ABSTRACT
Objective
In the Middle East, there is a paucity of data regarding germ cell tumor characteristics and treatment outcomes. Herein, we aim to present the largest series in Jordan reporting our cancer center experience managing GCT.
Methods:
Between 2010 and 2020, a total of 241 patients with a pathological diagnosis of GCT were treated at our cancer center. Demographic, epidemiologic, and pathological data were retrospectively collected. In addition, survival and relapse outcomes based on tumor stage and adjuvant treatment were collected.
Results
A total of 241 patients were diagnosed with GCT, of whom 108 (44.8%) had seminoma and 133 (55.2%) had non-seminoma tumors (NSGCT). Median age (interquartile range) at diagnosis was 31 years (25–36). Patients with seminoma (68.5%) had pT1 disease post orchiectomy, while only 37.5% of patients with NSGCT had pT1 on final pathology. Elevated tumor markers such as beta-human chorionic gonadotropin were present in 10% of seminomas. Following radical orchiectomy and staging, 88 (36.5%) went for active surveillance while 153 patients (63.5%) received adjuvant treatment. With regard to pathology slides read outside, rereading by our genitourinary pathologist yielded a discrepancy on GCT type in 41 (19.3%) out of 212 patients. The median follow-up was 36 (24–48) months. Twenty-two patients relapsed after an average follow-up time of 39 months. The 5-year overall survival for stage I, II, and III was 98%, 94%, and 87%, respectively, and 3-year recurrence-free survival for stage I, II, and III was 94.8%, 78%, and 67%, respectively.
Conclusion
Our data on testicular GCT including demographic, histological, and treatment outcomes were comparable to that of developed countries. In light of the pathology discrepancy rate revealed in our study, authors recommend a second review by expert genitourinary pathologists to ensure proper classification and management of GCT.
KEYWORDS: Testicular cancer, germ cell tumor, testicular tumor, RPLND
Introduction
Testicular cancer is the 25th most commonly diagnosed cancer in North America, and it accounts for 1–3% of all male cancers in Europe and globally [1]. To date, it is the most common cancer among young men, with half of the cases being diagnosed between the ages of 20 and 34 [2]. Worldwide, a 44-fold increased incidence of testicular cancer was recorded in 2012 where the Middle East witnessed a notable increase of 2–4% in the incidence of testicular cancer [1]. Nevertheless, advances in treatment modalities maintained a relative survival rate as high as 95.3% worldwide [3,4]. In the Arab world and Egypt specifically, mortality over incidence of testicular cancer is 17.6%, which is significantly better than all reported genitourinary cancers (46.7–57%), which a reflection of the excellent survivorship of testicular cancer in Egypt and the rest of world [5–7].
Currently, there is a paucity of epidemiologic data regarding testicular cancer in the Middle East [8]. A notable study from Saudi Arabia revealed a substantial increase in testicular cancer incidence among the young Saudi population [9], while another study from Lebanon showed a comparable distribution of testicular germ cell tumors (GCTs) with developed countries [10]. Similarly, treatment outcomes from another Lebanese cohort was comparable to other countries worldwide [11].
Hence, we sought to present the largest Middle Eastern series to date that reports on the histopathologic distribution of GCTs as well as the demographics and treatment outcomes of patients with GCTs.
Methods
This is a single-center retrospective study on patients with histologically proven GCT who were treated at the King Hussein Cancer Center (KHCC). This study was granted ethical community approval and an Institutional Review Board approval. Consents were waived. The data were obtained from the KHCC charts, which included all patients with testicular GCT who were treated at the institution between the years 2010 and 2020. Patient demographics, clinical, and pathological data were retrospectively collected by chart review. Patients underwent radical orchiectomy for primary staging either at KHCC or at an outside institution. As part of the cancer center protocol, all pathological specimens done outside were secondarily reviewed by a specialized genitourinary pathologist prior to initiation any treatment. Clinical staging was based on the 2018 AJCC Cancer Staging Manual [12]. Relevant data on tumor markers and follow-up treatments including chemotherapy regimens, retroperitoneal lymph node dissection (RPLND), or radiation therapy were also collected. Data on survival were retrieved from the country cancer registry, which has up-to-date information on survival of patients even if they were lost to follow-up. The cancer registry in Jordan is linked to the Ministry of Interior, and death reports are updated daily.
