Sequential bilateral testicular tumours presenting with intervals of 20 years and more

The phenomenon of malignant growths occurring in both of the testicles has been known for more than a century. Hamilton and Gilbert conducted the first systematic review in 1942. Based on 144 cases collected from the literature they opened their milestone article with the sentence: “Testicular tumors possess a pronounced tendency to bilateralism” [1]. According to recent reviews, 3 – 5% of patients with testicular germ cell tumour (GCT) develop contralateral cancer which corresponds to a 20–30 fold increased relative risk of tumour [2‐4]. About 50% of these events occur within 5 years after diagnosis of the primary while 90% do so within a 10 years time-span [5]. Only few more cancers arise thereafter. So far, little is known about the risk of contralateral GCT after very long intervals of more than two decades. All GCTs are preceded by a common precursor named testicular intraepithelial neoplasia (TIN; also called intratubular germ cell neoplasia unspecified, ITGCNU) which is thought to be present in the testicle many years before the clinical manifestation of GCT [6, 7]. To identify candidates for second GCTs, contralateral testicular biopsy at the time of orchiectomy of the primary is available [8, 9]. However, physicians caring for patients with GCT have widely remained disinclined to this pro-active method of early detection of GCT [10]. Thus clinically, the risk of bilateral testicular tumour needs to be considered during follow-up of patients with GCT. Importantly, as this event may occur beyond the usual 5-years time-span of oncological follow-up, extended observation time is required.

Here we present three cases with exceptionally late onset of second GCT and we provide a survey of the literature regarding the problem of very long intervals between metachronous bilateral testicular tumours.

There are at least four lessons to be learnt from these three cases:

According to the most recent review, about 50% of all contralateral testicular tumours arise later than 5 years or more after the primary [2]. In a French analysis, 23% of second tumours occurred between the 10^th and the 20^th year of follow-up [12], while no case developed later. All of the major investigations on bilateral testicular tumours accord with the contention, that the risk is high during the first ten years and that it is gradually decreasing thereafter forming an asymptotical curve approaching the zero line of risk beyond the 20 years mark [5, 13‐15]. As a matter of fact, this understanding implicates the sporadic occurrence of such tumours at exceptionally late time points. Accordingly, Table 1 provides a synopsis of 25 cases of the literature (including the present cases) with bilateral testicular germ cell tumours occurring after 20 or more years [1, 3, 12‐14, 16‐32]. It is of note that already Hamilton and Gilbert in their 1942 review briefly mentioned such a case [1], and Melicow in a scholarly review on testicular new growths did so in 1955 [21]. The longest interval ever reported is 40 years in a Danish man [16]. The present case (#1) is ranking second on this list with an interval of 36 years.

The median age at primary presentation of the patients with very late presenting contralateral testicular tumour is 28.5 years that is not at variance with the over-all median age of patients with germ cell cancer [33]. Yet, there appears to be a slight deviation from the contention that patients with bilateral tumours usually experience a rather early presentation of their primary [12, 34, 35]. All of our cases had a nonseminomatous histology at first presentation which is somehow at variance with the preponderance of seminoma usually encountered in cases with bilateral testicular GCT [36]. Table 1 does not suggest any association of histology with the particular risk of late second GCT. Little is known about clinical stage at primary diagnosis and during relapse for these particular patients. In most of the reports (Table 1) information on clinical staging is not provided. In our series, only one had metastasized disease at primary presentation while two had stage I disease. So, the basic message of this compilation of cases is the information that the risk of contralateral testicular cancer will persist life-long.

(2) Our first case experienced his second tumour despite interval chemotherapy. Pathogenetically, all GCTs are preceded by the premalignant lesion TIN (ITGCNU) that is believed to be present in the contralateral testicle already at the time of the first tumour. Concerns regarding the low sensitivity of chemotherapy to eradicate the precursor in the contralateral gonad had been raised already in the 1980ies [37]. Accordingly, large series of patients with bilateral testicular tumours clearly revealed that chemotherapy does not protect against second tumours [4, 15]. In the largest investigation of bilateral tumours performed on the SEER data base, 39 second tumours (> 1%) were found among 3157 nonseminoma patients receiving chemotherapy [35]. Recently, it was shown that low doses of two cycles of cisplatin-based chemotherapy are probably without any considerable effect on TIN, three or more cycles may eradicate it in about 75% of cases [38]. Our patient had received 4 cycles of chemotherapy, however, that treatment did not involve cisplatin, which clearly is the most efficacious drug. So, one might speculate that the vinblastin/bleomycin regimen could have suppressed TIN only temporarily . Accordingly, it took 36 years for the remaining TIN cells to recover and to finally progress to invasive seminoma. In fact, there is some indication of extended intervals in bilateral GCTs following chemotherapy [13, 15]. Our patient apparently represents the case with the longest lag time between sequential bilateral testicular tumours and interval chemotherapy. So, this case represents an exceptional example showing the low efficacy of chemotherapy to prevent sequential testicular neoplasms.

(3) Two brothers of case #2 had suffered from testicular cancer, too, one of whom had even bilateral disease. Approximately 1-3% of all patients with testicular GCT have close relatives with the same diagnosis [34]. Notably, 6-15% of all familial cases of GCT develop bilateral disease while second GCTs occur in only 3-5% among sporadic cases [39]. Accordingly, a strong hereditary predisposition of testicular GCT is assumed [40]. While the clinical evidence for the involvement of genetic factors in the etiology of GCT is undisputed, the assumed Testicular GCT 1 gene has so far not been identified [41]. From a practical point of view, it is concluded that history of familial testicular cancer should increase the clinician´s vigilance regarding the possible development of contralateral cancer. As elucidated by the case, this event may even occur after a very long lag time.

(4) In one of our patients (#3), contralateral GCT developed despite a previous testicular biopsy negative for TIN. False-negative biopsies do occur in less than 10% of cases [8]. Multiple probing has been recommended to reduce the rate of biopsy-failures. In fact, systematic two-site biopsies revealed an 18% extra yield of contralateral TIN [8]. Whether or not double biopsy would have disclosed the true diagnosis at that time remains elusive, but clearly, multiple biopsies are more sensitive than a single one.

Our three cases highlight one of the manifold problems in the long-time follow-up of patients with testicular GCT. The specific risk of a second testicular tumour is one threat in addition to the well-recognized hazards of metabolic disorders, cardiovascular diseases and non-testicular malignancies [42]. The risk of contralateral GCT is not eliminated by chemotherapy. As all of our patients had TIN in the tumour-surrounding tissue, histologically, a contralateral biopsy at the time of the primary might have identified the impending second tumour. Although not explicitly recommended by current guide-lines [43‐45], contralateral testicular biopsy is clearly valuable for exploring the particular risk of second testicular cancer [8, 46].

Written informed consent was obtained from all of the three patients for publication of these Case reports and the two accompanying images. A copy of the written consent is available for review by the Editor of this journal.