Farooq A Khan and Jas S Kalsi
Q. A 26-year-old previously healthy man is referred to the urology clinic on the 2-week wait proforma with a right-sided testicular mass. How will you assess the patient in clinic?
A. I would take a pertinent history and perform a physical examination with specific reference to the following sections.
History
Related to the mass
Length of symptoms Painful or painless mass Change in size of mass
Any previous history of surgery on the genitalia Sexual history - Recent sexual contact or penile discharge Associated urinary symptoms
Trauma - Does not cause testicular cancer but may be the cause of the testicular swelling in 10%-15%
Previous relevant history and risk factors
History of cryptorchidism (either side) - This increases the risk of testicular cancer between 4 and 13 times in the undescended testicle [1] with 7%-10% of testicular tumours arising in an undescended testis [2]. There still remains a 5%-10% risk of developing testicular cancer in the contralateral testis with those with a history of cryptorchidism [3,4].
Family history of testicular cancer - Especially in fathers and brothers - increases risk by six and eight times, respectively, with 1.35% providing a positive family history [5,6].
Race - Testicular cancer is three times more common in Caucasians and in Northern Europeans with the highest incidence in Scandinavia, 11 per 100,000 men (Norway and Denmark). In the United Kingdom the incidence is 7.1 per 100,000 men.
Maternal oestrogen exposure - Foetal exposure of diethylstilboestrol increases the risk of testicular cancer in the male offspring (relative risk 2.8%-5.3%). This is a difficult history to elicit [4].
History of subfertility and poor semen analysis parameters increases the risk of testicular cancer in some studies by 1.6 times and from the SEER (Surveillance, Epidemiology and End Results) database by 20 times.
Contralateral history of testicular tumour - There remains a 5%-10% risk of testis cancer in the remaining testicle.
HIV - Increased risk of seminoma - Cause unknown.
Q. What features are you particularly interested in on physical examination?
A. I would perform a general examination to include palpation of the supraclavicular nodes, chest examination and an abdominal examination to palpate for a retroperitoneal nodal mass and ensure there are no inguinal scars from childhood orchidopexy that the patient has failed to mention. I would complete my examination by examining the testicle for the mass, its size and whether it is painful or painless. I would also examine the contralateral testicle.
The presence of pain does not confidently discriminate infection from a neoplastic process as 10% of men presenting with a painful testicle, clinically resembling epididymo- orchitis, have a testicular tumour and up to 20% can present with testicular pain as their first symptom [1].
Q. His right testicle has a hard, irregular and painless mass arising from the upper pole. What would you do?
A. I would arrange an urgent scrotal ultrasound scan and in our department we would walk the patient round to the radiology department for this the same day (using a minimum of a 7.5 MHz transducer).
Q. The ultrasound shows the image presented in Figure 2.1. What do you see and how would you describe this?
A. Figure 2.1 shows a heterogenous, irregular mass in the upper pole of the right testis. Clinically this is a testicular tumour.
Q. Any other investigations you would like to do in clinic?
A. I would take tumour markers, namely, serum a-fetoprotein (AFP - half-life 5-7 days), β-human chorionic gonadotrophin (βhCG - half-life 24-36 hours) and lactate dehydrogenase (LDH) and arrange a contrast CT chest, abdomen and pelvis particularly if widespread metastases are suspected (the presence of widespread testicular metastases on imaging is an oncological emergency and the patient must be referred urgently to an oncologist - immediate chemotherapy may be necessary prior to radical inguinal orchidectomy in these cases).
Figure 2.1
Note: Historically one would obtain a pre-operative CXR from clinic to elucidate the presence of widespread metastases but with the recent ease of access to CT scans pre-operative CXRs are performed less often.
Q. Do all patients have raised tumour markers at presentation?
A. No. Across the board for all testicular tumours, 51% will have raised tumour markers. This varies for the type of tumour present. For germ cell tumours, 5%-10% of pure seminomas will have a raised |3hCG (produced by syncytiotrophoblast elements). Pure seminomas do not secrete AFP.
For non-seminomatous germ cell tumours (NSGCTs) elevated tumour markers can be found in up to 90% of cases, with 50%-70% having raised AFP (produced by yolk sac elements) and ~40% having a raised |3hCG. Elevated |3hCG is found in 100% of choriocarcinoma and 40%-60% of embryonal carcinoma cases.
