Is a contralateral testicular biopsy in patients with unilateral germ cell testicular cancer indicated as a routine procedure?

Carcinoma in situ (CIS) of the testis, also named testicular intraepithelial neoplasia (TIN), is a precurser of seminomatous as well as non-seminomatous testicular germ cell tumors with the exception of the spermatocytic seminoma.

About 5% of all patients with unilateral testicular germ cell cancer harbor CIS in the contralateral testis [1], [2] and it has been demonstrated that about 50% of these patients will develop invasive cancer within 5 years [3]. It is assumed that all cases of CIS – in time – will progress into invasive cancer. However, this will probably remain unknown, as detection of CIS has provided an indication for specific treatment for many years. Thus, we initiated the first study of localized irradiation for CIS of the testis in 1985 [4]. In our follow-up publication in 2002, all patients treated at dose levels from 20 Gy to 16 Gy obtained complete remission without signs of recurrence after an observation period of more than 5 years, whereas 1 of 14 patients receiving 14 Gy had a relapse of CIS 20 months after irradiation [5]. Other groups have confirmed the efficacy of low dose localized irradiation to eradicate CIS of the testis [6], [7], although relapses have also been observed with the use of 16 Gy dose level [8]. Thus, a safe radiation dose is probably 18–20 Gy in 9–10 fractions with 5 fractions per week. The increase of the dose level from 14–16 Gy to 18–20 Gy is not considered a problem as the influence on the hormone production is without clinically significant dose dependency in the dose range from 14 Gy to 20 Gy [5]. Some patients receiving localized irradiation for CIS of the contralateral testis require testosterone supplementation before radiation treatment, but in about one quarter of the patients, the localized irradiation by itself will induce androgen deficiency requiring testosterone supplementation [5], [9]. It should be noted that also patients with CIS of the contralateral testis receiving chemotherapy for their primary testicular cancer should be offered localized irradiation of the remaining testis as cisplatin-containing chemotherapy postpones but does not prevent the development of invasive growth [10].

In this issue of Acta Oncologica, Hentrich et al. [11] reports on a retrospective analysis of the treatment and outcome of patients with bilateral testicular germ cell tumors from a 25-year period from 1970 till 2003 at institutions in Munich, Germany. Their primary objective was to investigate whether the clinical course and outcome of a secondary metacronous testicular germ cell tumor justifies a contralateral testicular biopsy. Among a total of 1180 patients, 14 patients were found to have a synchronous and 33 patients a metacronous bilateral testicular germ cell cancer. Biopsy of the contralateral testicle was not routinely performed. The median time to the contralateral tumor was 71 months (range 19 to 216 months). Two of the 33 patients with metacronous testicular germ cell cancer underwent testis sparing surgery for the second tumor followed by irradiation with 20 Gy of the remaining testis. All other patients had an orchidectomy performed, 12 patients received different kinds of chemotherapy, 2 patients had adjuvant radiation therapy, 1 patient underwent retroperitoneal lymph node dissection, and 18 patients were followed by surveillance only. Thirty-two patients were alive without evidence of disease after a median follow-up time of 41 months (range 1–184 months), the remaining patient died of a late relapse of the first testicular germ cell tumor. Based on this retrospective analysis and a review of the literature, the authors argue that a routine biopsy of the contralateral testis cannot be recommended. The main arguments for this conclusion seem to be that the prognosis of patients with bilateral metacronous testicular germ cell tumors is excellent, follow-up examinations are mandatory independent of having detected CIS or not, the knowledge of CIS may cause emotional problems and infertility is an inevitable consequence of low-dose radiotherapy to the testis [11].

It is correct that the prognosis of patients with a contralateral testicular cancer is excellent. Thus, in the first study of CIS of the contralateral testis [3], all patients who developed invasive cancer were diagnosed as stage I and were cured by surveillance only. It is therefore very important to emphasize that the background for the diagnosis and treatment of CIS of the contralateral testis is not to improve overall survival but primarily to avoid a second orchidectomy and furthermore to avoid a toxic treatment of patients that otherwise may develop a second cancer in an advanced stage later on.

It is not correct that specific follow-up after a negative contralateral testicular biopsy is mandatory. The frequency of patients with a negative contralateral biopsy who later on develops invasive cancer is between 0 and 0.5% [1], [9], which is similar to the incidence of CIS in the general male population [12], [13]. Thus, patients with a negative biopsy should just be followed routinely according to the follow-up plan for their testicular cancer.

It is obvious that the diagnosis of CIS may cause emotional problems similar to what may happen associated with the diagnosis of all other pre-malignant or malignant lesions. On the other hand, the patient can be offered localized irradiation, which will cure about 100% of cases. It is also correct that localized irradiation will induce sterility. Many patients with unilateral testicular cancer and CIS of the contralateral testis have, beforehand, a very poor semen quality but, importantly, some patients may in fact be fertile [14], [15]. Patients should therefore be carefully informed about this issue and be offered a semen analysis and, if appropriate, storage of semen.

When the authors point out that knowledge of CIS may cause emotional problems, it is difficult to understand that the authors do not point out the psychological problems associated with the diagnosis of a second testicular cancer and subsequent removal of the remaining testicle. This will certainly induce sterility and furthermore all patients will require total testosterone supplementation in contrast to the situation following localized irradiation, where about one quarter of the patients will require partly testosterone supplementation.

In Denmark, we have used routine contralateral testicular biopsy – performed during orchidectomy for the primary tumor – in patients with unilateral testicular cancer since the early 1980s in the eastern part of the country and since the early 1990s in the whole country. The procedure is safe with only minor and short-lasting discomfort. The strategy represents a close to optimal screening situation. If the biopsy is without CIS, the patient can be assured that the risk of developing a tumor in the remaining testicle is negligible or – if the biopsy is positive for CIS – the patient can be offered localized irradiation, which in nearly all cases will prevent development of a second testicular cancer. As mentioned, it is very important to discuss the fertility problem with the patient and if relevant offer the patient a semen analysis and eventual storage of semen before initiation of the radiation treatment. Some patients will prefer to try to obtain fatherhood before initiation of localized irradiation and if so, the irradiation should be delayed and in that period, the testis should be followed closely by use of ultrasound scanning.

In conclusion, we strongly recommend that all patients with unilateral testicular germ cell cancer are routinely offered a contralateral testicular biopsy which most appropriately is performed during orchidectomy for the primary testicular cancer. Our strategy has been adapted by some countries and abandoned by others and therefore we have to recognize that the strategy is still debatable. Some centers recommend an in-between solution, i.e. to offer patients with a high risk of harboring CIS of the contralateral testis, a contralateral biopsy. However, such a strategy would miss about half the patients with CIS of the contralateral testis [2]. Therefore, we find it important to apply contralateral testicular biopsy for the entire patient population. In centers where this strategy is not implemented, we recommend that as a minimum patients should be informed about the possibility of having a contralateral testicular biopsy performed and thereby having the opportunity to chose themselves.