Statistical analysis
Continuous variables were described with mean and interquartile range (IQR), whereas categorical variables were described with count and percentage. For normally distributed continuous variables, independent-T test was used to test for significance, while for categorical variables, Chi-squared test was used to test for significant association between an independent (predictor) and dependent (outcome) variables. Two-sided statistical significance was set at P-value <0.05 for all variables. All analyses were conducted using the statistical analysis software platform (IBM SPSS) For MAC version 28.0.0.0 (SPSS, Chicago, IL, USA).
Results
Patient and tumor characteristics
A total of 241 patients diagnosed with GCT of the testis were included in this study with a median (IQR) age at diagnosis of 31 years (25–36). Forty-seven percent of the patients had tumors on the right, while 52% had tumors on the left, whereas synchronous bilateral involvement was seen in less than 1% of cases. (Table 1) Moreover, 210 (87%) patients diagnosed with GCT were <40 years of age, while only 31 (13%) were ≥40 years of age (Table 2).
Table 1.
Clinical characteristics of patients with testicular germ cell tumors.
| N | % | Median (IQR) | |
|---|---|---|---|
| All GCT | 241 | 100% | 31 (25–36) |
| Seminoma | 108 | 44.8% | 32 (28–38) |
| pTx | 6 | 5.6% | 37.5 (28–40) |
| pT1 | 74 | 68.5% | 32.5 (29–37) |
| pT2 | 26 | 24.1% | 30.5 (25–39) |
| pT3 | 2 | 1.9% | 35 |
| Non-seminoma | 133 | 55.2% | 30 (25–34.5) |
| pTx | 8 | 6% | 31.5 (24–36) |
| pT1 | 50 | 37.5% | 29 (25–34) |
| pT2 | 64 | 48.1% | 30 (25–34) |
| pT3 | 10 | 7.5% | 36 (23–36.5) |
| pT4 | 1 | 0.8% | 29 |
| Stages of GCT | 241 | 100% | 31 (25–36) |
| Stage I–III | 234 | 97% | 31 (25–36) |
| Unknown stage | 7 | 3% | 30 (28–39) |
| Stage I | 130 | 54% | 31 (26–36) |
| Ia | 79 | 33% | 32 (28–37) |
| Ib | 41 | 17% | 28 (24–33) |
| IS | 10 | 4% | 31.5 (26–37) |
| Stage II | 59 | 24.5% | 32 (26–38) |
| IIA | 27 | 11.2% | 31 (26–36) |
| IIB | 15 | 6.2% | 29 (26–34) |
| IIC | 17 | 7.1% | 34 (28–41) |
| Stage III | 45 | 18.7% | 31 (23–36) |
| IIIx | 15 | 6.2% | 31 (23–34) |
| IIIA | 11 | 4.6% | 32 (28–34) |
| IIIB | 1 | 0.4% | 36 |
| IIIC | 18 | 7.5% | 28 (21–36) |
| Laterality | |||
| Right | 82 | 34% | 31 (25–36) |
| Left | 91 | 37.8% | 31 (26–36) |
| Bilateral synchronous | 1 | 0.4% | 25 |
| Unknown | 67 | 27.8% | 31 (26–37) |
GCT, germ cell tumor; CS, clinical stages; IQR, interquartile range; pT, pathological; NS, nonseminoma. IIIx = stage III (not subclassified as A, B, or C)
Table 2.
Comparison of age groups <40 and ≥40 years.
| <40 | ≥40 | P-value | |
|---|---|---|---|
| All GCT | 210 (87%) | 31 (13%) | |
| Seminoma | 89 (82%) | 19 (18%) | 0.048 |
| Non-seminoma | 121 (91%) | 12 (9%) | |
| Pathological stage (all) | 148 | 17 | |
| pT1 | 107 (53.8%) | 17 (60.7%) | <0.0001 |
| >pT1 | 92 (46.2%) | 11 (35.7%) | |
| Stage I | 117 (57.4%) | 13 (43%) | 0.15 |
| Stage II and III | 87 (42.6%) | 17 (57%) | |
| Seminoma | |||
| pT1 | 63 (74%) | 11 (64.7%) | 0.42 |
| >pT1 | 22 (26%) | 6 (35.3%) | |
| Stage I | 65 (76%) | 11 (61%) | |
| Stage II | 17 (19%) | 4 (22%) | |
| Stage III | 4 (5%) | 3 (17%) | |
| Non-seminoma | |||
| pT1 | 44 (38.6%) | 6 (54.5%) | 0.30 |
| >pT1 | 70 (61.4%) | 5 (45.5%) | |
| Stage I | 52 (44%) | 2 (17%) | |
| Stage II | 31 (26%) | 7 (59%) | |
| Stage III | 35 (30%) | 3 (24%) |
Horizontal boxes denote relative proportions (%) of clinical characteristics in age groups <40 and ≥40 years.
