lymph nodes has historically been the standard treatment for early-stage seminoma, long-term deleterious impacts on cardiovascular health and secondary malignancies have limited its use in many contemporary series.[104][105] Short-term complications of gastrointestinal upset, nausea, and fatigue are typically managed conservatively.[106] Typical dosing regimens apply 20 to 30 Gy over 10 to 15 fractions in a dog-leg configuration.[107]

Pertinent Studies and Ongoing Trials

The SEMS and PRIMETEST trials are ongoing to evaluate the role of RPLND in seminoma. The TIGER trial is a phase III international trial to determine the optimal first salvage treatment in relapsed or refractory germ cell tumors. In this trial, Paclitaxel, Ifosfamide, cisplatin (TIP) is compared with high-dose chemotherapy with paclitaxel followed by carboplatin and etoposide TICE in relapsed germ cell tumors.

Treatment Planning

Treatment of testicular cancer requires cooperative evaluation by urologists, medical oncologists, and radiation oncologists. Expert radiologic evaluation during surveillance is mandatory to detect recurrent disease. Careful pathologic evaluation is needed to describe different components of seminomatous and non-seminomatous germ cell tumors or GCNIS within specimens. Multidisciplinary discussions and planning result in the optimization of treatment, which results in an excellent prognosis for testicular cancer patients within all risk categories.

Staging

Staging of testicular germ cell tumors is commonly performed using the American Joint Committee on Cancer (AJCC) tumor–node–metastasis (TNM) staging; it also includes a serum tumor marker (S) classification.[108] Notably, a patient is staged only once and this staging is determined only after

Tumor (T) Classification

pTX: primary tumor cannot be assessed
pT0: No evidence of primary tumors
pTis: germ cell neoplasia in situ
pT1: tumor limited to the testis (including rete testis invasion) without lymphovascular invasion
pT1a: tumor <3 cm in size
pT1b: tumor ≥3 cm in size
pT2: tumor limited to the testis (including rete testis invasion) with lymphovascular invasion, or tumor invading hilar soft tissue or epididymis or penetrating visceral mesothelial layer covering the external surface of tunica albuginea with or without lymphovascular invasion
pT3: tumor invades spermatic cord with or without lymphovascular invasion
pT4: tumor invades scrotum with or without lymphovascular invasion

Clinical Node (N) Classification (imaging-based)

cNX: regional lymph nodes cannot be assessed
cN0: No clinically enlarged regional lymph nodes
cN1: Imaging reveals one or more enlarged lymph nodes with no node larger than 2cm in greatest dimension
cN2: Imaging reveals at least one enlarged lymph node larger than 2cm in greatest dimension but less than 5cm in greatest dimension
cN3: Imaging reveals at least one enlarged lymph node larger than 5cm in greatest dimension

Pathologic Node (N) Classification (obtained after retroperitoneal lymph node dissection)

pNX: regional lymph nodes cannot be assessed
pN0: No regional lymph node metastasis
pN1: metastasis with a lymph node mass ≤2 cm in the greatest dimension and ≤5 nodes positive (none >2 cm in the greatest dimension)
pN2: metastasis with a lymph node mass >2 cm but not >5 cm in the greatest dimension; or >5 nodes positive (none >5 cm); or evidence of extra-nodal extension of tumor
pN3: metastasis with a lymph node mass >5 cm in the greatest dimension

Metastasis (M) Classification

M0: no distant metastases
M1a: nonregional nodal or lung metastases
M1b: distant metastases other than nonregional nodal or lung

TNM Descriptors

p indicates pathological classification. For identification of special cases of TNM or pTNM classifications, the m suffix and y and r prefixes are used. The m suffix indicates the presence of multiple primary tumors in a single site and is recorded in parentheses: pT(m)NM. The y prefix indicates those patients in which classification is performed during or following initial multimodality therapy. The r prefix indicates a recurrent tumor when staged after a documented disease-free interval: rTNM.

Serum Markers (S)

SX: marker studies not available or not performed
S0: marker study levels within normal limits
S1: LDH <1.5 × ULN and HCG <5,000 mIU/ml and AFP <1,000 ng/ml
S2: LDH 1.5–10.0 × ULN or HCG 5,000–50,000 mIU/ml or AFP 1,000 to 10,000 ng/ml
S3: LDH >10.0 × ULN or HCG >50,000 mIU/ml or AFP >10,000 ng/ml

The S stage is based on post-orchiectomy tumor markers. For patients undergoing chemotherapy, the S stage should be based on the tumor marker levels on the first day of the first cycle of chemotherapy.[109]

The tables outline various clinical stages.