Q. What is the role of tumour markers in this case?
A. ttey are both diagnostic and prognostic. Measurement of tumour markers following orchidectomy and their half-life decline are useful in assessing the likelihood of retroperitoneal and metastatic disease. Given the half-life of the markers we would expect the |3hCG to halve every 36 hours and the AFP every 5 days.
The presence of normal markers prior to orchidectomy does not exclude metastatic disease and equally normalisation of markers post-orchidectomy does not mean the absence of distant disease.
Q. What is the significance of measuring the LDH?
A. This is useful in determining tumour burden and is a surrogate marker for tumour volume and cell necrosis. This is usually helpful for seminomas and to the oncologist as a measure of tumour response. It is raised in approximately 10% of seminomas.
Q. Are there any other conditions in which the above tumour markers may be raised other than in testicular cancer?
A. Yes. Other malignancies can raise the |3hCG such as pancreatic, liver, stomach, lung, breast, kidney and bladder and strangely in marijuana smokers. AFP can be raised with liver, pancreas, stomach and lung malignancies and with benign liver dysfunction.
In addition raised levels of luteinizing hormone in hypo-gonadotrophic patients may cross-react with some radio-immunoassay techniques for |3hCG resulting in spuriously high results.
Q. Is there any other pre-operative imaging you might wish to undertake other than a scrotal ultrasound scan?
A. Ideally a contrast CT scan of the chest, abdomen and pelvis should be performed preoperatively for staging purposes. However, surgery should be undertaken at the earliest opportunity and should not be delayed if CT scan cannot be performed in a timely manner in which case the CT can be performed after inguinal orchidectomy. Importantly, as mentioned earlier, in the scenario where widespread metastases are suspected on presentation pre-operative contrast CT of the chest, abdomen and pelvis (or CXR if CT not easily accessible) is mandatory.
There is no role for the routine use of pre-operative magnetic resonance imaging (MRI) or positron emission tomography (PET), as these do not alter the initial treatment plan. They may have a role in select cases in assessing the retroperitoneal nodes - in the case of MRI in patients with a contrast allergy preventing the use of CT, or in the case of PET in assessing whether a residual retroperitoneal mass after chemotherapy (in seminomas) can be safely watched or needs active treatment.
Q. What would you do with this young man?
A. I would arrange for an urgent radical inguinal orchidectomy (<1 week) and consideration for contralateral testis biopsy in high-risk cases.
Q. How do you perform a radical inguinal orchidectomy?
A. Through an inguinal incision, the tumour-bearing testicle is removed along with the epididymis and spermatic coverings and cord. Prior to manipulation of the testis the cord is isolated and clamped to allow control of the draining lymphatics to minimise tumour spill and metastatic release into the lymphatics towards the landing retroperitoneal nodes. The tumour-bearing testicle is resected to the deep inguinal ring and is transected and secured with one heavy tie (0 or 1 Vicryl) and a transfixation suture. Some suggest that a Prolene suture be used at the cut end of the cord to act as a marker for possible future nodal dissection. (We do not do this during our orchidectomies.)
I would warn him of the common complications of bleeding, infection and specifically loss of sensation on the inner thigh and ipsilateral scrotal wall or chronic groin pain as a consequence of damage to the ilio-inguinal nerve. It is also important to warn of possible reduced hormonal and fertility potential.
Q. Is there anything you would offer him or consider prior to inguinal orchidectomy?
A. I would offer him the opportunity to sperm-bank and consider insertion of a prosthesis. The EAU recommends that sperm-banking take place prior to orchidectomy although for adequate specimens to be banked practically means that this happens after orchidectomy in most units. If there is a history of sub-fertility or a small contralateral testicle and fertility is an issue for the patient then sperm-banking prior to orchidectomy is highly advisable. I would offer him a prosthesis at the same sitting but caution should be advised
in those who are likely to need early post-operative chemotherapy (pulmonary metastases, markedly raised markers) because prosthesis-related infection (0.6%-2%) [7] may delay this. Some oncologists would There fore prefer not to offer this in this setting but at a later date.
