Testicles are egg-shaped organs that are approximately 5cm long. Each testicle is covered by a fibrous layer called the tunica albuginea which is then surrounded by the visceral and parietal layers of the tunica vaginalis, as shown in Figure 1. The parietal layer encases the epididymis as well. The skin covering all of these structures is called the scrotum [1,2].
The testicles are held in the scrotum by their respective spermatic cords. These cords contain the testicular neurovascular supply, lymphatic vessels, and the vas deferens housed within a connective tissue and muscle sheath [1,2,3].
The testicular arteries arise from the abdominal aorta to supply their respective testicles. The venous drainage of the testicles begins in the pampiniform plexuses which drain into the right or left testicular vein. The left testicular vein empties into the left renal vein while the right empties directly into the inferior vena cava [4,5].
Testicles are comprised of both stromal and parenchymal components. The stroma houses the neurovascular supply, lymph vessels, connective tissue, and specialized cells. It functions to support the parenchyma. The parenchyma is organized into seminiferous tubules and functions to produce and mature spermatozoa [1,2,4].
A testicle consists of about 250-400 units called lobules which produce sperm and male hormones. Within each lobule are 1-4 seminiferous tubules that are lined with immature germ cells. The seminiferous tubules are separated from one another by stroma. The germ cells shown in Figure 2 (spermatogonia, spermatocytes, spermatids) begin maturing in the seminiferous tubules as they empty into the rete testis. The rete testis drains into the tightly coiled tube that is called the epididymis. Here, the maturation of spermatozoa is completed. The epididymis connects directly to the vas deferens; mature sperm cells eventually travel through the vas deferens and combine with the products of the seminal vesicles and prostate gland to produce semen, which is expelled through the urethra during ejaculation [1,2].
Specialized cells in the testicle include Sertoli and Leydig cells. Sertoli cells are found within the seminiferous tubules and aid in the transport and maturation of germ cells. Leydig cells lie in connective tissue stroma that is in between the seminiferous tubules. Leydig cells produce testosterone [1,2]. Testicular cancer usually arises in the germ cells rather than the sex cord or stromal cells .
The primary lymphatic drainage of the testes is to the retroperitoneal lymph nodes . The lymph typically then travels to the cisterna chyli, thoracic duct, posterior mediastinum and left supraclavicular fossa. In the region of the left supraclavicular fossa, the thoracic duct drains into the left subclavian vein. The scrotum, however, drains directly into the inguinal and external iliac lymph nodes. Obtaining a testicular specimen through the scrotum is thus contraindicated as the potential for seeding is not only within the biopsy tract, but also through the lymphatic system .
As shown in Figure 3, testicular cancers are classified as either germ cell tumours or non-germ cell tumours.
Over 95% of all testicular cancers are germ cell tumours [1,4]. There are 3 types of germ cell tumours: seminomas, non-seminomas, and mixed germ cell tumours. There is nearly equal reported incidence of germ cell tumours that are pure seminoma and tumours that contain some component of nonseminoma (non-seminomas and mixed germ cell tumours) . The pathogenesis of these three types of GCTs begins in utero with totipotent primordial germ cells .
Seminomas arise from the germ cell lineage of these primordial totipotent cells. They originate from the malignant transformation of a germ cell that has been blocked in spermatogenesis and thus will not mature into a spermatogonium, spermatocyte, spermatid, and spermatozoa. These rarely metastasize and have a cure rate close to 100%. They are very chemo- and radiosensitive. Seminomas are most common in males 25-45 years of age [1,3]. It has been shown that seminomas can transform into non-seminomas, although the mechanism by which this occurs is unclear [6,7]. Grossly, seminomas appear as light-brown multinodular masses .
Non seminomas also originate from primordial germ cells, but they differentiate into one or several different cell lineages. Embryonal carcinomas represent the first stage of differentiation. These can undergo somatic differentiation into teratomas, or extra-embryonal differentiation into choriocarcinomas or yolk-sac tumours . Usually nonseminomas are mixtures of these [1,2]. Nonseminomas spread more quickly than seminomas and have a higher capacity for hematogenous spread. These usually occur in men in their mid-twenties. In general, nonseminomas are still very chemosensitive but are less radiosensitive than seminomas. Yolk sac carcinoma are very rare in adults but comprise 90% of testicular cancer cases in children under 15 . On gross examination, non-seminomas are typically found with associated hemorrhage and necrosis .
