Testicular Cancer

Testicular cancer is the most common malignancy in young adults

Which of the following statement about testicular cancer is NOT correct?

• Treatment depends on tumour types: seminoma vs non-seminomaa
• 5-year survival rate in England is higher than 95%
• More than 50% of cases occur in men aged 60 or above
• The cells of seminoma have a 'fried egg' appearance

32-year-old man presents with the feeling of a mass in the left testis. On examination, a painless, round and firm mass is palpated in the left testes with a size of 1.5 cm by 1 cm. The mass does not transilluminate with light.

29-year-old man presents with palpitations, heat intolerance, increased sweating, increased bowel movement and unintentional weight loss. On examination, a thyroid gland is normal. A hard nodule in the right testicle is palpable which does not transilluminate with light.

Key Points

• Testicular cancer is the most common malignancy in young adults.

• A painless testicular mass is an important sign. Although 10% of patients may present with painful swelling due to associated haemorrhage or infection.

• 5-10% of patients may not present with a palpable mass but extra-testicular symptoms.

• Ultrasound with colour Doppler is the first standard investigation.

• Tumour markers include beta-HCG, AFP and LDH.

• Biopsy is not advised due to the risk of spreading.

• Radical inguinal orchiectomy is the initial treatment in most cases.

• Prognosis is generally excellent

Introduction

Testicular cancer is the most common malignancy in young adult men aged 20 to 34 years of age, highly curable when diagnosed early [1]. Germ cell tumours constitute 95% of all testicular neoplasms [2]. Germ Cell Tumours Testicular germ cell tumours can be divided into: Seminoma and Non-seminoma [2-4]. Some testicular tumours are made up of both seminoma cells and non-seminoma cells; the management will be guided by the more aggressive non-seminoma component.

1. Seminoma – derived from transformed monocytes or germ cells that are responsible for sperm production

2. Non-seminoma has 4 main histological types:

• Embryonal Carcinoma – cells resembling undifferentiated stem cells during embryonic development.

• Endodermal Sinus (Yolk Sac) Tumour – cells reminiscent of yolk sac, allantois and extra-embryonic mesenchyme.

• Teratoma – cells derived from 2 > embryonic germ layers: ectoderm, mesoderm or endoderm.

• Choriocarcinoma – malignant trophoblastic differentiation: both syncytiotrophoblasts and cytotrophoblasts.

Non-germ Cell Tumours In rare cases, testicular cancer may derive from a non-germ cell origin [4]. These testicular non-germ cell tumours may rise in the strome or the sex bords which are tissues that support the testicle. Examples of sex cord stromal tumours are Leydig cell tumours. Sertoli cell tumours and granulosa cell tumours. In males over the age of 50, a testicular mass could represent a lymphoma.

Epidemiology

• 0.4% of all diagnosed cancers and < 0.1% of all deaths in males worldwide [5].

• In the UK, testicular cancer accounts for 1% of all new cancers in males. There are around 2,400 new cases each year or more than 6 each day [6].

• Incidence rates are the highest in White males compared to African and Asian.

• Seminomas are usually diagnosed at the age of 35, whilst non-seminomas at 25 [7].

• Incidence rates have been increasing in multiple countries over several decades without clear explanation.

Aetiology

It is believed that all germ cell tumours start to develop during foetal development into germ-cell neoplasia or carcinoma in situ [1]. This condition is considered to be a pre-cancerous lesion that will eventually lead to malignant transformation.

Risk Factors

Congenital Abnormalities

• Cryptorchidism 'undescended testis'

Genetic Predisposition

• White ethnicity

• Positive family history

• Personal history of testicular cancer

• Gain of chromosomal arm 12p

• Klinefelter's syndrome

• Androgen insensitivity syndrome

• Peutz-Jeghers syndrome

Environmental Factors

• HIV Infection

• Testicular atrophy secondary to trauma, hormones and Mumps orchitis

• Chemical carcinogens: agriculture pesticide, textile dust

Screening and Prevention

Screening

Routine Screening is not recommended given low incidence and good outcomes [1]. However, those males at increased risks should be informed about the importance of physical self-examination.