Q. How does a patient bank sperm? Are there any issues the patient needs to be aware of?
A. The patient is asked to attend the local designated fertility clinic to provide three semen samples with a 2-3 day period of abstinence. A brief assessment of sperm quality is undertaken microscopically and then the sample is frozen in liquid nitrogen at — 196°C. Patients should be aware of the following as part of the consent process for sperm-banking:
Quality of sperm is not guaranteed if and when it is thawed.
Illness prior to or at the time of sperm-banking may affect the quality of sperm. If chemotherapy is planned sperm-banking can still be done in the first week or so following its initiation as sperm produced prior to the start of chemotherapy will still be healthy and usable.
There is some evidence that the quality of semen in men with germ cell tumours is poor in comparison to similarly matched healthy males and assisted conception techniques may be required [8].
Maximum storage is for 10 years (until the age of 55 in the United Kingdom).
The Human Fertilisation and Embryology Authority (HFEA) require all men banking sperm to be screened for HIV and hepatitis B and C prior to its transfer to a longterm storage facility. Men with HIV/hepatitis can bank sperm in separate storage vessels.
At present the cost of initial consultations, blood tests and storage for the first year are met by the National Health Service (NHS). Most centres charge £200 per year of storage after the first year which at present is met by the patient.
The patient may need to travel some distance to the nearest facility to be able to sperm-bank.
Q. The patient decides he wishes to have a prosthesis. What complications would you warn the patient regarding prosthesis insertion?
A. The complications based on a review of 2,500 prostheses for a variety of indications [7] include
Extrusion from the scrotum - 3%-8%
Scrotal contraction and migration - 3%-5%
Chronic pain - 1%-3%
Haematoma - 0.3%-3%
Infection - 0.6%-2%
Q. You mentioned a little earlier that you would consider a contralateral testis biopsy? How will you decide this for individual patients?
A. The purpose of a contralateral biopsy is to identify the presence of carcinoma in situ or intratubular germ cell neoplasia (ITGCN) the risk of which is ~5%-9% of patients with testicular cancer. The EAU recommends that men under the age of 40 with a contralateral testis volume of <12 mL (relative risk for developing ITGCN is 3.78) have a 34% risk of ITGCN on biopsy [9]. Contralateral testicular biopsy should also be considered in men with a history of undescended testis (normal volume testis) and subfertility/poor spermatogenesis as these are associated with ITGCN [9,10].
Q. How would you biopsy the contralateral side?
A. Through a scrotal incision the tunica vaginalis is opened and the testicle is delivered. Small incisions of the tunica albuginea at each pole (5 mm) are made with a scalpel allowing extrusion of the seminiferous tubules. These are then cut with a pair of scissors or taken flush to the albuginea with a scalpel and placed into Bouin’s solution (and not formalin). Using a double biopsy open technique (biopsies from each pole) it can be anticipated that 99% of ITGCN will be identified [11].
There is evidence that using a biopsy gun and Tru-Cut needle (with the testis delivered through a scrotal incision) provides the same quality of biopsy and detection rate for a diagnosis of ITGCN as does an open technique.
Q. Are there any occasions where an immediate orchidectomy is not undertaken?
A. Yes. In rare cases patients may present with extensive life-threatening metastatic disease
(respiratory compromise from widespread metastases, severe back pain from retroperitoneal disease). In such cases an immediate orchidectomy is not required but urgent chemotherapy is under the care of an oncologist. A later orchidectomy may be required that may reveal the original tumour or often a residual scar in the testis.
In men with no obvious testicular tumour, but who have widespread disease of unknown origin, the diagnosis of a germ cell tumour should be considered and raised tumour markers can be diagnostic. Given that results of marker estimation will take some time before they are available, a urine pregnancy test can be considered to confirm the presence of urinary |3hCG, which would be an indication that the widespread metastatic disease is in fact a germ cell tumour. Initial chemotherapy can then be given without delay.
Q. You perform the radical inguinal orchidectomy and your patient goes home the same day. What information do you want your pathologist to tell you about the orchidectomy specimen?
A. Macroscopically we want to know the size of the testicle and tumour and any macroscopic invasion of the epididymis, tunica vaginalis and cord structures.