These are germ cell tumours that contain both seminoma and nonseminoma cells. They are treated as nonseminomas .
These are rare and occur more frequently in children than in adults. They are usually treated surgically. Examples include Leydig cell tumour, Sertoli cell tumour, granulosa cell tumour, thecoma, and tumours of the collecting system and Rete testis [2,3].
Although these entities are not the focus of this module, it is important to know that testicular tumours may be metastatic carcinomas or primary testicular lymphoma. Primary testicular lymphoma accounts for 1-2% of non-Hodgkin lymphoma cases and is more common in men over 60 years old . Metastases to the testicle are very rare, but usually originate from a primary in the prostate, colon, rectum or kidneys .
Overall, testicular cancer is relatively rare compared to other cancers. In the U.S. it comprises 0.5% of all new cancer cases and 0.1% of cancer deaths . However, testicular cancer is the second most commonly diagnosed cancer among all youth and young adults aged 15 to 19 years and the most frequent cancer found in males aged 15-35 years as reported by the 2019 Canadian Cancer Statistics . For unknown reasons the incidence has quadrupled over the past 40 years and been rising by 0.8% per year over the last ten years [2,3,10]
The overall incidence (per 100,000 population) in BC in 2016 was 6.9. There were 5 testicular cancer attributed deaths in BC in 2016.
BC Cancer estimates that 1 in 213 BC men (0.47%) are expected to develop testicular cancer in their lifetime and 1 in 5437 men is expected to die as a result of testicular cancer . The National Institute of Health’s Surveillance, Epidemiology, and End Results Program (SEER) similarly predicts that 0.4% of men will be diagnosed with testicular cancer in their lifetime .
Testicular cancer incidence is not uniform around the world. It is the lowest in Africa and Asia and is highest in Scandinavian countries as well as Germany, Switzerland and New Zealand for unknown reasons 
A history of cryptorchidism is the most significant risk factor and is present in 10% of those diagnosed with testicular cancer. Cryptorchidism is a condition where one or both testicles do not spontaneously descend from the abdomen to the scrotum by 4 months of age. The risk of testicular cancer is higher if the undescended testicle remains in the abdomen than if it is trapped in the inguinal canal. Furthermore, the risk is reduced if males with cryptorchidism undergo orchiopexy, the surgical repositioning of a testicle. However, in these cases the patient’s risk is still above that of the general population. It is thought that the increased risk of testicular cancer is due to malposition as well as additional unknown factors. Supporting the idea that the risk is not completely due to malposition is the finding that in 20% of cases, the neoplasm develops in the testicle that descended normally .
Genetics are known to contribute to increased risk of testicular cancer but the impact is not as significant. Of men with testicular germ cell tumours, 1-3% have a relative with the disease. With regards to personal testicular cancer history, one study found the 15-year cumulative risk for the development of a contralateral testicular cancer to be 15% .
The remainder of the known risk factors also confer only modest risk . Vasectomy, trauma, alcohol, tobacco, and diet do not increase testicular cancer risk .
Unfortunately, there are no lifestyle or behavioural modifications that are proven to prevent testicular cancer [2,3].
Currently, there is no screening program for testicular cancer [1,2]. It is recommended that asymptomatic men are not screened with routine testicular examination as the benefits are likely limited. Furthermore, the biomarkers used in diagnosis, treatment and surveillance are non-specific and should not be used for screening . However, all men 13-39 are encouraged to perform monthly testicular self-examinations (TSEs) to improve the chance of early detection.
Men with one or more risk factors are recommended to perform monthly TSEs [1-3]. If a patient has had prior testicular cancer, they should also have regular examination by a physician (see follow up) [1-3].
Sertoli and Leydig cell tumours can present with any of the signs and symptoms mentioned for germ cell tumours. In addition, they may present with signs and symptoms of estrogen excess, which include gynecomastia, impotence, and loss of libido. They may also present with precocious puberty in those who develop one of these tumours young .
Common sites of testicular cancer metastases include the lymph nodes, lungs, liver, brain, and bone. In 10% of testicular cancer cases, patients present with symptoms related to metastatic disease (e.g. palpable nodes, respiratory symptoms, neurological symptoms, or bone pain) [11,16].