Prevention

Early Orchiopexy for those children with undescended testis before the age of 13 significantly reduces the risk of testicular cancer [8].

Diagnostic Approach : History 

1. Age: 20 – 34 years of age in about 50% of cases.

2. Positive risk factors: Cryptorchidism, positive family history, previous diagnosis of testicular cancer, white ethnicity.

3. Symptom onset: usually more than 2 weeks, 10% can be acute onset.

4. Non-specific testicular discomfort or the feeling of a mass in the testis.

5. Extra-testicular manifestations in 5-10% of cases.

• Neck pain – supraclavicular lymph nodes

• Respiratory symptoms – pulmonary metastasis

• Non-specific gastro-intestinal symptoms, back pain – retroperitoneal disease

• Bone pain – skeletal metastasis

• Nervous system abnormalities – mechanical nerve root involvement

• Lower extremity swelling – venous occlusion

• Hyperthyroidism

• Gynaecomastia – increased production of Oestradiol, either through direct secretion or indirect stimulation by beta-hCG

Diagnostic Approach : Physical Examination 

1. Testicular Mass

• Location: 55% on the right, 2% bilateral

• Shape/Consistency: Smooth, firm and non-fluctuating

• 85% painless mass

• 10% painful swelling due to associated haemorrhage or infection

2. Transillumination Test

• Performed in a dark room, applying a light shined directly to the scrotum

• Transillumination indicates the presence of fluid

• Solid tumours do not transilluminate with light, unlikely hydrocele or cyst

3. Full Systemic Examination – given 5-10% of patients have extra-testicular manifestations with or without a clinically palpable testicular mass

Diagnostic Approach : Investigations 

1. Ultrasound with colour Doppler of testis

• Colour Doppler helps distinguish from other testicular swelling e.g. varicocele.

• If ultrasound. does not confirm a mass and suspicion is high i.e. abnormal tumour markers, proceed to CT scan of pelvis and abdomen.

2. Tumour markers

• Beta-human chorionic gonadotropin (beta-hCG) – elevated in all cases of choriocarcinoma, increase in 5-10% of pure seminoma.

• Alpha feto-protein (AFP) – elevated in embryonal carcinoma, teratoma, yolk sac tumour. not associated with pure choriocarcinoma and seminoma.

• Lactate dehydrogenase (LDH) – elevated in 50% of all cases. could be the only elevated marker in 10% of non-seminomas. high false positive rate, should be used mainly to assess tumour burden.

3. Imaging

• Initial staging imaging – chest x-ray and CT Abdomen-Pelvis.

• CT Chest is suggest when CT Abdomen is positive or chest x-ray is abnormal. Though in practice CT Chest-Abdomen-Pelvis might be performed in one setting.

• Consider MRI Abdomen Pelvis if CT is inconclusive or contraindicated due to allergy to contrast media.

4. Histological examination post-orchiectomy

• Orchiectomy is generally performed using an inguinal approach.

• Biopsy is not normally advised due to the potential risk of spreading.

Differential Diagnosis

Ultrasound is the key investigation that helps distinguish these conditions.

• Testicular: testicular torsion, intra-testicular benign cyst, orchitis

• Extra-testicular: scrotal hernia, hydrocele, varicocele, epididymal cyst

Staging 

The TNM staging system is a universal standard for classifying the extent of cancer. For testicular cancer, another component is incorporated into this system [9].

• Tumour (T): size and extent of the primary tumour

• Node (N): regional lymph node involvement

• Metastasis (M): presence of metastatic spread

• Serum tumour marker (S): levels of beta-hCG, AFP and LDH

Stages of Testicular Cancer

Stage 0:

Carcinoma in situ

Stage I A/B:

No evidence of disease outside testis, tumour marks are usually normal. If tumour makers above normal, management may be treated as one of the higher stages.

Stage II A/B/C:

Spread to any number of regional lymph nodes, tumour markers slightly raised.

Stage III:

Spread beyond retroperitoneal nodes or distant organs, or spread only to regional nodes but tumour marker(s) substantially elevated.