Prognosis

Prognosis is majorly determined by the histology, extent of distant tumor spread, and extent of tumor marker elevations. For men with disseminated seminomas, the main adverse prognostic variable is the presence of metastases to visceral organs other than the lungs. A tumor that originated in the mediastinum has a worse prognosis when compared to a tumor that originated within the testicle. Nonetheless, even patients with widespread metastases at presentation, including those with brain metastases, may have a curable disease and should be treated with this intent.[110]

Several studies have suggested that a larger tumor size (at least 3 to 4 cm) is predictive of recurrence for seminomas.[111][65] Invasion of rete testis and lymphovascular invasion have also been shown to predict the recurrence of TGCTs.[64][112][65][113][114] A new biomarker, CXC-chemokine ligand 12 (CXCL12), has provisionally been shown to independently predict recurrence in non-seminomatous germ cell tumors.[115]

Complications

Complications due to testicular malignancy can be broadly classified into two groups:

Complications secondary to the disease itself:

Chronic fatigue[116]
Anxiety disorders[117]
Metastatic complications
Venous thromboembolism[118]

Complications secondary to the treatment:

Hypogonadism, leading to depression, sexual problems, and decreased physical well-being[119][120][121]
Peripheral neuropathy (cisplatin use)[122][123]
Hearing loss (cisplatin use)[122]
Tinnitus (cisplatin use)
Raynaud phenomenon (cisplatin use)
Secondary malignancies[124][125]
Cardiovascular disease[126][127]
Infertility[128]
Infections[129]
Surgical complications(antegrade ejaculation failure, small bowel obstruction, etc.)[130][131]

Postoperative and Rehabilitation Care

Following radical inguinal orchiectomy, patients should avoid heavy lifting and high-impact activities for four weeks and should wear supportive underwear to prevent scrotal swelling or hematoma. Retroperitoneal lymph node dissection is major intra-abdominal surgery, after which dedicated postoperative rehabilitation should be undertaken.

Consultations

Treatment of testicular cancer commonly involves primary care physicians, urologists, medical oncologists, and radiation oncologists. Fertility services may be required for sperm banking.

Deterrence and Patient Education

Testicles are the male reproductive glands located within the scrotum. Testicular cancer is cancer that develops from the cells in the testicles. Testicular cancer is the most common cancer in young men and is one of the most curable of all cancers. More than 95 percent of all men diagnosed with testicular cancer survive their disease. It most commonly presents a painless hard mass within the scrotum, in the testicles, mostly on only one side, and uncommonly on both sides. When cancer spreads to other sites such as the lungs, brain, abdomen, neck, etc., symptoms including nausea, vomiting, stomach upset, cough, shortness of breath, weakness, sensory disturbances, abdominal pain, lumps in the neck/groin areas, and back pain, can occur. Prompt evaluation is important to ensure early diagnosis and treatment and decrease the burden of treatment in advanced disease—medical evaluation, physical examination, and ultrasound of the testis. Serum tumor markers and cross-sectional imaging follow. When suspicion for metastatic disease is present, additional imaging with computed tomography (CT) of the chest and abdomen may be done for staging.

Both definitive diagnosis and initial management can be achieved by removing the mass along with the testicle. Further surgery or radiotherapy or chemotherapy will be based on the disease's stage and response to the initial management. In summary, it is one of the most curable cancers with excellent survival rates; having awareness about the disease and seeking prompt healthcare evaluation is of utmost importance.

Pearls and Other Issues

No significant difference in clinical outcomes was observed with screening for testicular cancer in men with a family history of testicular cancer. Routine screening (with ultrasonography) should not be performed in men with no palpable testicular mass. The risk of testicular cancer can be lowered by prepubertal orchiopexy in men with cryptorchidism. In such individuals, a twofold to a sixfold higher risk of developing testicular cancer has been observed in men who undergo orchiopexy after age 12 when compared to orchiopexy before age 12.[132] In men with testicular cancer, adequate counseling should be given regarding the possibility of infertility and testicular prosthesis. Sperm banking should also be considered.

Enhancing Healthcare Team Outcomes

A collaborative team approach is essential in the evaluation and management of testicular cancer. Excellent cure rates in testicular cancer are a testament to multimodal evaluation and treatment. Testicular cancer is exquisitely sensitive to platinum-based chemotherapy and careful surgical management. The chain of care begins with the patient himself (noticing a palpable mass and seeking prompt medical evaluation), followed by prompt initiation of investigations by the primary care physician, followed by appropriate referrals to radiology, medical oncology, urology, and radiation oncology. Other services making a significant impact in the management of testicular cancer, both pre-treatment, and post-treatment, include physical therapy, pain medicine, pharmacists, nursing staff, and fertility counselors. Effective communication and utilization of expert skills with clearly defined responsibilities and care coordination amongst all the above individuals or services are required to enhance patient-centered care and to improve clinical outcomes.

Media

(Click Image to Enlarge)

Flow Chart showing Pathogenesis of Testicular Cancer. Contributed by Shiva Jashwanth Gaddam; MBBS, MDc

(Click Image to Enlarge)

Figure showing Tumour, Node, Metastasis and Staging Table with Serum Tumor Markers. Contributed by Shiva Jashwanth Gaddam; MBBS, MDc

(Click Image to Enlarge)

Prognostic grouping by Risk Status Categories. Contributed by Shiva Jashwanth Gaddam; MBBS, MDc

(Click Image to Enlarge)

Advanced stage testicular cancer management. Contributed by Shiva Jashwanth Gaddam; MBBS, MDc

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