Anytime a male presents with a solid and firm mass within his testes, testicular cancer needs to be ruled out .
The differential diagnosis of a testicular mass includes testicular cancers, epidermoid cysts, lipomas, hemangiomas, fibromas, benign teratomas, and benign sex cord stromal tumours . In addition, the differential diagnosis of a scrotal mass includes epididymitis, testicular torsion, epididymo-orchitis, hydrocele, varicocele, hernia, hematoma, spermatocele, and syphilitic gumma [5,16]. The vast majority of these presentations are benign .
The symptoms and risk factors of testicular cancer (discussed above) should be reviewed when a patient presents with a scrotal mass . For example it would be important to ask about cryptorchidism as well as personal and family history of testicular cancer. There should be a detailed history characterizing the onset and progression of masses, pain, and edema.
It is also important to explore the rest of the differential with your history. Thorough detail regarding the other diagnoses for a scrotal mass will not be reviewed here, but the following pearls are from the American Academy of Family Physicians (AAFP) :
Bimanual examination of the scrotal contents should assess the size, contour, and consistency of the testes. Testicular consistency should be homogenous and testicles should be freely movable and separable from the epididymis. Masses should be likewise characterized. The spermatic cord on the affected side should be examined. As well, the abdomen and groin should be palpated for lymphadenopathy or abdominal visceral involvement. The chest can be evaluated for gynecomastia and the supraclavicular nodes can be assessed for advanced disease [4,16]. Again, physical examination for other etiologies should be performed as appropriate for the specific presentation.
All of the extratesticular diagnoses mentioned, such as epididymitis, testicular torsion, hydrocele and varicocele, are either made clinically or via ultrasound. Intratesticular diagnoses usually warrant ultrasonography . Therefore, in the work up of a scrotal mass, if the diagnosis is not clear after the clinical assessment the next step is usually an ultrasound .
Scrotal ultrasound is the appropriate first investigation in the workup of testicular cancer. Scrotal ultrasound can detect lesions as small as 1-2mm in diameter and is useful for differentiating intra- and extratesticular lesions. For example, scrotal ultrasound is a reliable way to differentiate testicular tumour from hydrocele or epididymitis.
Seminomas are typically well-defined, hypoechoic, and without cystic areas. In contrast, non-seminomas are classically inhomogeneous, have cystic areas and have poorly defined borders.
Despite its strengths, scrotal ultrasound is typically not specific enough to distinguish between germ cells tumour type and has been shown to be unreliable with regards to staging [3,11]. Ultrasound is useful in deciding whether or not to proceed with diagnostic/therapeutic surgery, but is not diagnostic itself.
AFP (alpha-fetoprotein), hCG (human chorionic gonadotropin), and LDH (lactate dehydrogenase) are tumour markers used in testicular cancer staging, treatment evaluation, and follow up [1,11]. These biomarkers should be checked prior to any treatment so as to help determine the appropriate therapy and assess treatment response. However, they are most useful in follow up [3,4].
AFP or beta-hCG is elevated in 80-85% of non-seminomas, including those that have not metastasized. In contrast, hCG is elevated in less than 25% of seminomas and AFP is not elevated in patients with pure seminoma. LDH is the least sensitive and specific of the three markers but can be elevated with either type of germ cell tumour [1,11]. Independent of testicular cancer, AFP can be elevated in those with liver disease, LDH can be elevated when there is any type of tissue injury, and there are a variety of factors that can contribute to an elevated hCG .
Overall, these serum tumour markers are neither sensitive nor specific enough to preclude histological diagnosis in most situations .
A chest radiograph and a CT of the abdomen and pelvis are recommended to complete staging and rule out metastatic disease. If there are signs/symptoms of neurologic involvement, a MRI of the brain is also recommended. MRI of the abdomen, pelvis, and scrotum has not been shown to be superior to CT and ultrasound for the evaluation of the testicles and retroperitoneal lymph nodes. A PET-CT scan is not indicated as part of the diagnosis and staging of testicular cancer . Currently, there is no established role for PET scans in testicular cancer.