Microscopically we would want to know the following:
Histological type of tumour - Germ cell tumour, sex cord tumours
Size
Multiplicity
Rete testis involvement
Pathological stage
Presence of ITGCN
Presence of microvascular invasion
If seminoma - Are there any non-seminomatous elements which would then dictate how the patient is managed in the long term?
Specifically for seminoma tumour size greater than 4 cm and rete testis invasion have been shown to be important prognosticators for relapse for stage I disease.
For NSGCT the presence of vascular and lymphatic invasion, the percentage of embryonal carcinoma (>50%) and the proliferation rate (>70%) predict for metastatic disease.
Note should be made of the pathological classification of testicular tumours which separates tumours into those of germ-cell origin (subdivided into those with one histological type and those with more than one histological type) and the less common sex cord and paratesticular tumours (see Table 2.1).
Table 2.1 Pathological classification of testicular tumours and comparison of the World Health Organisation (WHO) and British Testicular Tumour Panel and Registry (BTTP&R) pathological classifications of testicular germ cell tumours
|
WHO |
BTTP&R |
|
Germ cell tumours |
Germ cell tumours |
|
Seminoma |
Seminoma |
|
Spermatocytic seminoma |
Spermatocytic seminoma |
|
Non-seminomatous germ cell tumour |
Teratoma |
|
1. Mature teratoma |
1. Malignant teratoma differentiated (MTD) |
|
2. Embryonal carcinoma with teratoma (teratocarcinoma) |
2. Malignant teratoma intermediate (MTI) |
|
3. Embryonal carcinoma |
3. Malignant teratoma undifferentiated (MTU) |
|
4. Yolk sac tumour |
4. Yolk sac tumour |
|
5. Choriocarcinoma |
5. Malignant teratoma trophoblastic (MTT) |
|
Sex cord stromal tumours |
|
|
Leydig cell tumour |
|
|
Sertoli cell tumour |
|
|
Granulosa cell tumour |
|
|
Mixed |
|
|
Unclassified |
|
|
Mixed germ cell/sex cord stromal tumours |
|
|
Other tumours |
|
|
Adenocarcinoma of rete testis |
|
|
Lymphoma |
|
|
Metastatic |
Q. Microscopically the specimen looks like this - Figure 2.2 - can you describe the likely histological diagnosis?
A. Figure 2.2: There are islands and sheets of large cells with clear cytoplasm with densely staining nuclei of varying sizes with prominent nucleoli in keeping with the appearances of a seminoma. There are also fibrous glands traversing the tumour and an associated lymphocytic infiltrate which are also characteristic of a seminoma.
Figure 2.2
Q. The pathologist agrees with you and reports the specimen as being a seminoma. What would you do now?
A. I would complete the staging of the patient by way of a contrast abdominal and chest CT. In our department all patients with seminoma undergo this along with NSGCTs.
In addition, if there had been any elevated tumour markers pre-operatively I would repeat these and document the post-operative tumour marker kinetics.
When asked ‘How would you assess a patient?’ always start with a history and examination and specifically tell them what things you want to know in the history, i.e. risk factors for testicular cancer.
Ultrasound study in essence has almost 100% sensitivity for testicular tumour detection. MRI is just as good but expensive and There fore not cost effective.
Overall 51% of new testicular tumours have raised markers.
AFP is made by yolk sac elements and not raised with seminoma.
|3hCG is raised in all choriocarcinomas and only ~10% of seminomas. It is produced by the giant syncytiotrophoblastic cells.
AFP half-life is 3-5 days. βhCG half-life is 36 hours.
EAU guidelines recommend staging CT of abdomen/pelvis and chest for germ cell tumours. Always offer sperm-banking to a patient prior to orchidectomy, especially if there is a history of subfertility or small contralateral testis with patient desire to maintain fertility.
EAU guidelines for a contralateral testis biopsy are as follows:
<40 years of age
Testicular volume <12 mL
Considered in men with history of undescended testis and subfertility The contralateral biopsy technique - open two-pole technique - will pick up 99% of ITGCN. Pathological prognostic factors for relapsing disease are as follows:
|
Seminoma: |
Rete testis invasion Tumour size >4 cm |
|
NSGCTs: |
Microvascular/lymphatic invasion Embryonal cancer content >50% Proliferation rate >70% |