Tumour markers are considered to be substantially above normal when:

• beta-hCG ≥ 5,000 IU/L

• AFP ≥ 1,000 micrograms/L or nanograms/mL

• LDH ≥ 1.5 times the upper limit of normal range

Management

Treatment depends on whether the tumour is a seminoma or a non-seminoma and what stage of the tumour is [1, 2]. Inguinal orchiectomy is the initial treatment in most cases.

Early-stage Seminoma

Stage I to Stage II

• Inguinal orchiectomy and surveillance.

• Adjuvant chemotherapy or radiotherapy might be offered especially in those cases where a surveillance strategy is not acceptable.

Primary Options for Seminoma Stage I: 
Carboplatin

Primary Options for Seminoma Stage II:  
Bleomycin
Etoposide
Cisplatin
(BEP)

Early-stage Non-seminoma

Stage I to Stage IIB

• Inguinal orchiectomy and surveillance.

• Retroperitoneal lymph node dissection (RPLND) may be offered shortly after orchiectomy, especially in those locally invasive cases.

• Adjuvant chemotherapy might be offered as an alternative to RPLND or in those cases where a surveillance strategy is not acceptable.

Primary Options for Non-Seminoma:
Bleomycin
Etoposide
Cisplatin
(BEP)

Advanced Cancer

Seminoma or Non-seminoma: Stage IIC – Stage III

• Adjuvant chemotherapy post-orchiectomy.

• Residual mass resection.

Primary Options for Advanced Cancer:
Bleomycin
Etoposide
Cisplatin
(BEP)

There is strong evidence that this combination is effective and considered as the first-line treatment for advanced disease [10].

Prognosis

Prognosis is generally excellent:

• 5-year survival for men diagnosed with testicular cancer in England 95.3% [6].

• It is predicted that 91.3% of men diagnosed with testicular cancer in England will survive longer than 10 years.

Prognosis Classification for Advanced Germ Cell Tumours, International Germ Cell Cancer Consensus Group (IGCCCG) [11]

Resources

[1] Barqawi A, Bernard B, Testicular Cancer, BMJ Best Practice, 7 Sep 2022, https://bestpractice.bmj.com/topics/en-gb/255?q=Testicular%20cancer&c=recentlyviewed. Last accessed 4 Dec 2022.

[2] Motzer RJ, Feldman DR, Bosl GJ, Testicular Cancer, Harrison’s Principles of Internal Medicine 19th Edition, 2015, p. 588-592.

[3] Downes MR, Seminoma, PathologyOutlines, 19 Apr 2022, https://www.pathologyoutlines.com/topic/testisseminomas.html. Last accessed 4 Dec 2022.

[4] Types of Testicular Cancer, Cancer Research UK, 06 Feb 2022, https://www.cancerresearchuk.org/about-cancer-testicular-cancer/types. Last accessed 4 Dec 2022.

[5] Sung H, Ferlay J, Siegel RL et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries, CA Cancer J Clin, 2021, 71(3): 209-249.

[6] Testicular Cancer Statistics, Cancer Research UK, https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/testicular-cancer#heading-Two. Last accessed 4 Dec 2022.

[7] Gurney JK, Florio AA, Znaor A et al. International trends in the incidence of testicular cancer: lessons from 35 years and 41 countries, Eur Urol, 2019, 76(5): 615-623.

[8] Petterson A, Richiardi L, Nordenskjold A, et al. Age at surgery for undescended testis and risk of testicular cancer, N Engl J med, 2007, 356(18): 1835-1841.

[9] Brierley JD, Gospodarowicz MK, Wittekind C, Union for International Cancer Control (UICC), TNM classification of malignant tumours 8th edition, 2017.

[10] Nichols CR, Catalano Pj, Crawford ED, et al. Randomised comparison of cisplatin and etoposide with either bleomycin or ifosfamide in treatment of advanced disseminated germ cell tumours, J Clin Oncol, 1998, 16(4): 1287-1293.

[11] International Germ Cell Cancer Collaborative Group, International germ cell consensus classification: a prognostic factor-based staging system for metastatic germ cell cancers, J Clin Oncol, 1997, 15(2): 594-603.

Authors: Emma Khoury, Thitikorn Nuamek