The diagnosis of testicular cancer is made via histological evaluation of the surgical specimen following a radical inguinal orchiectomy. In the absence of pathology, tumour markers and scrotal ultrasound are insufficient for the diagnosis and staging of testicular cancers. Needle or incisional biopsy through the scrotum is contraindicated as it has the potential for introducing malignant cells into the lymphatic system that drains the scrotum . As mentioned earlier, the primary lymphatic drainage sites of the testes are different from those of the scrotum . Pathologic diagnosis can be delayed if neoadjuvant chemotherapy is required . For example, neoadjuvant chemotherapy would be considered in the case of a marker positive suspected germ cell tumour in a patient with life-threatening disease .
Retroperitoneal lymph node dissection allows for the detection of nodal micrometastases that are too small to be seen on CT scan. At diagnosis,this is considered for a subset of patients following radiographic evaluation to rule out metastatic disease. The subset of patients that this is considered for have low-stage disease and no known metastases .
In summary, diagnosis is definitively made via pathological assessment of the surgical specimen. However, the pathway to staging and diagnosis is as follows [4,16]:
**Baseline CBC, creatinine, and liver function tests should be obtained prior to therapy .
The American Joint Committee on Cancer (AJCC) staging method is widely accepted and uses the TNM system in conjunction with serum tumour markers, as shown in Table 2, to generate the 4 prognostic groups shown in Table 3 [1, 4,16,18].
*WNL = within normal limits
** Elevated, Elevated (+), and Elevated (++) refer to the S1, S2, and S3 tumour marker cut-offs reported by AJCC respectively .
In BC 68% of testicular cancers are diagnosed at stage I, 19% at stage II, 12% at stage III and 1% at an unknown stage .
All testicular tumours at any stage can be treated for cure, regardless of metastatic involvement . There is a risk of infertility associated with all treatments, so fertility preservation options (i.e. sperm banking) should be discussed with patients before treatment initiation if possible.
Surgical management is usually offered as the first-line treatment for any type and stage of testicular cancer. Most commonly the procedure performed will be a radical inguinal orchiectomy with or without retroperitoneal lymph node dissection. Testicular prosthetics are commonly inserted at the same time as the therapeutic surgery. Surgery may also be used for metastases [1,2].
Possible side effects particular to orchiectomy include changes to the appearance of the genitals, erectile dysfunction, retrograde ejaculation, and issues with fertility (in addition to the standard risks of surgery) [1,2].
If the patient has stage 1 testicular cancer, active surveillance following surgery is typically preferred instead of adjuvant chemotherapy or radiotherapy [1,2]. After radical orchiectomy alone, the rate of relapse in stage 1 patients is under 20% at five years. This favourable rate coupled with the additional morbidity of adjuvant treatments, lead to the recommendation for active surveillance following surgical management of stage 1 disease .
Patients are offered adjuvant chemotherapy if they are in more advanced stages (II and III) and sometimes if they have stage I testicular cancer but cannot comply with an appropriate surveillance program. Chemotherapeutic regimens used include either single agent carboplatin, BEP (bleomycin, etoposide, and cisplatin), EP (etoposide and cisplatin), or VIP ( ifosfamide, etoposide, and cisplatin) [1,2,19].
Possible side effects of chemotherapy for testicular cancer include nausea, vomiting, pancytopenia, anorexia, weight loss, diarrhea, alopecia, ototoxicity, infertility, sexual dysfunction, renal injury, pulmonary injury, neurotoxicity, fatigue, metabolic syndrome, Raynaud phenomenon, hypertension, and the risk of secondary cancers [1,2,4,15].
Adjuvant external beam radiation therapy to the para-aortic and ipsilateral iliac nodes can be considered for patients with Stage II A seminomas[1,2,15].
Otherwise, adjuvant radiation therapy is considered for seminoma patients unable to undergo routine surveillance or adjuvant chemotherapy .
Possible acute/short term side effects of radiotherapy include fatigue, skin irritation, and diarrhea. Potential long term side effects include infertility, sexual dysfunction and secondary cancers [1,2,4].
Patients with recurrent disease are typically managed with either chemotherapy or radiation. The decision between radiation and chemotherapy depends on patient factors, such as age, and comorbidities, such as contraindications to chemotherapy. Other factors to consider when deciding between these modalities include the response to prior therapy, the location and timing of the relapse, and the tumour histology .
