Q. What do you understand by the term testicular intraepithelial neoplasia (TIN) or intratubular germ cell neoplasia (ITGCN)?
A. Intratubular germ cell neoplasia (ITGCN) is a malignant pre-invasive testicular germ cell lesion also known as carcinoma in situ. It is believed to be the precursor for all germ cell tumours except spermatocytic seminoma.
Q. Why is ITGCN important?
A. Its presence denotes that there is a 50% chance of progression to germ cell tumours over a 5-year period and a cumulative probability of 70% of developing cancer at 7 years [12].
Q. Pathologically how would you describe ITGCN? (Figure 2.3)
A. Histologically ITGCN is characterised by malignant germ cells lining seminiferous tubules containing Sertoli cells in a single row with nuclear pleomorphism with an intact basement membrane. The tubules are usually of smaller diameter than normal, with thickened walls, and show decreased or absent spermatogenesis. The atypical cells are usually aligned along the basement membrane and are similar in appearance to seminoma tumour cells - clear cytoplasm and large nuclei, round or irregular, with prominent nucleoli.
Figure 2.3 Intratubular germ cell neoplasia (ITGCN).
Q. How often do we see ITGCN in testicular tumours? Are there any other conditions associated with this condition?
A. It is present in the contralateral testis in about 5%-9% of patients; this number rises to 34% in those less than 40 years of age and with testicular volumes less than 12 mL, hence the recommended criteria for contralateral testis biopsy in this group of patients [9]. The presence of ITGCN in the tumour-bearing testicle has no bearing on overall prognosis. In the general population the overall incidence is ~0.8%.
Other risk factors for the development of ITGCN are as follows:
Cryptorchidism (3%)
Extra-gonadal germ cell tumour (40%)
45XO karyotype
Subfertility (0.4%-1.1%)
Q. Does ITGCN raise tumour markers?
A. No.
Q. What would you tell the patient who has had an orchidectomy with ITGCN in the contralateral testis?
A. I would tell him that there is a risk of progression to invasive germ cell tumour over the following 5 years equating to 50%.
Q. The patient asks you what are you going to do about it?
A. This poses a difficult problem. The options for the patient are surveillance, treatment by way of radiotherapy or orchidectomy rendering the patient anorchic and reliant on testosterone replacement.
The case should be discussed with the patient. For those men who have not completed their family it is entirely reasonable to encourage them to do so naturally or by assisted conception techniques, if they wish, with a close surveillance programme. This will require regular self physical examinations and an annual ultrasound of the testis.
Radiation treatment is by way of a total dose of 20 Gy delivered at single 2 Gy doses over 5 days per week. This dose seems to be adequate to eliminate all foci of ITGCN but possibly at the loss of Leydig cell function necessitating the need for regular follow-up testosterone measurement. There is evidence that a smaller dose of 16 Gy is not adequate to completely eradicate ITGCN [13].
Undertaking an orchidectomy requires testosterone replacement therapy and loss of fertility.
Q. Is there any role for chemotherapy with ITGCN?
A. The answer to the question ‘Will chemotherapy eradicate ITGCN in some patients?’ is yes; but we would not use it routinely unless otherwise indicated.
Two-thirds of patients with ITGCN who need post-orchidectomy chemotherapy will have their ITGCN eradicated on follow-up biopsy. Any follow-up biopsy should be timed no earlier than 2 years after the completion of chemotherapy to minimise the risk of missing the ITGCN soon after chemotherapy. If the biopsies show persistent ITGCN then the above options can still be used although the likelihood of a low testosterone status is increased with radiation therapy at this stage.
Q. A young patient is referred by the GP with a testicular ultrasound showing widespread testicular microlithiasis. What is microlithiasis?
A. Microlithiasis is the presence of widespread calcifications present throughout the testicular parenchyma. Strictly the definition is the presence of more than five calcifications per image field on ultrasound with each calcification being less than 2 mm with no change in testicular shape or volume [14]. Its incidence in the population is 2%-6%.
Q. Is microlithiasis important? What would you tell the patient?
A. We now believe that microlithiasis is not as important as it once was thought to be. Originally, because of the finding of microlithiasis in association with testicular tumours, in some cases up to 74% of testicular cancer, it was believed that this may be a premalignant marker lesion and in some way aetiological in the development of testicular cancer. It is now clear that the rate of testicular cancer in with those with microlithiasis on long-term follow-up is no different to the rate of developing testicular cancer in the population as a whole [15], and for this reason we would not follow-up such patients in the urology clinic. Advice is given about self-examination and early referral on any palpable abnormality rather than annual testicular ultrasound that used to be the norm in many departments until recently.
Q. Is this advice true across the board for all patients?
A. Yes, although there is a suggestion that the risk of testicular cancer be stratified according to risk factors that the patient may have and the initial reason for the ultrasound.
Q. How would you stratify this risk?
A. For those without any risk factors for testicular cancer, advice on self-examination by the patient is given without urology follow-up. For those with risk factors an annual ultrasound is reasonable along with self-examination and possibly review with a urologist [16].
Q. What do you do in your department with a patient with microlithiasis?
A. We advise and educate patients to self-examine and do not undertake regular follow-up but will provide ultrasound testing to those patients who seek the additional reassurance this may provide, especially those who in the past may have been given advice that regular follow-up was recommended.