For non-seminoma recurrence, surgery is usually recommended when there is residual disease following chemotherapy or radiation. Surgery following chemotherapy or radiation is also recommended when the disease recurs after a two-year disease free interval. For non-seminomas recurring after 2 years, surgery has been shown to significantly improve 5-year survival. Surgical consideration is especially important if the non-seminoma is a teratoma, due to the risk of transformation and a relative insensitivity to chemotherapy .
For seminoma recurrence, residual disease after chemotherapy or radiation is usually only considered for resection if it has enlarged following serial observations. Despite, the retroperitoneal lymph nodes being a common site for relapse, there is currently no established role for retroperitoneal lymph node dissection in relapsed seminoma. However, there are two ongoing studies that are exploring retroperitoneal lymph node dissection in relapsed seminoma to investigate this approach further. In contrast to non-seminomas, late recurring seminomas have not been shown to have different outcomes than early-recurring seminomas and thus the time to relapse does not influence seminoma management .
Side effects of the three main treatment modalities are listed above. Further explanation and recommendation regarding particular side effects will be addressed here.
A baseline sperm count and sperm cryopreservation should be discussed with all males diagnosed with testicular cancer as treatment can lead to temporary or permanent issues with fertility [2,4]. The etiology of the infertility is not fully understood as many males diagnosed with testicular cancer have existing infertility. It is thought that chemotherapy and radiation impair spermatogenesis while retroperitoneal lymph node dissection disrupts sympathetic nerve complexes feeding the gonads. Roughly 80% of men recover spermatogenesis five years after diagnosis . However, it is estimated that with current assisted reproductive technology, only 30-60% of males who undergo testicular cancer treatment will be successful in creating future pregnancy .
Following orchiectomy, the scrotum will take on a different shape and this is an aesthetic concern for many men. Testicular prostheses are available and can be placed at the same time as the orchiectomy or later. The prosthetics are non-functional. 
There is some evidence suggesting that men who have undergone testicular cancer treatment have higher cardiovascular risk profiles. The source of the increased risk is not completely understood, but it is known that a potential long term side effect of chemotherapy and radiation is hypertension .
Hypogonadism is another potential side effect of testicular cancer treatment. There is additional long term risk for patients who receive chemotherapy or radiation. Patients who receive adjuvant therapy should have annual assessments of testosterone and luteinizing hormone levels. They should also be routinely screened for signs and symptoms of hypogonadism such as sexual dysfunction, depression, fatigue, obesity, small testicular size, and poor muscular development. Testosterone replacement can be initiated for men with hypogonadism secondary to testicular cancer treatment .
Testicular cancer has a five-year survival rate of 97%, which is one of the highest among all cancers reported by the Canadian Cancer Society . Mortality rates have declined significantly in the past 25 years due to improved treatment modalities. SEER reports 5-year survival rates of 99.2 and 96.4% for Stage I and Stage II testicular cancer respectively. For Stage III, the 5-year survival rate reported by SEER is 72.8%. . The Canadian Cancer Society 5-year survival rates are nearly identical . Therefore, all testicular tumours at any stage can be treated for cure . Even patients with brain metastases are still considered potentially curable . Overall, testicular cancer is one of the most treatable solid neoplasms, even when diagnosed at advanced stages .
The International Germ Cell Cancer Collaborative Group (IGCCCG) has created a consensus prognostic staging model that stratifies men with advanced disease into good, intermediate, and poor risk groups as shown in Table 4 [23,24].
Specific prognostic factors to consider :
After orchiectomy, the median time of seminoma relapse is reported to be 13 to 16 months, and 95% of non-seminoma relapses occur within the first two years . 5-10 years of active surveillance is recommended 
The follow up protocol recommended by BC Cancer includes history, physical examination, chest x-ray, CT abdomen/pelvis, LDH, AFP, and HCG for all patients regardless of tumour type and stage . However the proposed interval of the follow up depends on the principal treatment, adjuvant treatment, tumour type and tumour stage. In general, patients are seen every 2-6 months for the first three years and the frequency gradually decreases to yearly assessments from years 5-10 [1,2].
After 5 years time, the yearly follow up is often with a patient's family doctor. At this point it is recommended to check AFP and HCG, examine the remaining testicle, and monitor for potential cardiac risk factors. As well, if radiotherapy was used then appropriate colon cancer screening should be initiated in compliance with BC Cancer screening guidelines .
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