A total of 108 (44.8%) patients had seminoma, while 133 (55.2%) had non-seminoma tumors (NSGCT). The median age (IQR) for the seminoma group was 32 years (28–38), while the latter had a median age (IQR) of 30 years (25–34.5) (Table 1). The majority of patients with seminoma (68.5%) had pT1 disease post radical orchiectomy, while only 37.5% of patients with NSGCT had pT1 on final pathology. Elevated tumor markers such as beta-human chorionic gonadotropin were present in 10% of seminomas. To note, the NSGCT group had a higher percentage of initial presentation with elevated markers (Table 3).
Table 3.
Comparison of seminoma with non-seminoma, excluding pTx.
| Parameter | Seminoma (n = 108) | Non-seminoma (n = 133) | P-value |
|---|---|---|---|
| Average age | 32 | 30 | P = 0.003 |
| Proportion of pT1 n (%) | 74 (68.5%) | 50 (37.5%) | P < 0.0001 |
| Positive serum markers | 11 (10%) | 32 (24%) | P = 0.006 |
| Elevated β-HCG n (%) Normal range <5 IU/I |
8 (7.4%) | 23 (17.2%) | P = 0.032 |
| Elevated AFP n (%) Normal Range <40 µg/I |
0 | 17 (12.8%) | P < 0.0001 |
IQR, interquartile range; CS, clinical stages; pT, pathological; β-HCG, beta-human chorionic gonadotropin; AFP, alpha-fetoprotein; LDH, lactate dehydrogenase
Histopathology and second specialized pathology review
Of the 212 slides reread by a genitourinary pathologist at KHCC, a discrepancy rate of 19.8% was found. Forty-one patients had different pathology classification upon rereading. A total of 14 (6.6%) patients with seminoma were reclassified as NSGCT, and 7 (3.3%) NSGCT were reclassified as seminoma. In addition, seven patients with mixed GCT were reclassified as embryonal (5) and teratoma (2) subtypes (Table 4).
Table 4.
Congruence and discrepancy between the pathology slides read outside and the ones reread at KHCC, by an expert GU genitourinary pathologist.
| Type of histology | Original histology (N = 241) | Reread histology (N = 212) |
|---|---|---|
| Seminoma | 112 (46.4%) | 92 (43.4%) |
| Non-seminoma | 121 (50%) | 120 (56.6%) |
| Other | 8 (3.3%) | 0 |
| Discrepancy rate [N = 41 (19.3%)] of the patients | ||
| Seminoma → To NSGCT | 14 (6.6%) | |
| NSGCT → To seminoma | 7 (3.3%) | |
| NSGCT → NSGCT | N = 12 (5.6%) | |
| (Mixed → Embryonal) | 5 | |
| (Mixed → Teratoma) | 2 | |
| (Embryonal → Mixed) | 3 | |
| (Yolk → Mixed) | 1 | |
| (Teratoma → Mixed) | 1 | |
| Other → Seminoma or NSGCT | N = 8 (3.7%) | |
| (Intratubular germ cell → Seminoma) | 1 | |
| (Germinoma → Seminoma) | 2 | |
| (Germinoma → Mixed) | 4 | |
| (Germinoma → Embryonal) | 1 | |
Treatment and outcomes
Following radical orchiectomy and staging, 153 (63.4%) patients received adjuvant treatment, whereas 88 (36.5%) patients underwent active surveillance. Among the former group, chemotherapy was the most common type of adjuvant therapy administered with the majority receiving a bleomycin, etoposide, and platinum combination (108/125). Adjuvant radiotherapy was administered to 22 (9.1%) patients, and adjuvant chemoradiation was administered to 6 (2.5%) patients (Table 5). The median (IQR) follow-up was 36 (24–48) months where 22 patients relapsed after an average follow-up time of 39 months. In contrast, 173 patients did not recur over a 5-year period while 46 (19%) patients were lost to follow-up. In addition, 6 patients with seminoma and 19 with NSGCT underwent salvage RPLND (Table 6). Five-year overall survival (OS) for stages I, II, and III is 98%, 94%, and 87%, respectively, and 3-year recurrence-free survival (RFS) for stages I, II, and III is 94.8%, 78%, and 67%, respectively (Figures 1 and 2).
Table 5.
Management post radical orchiectomy, active surveillance, types of adjuvants treatments, and recurrence.
| Adjuvant course | |
|---|---|
| Surveillance | 88 (36.5%) |
| Radiation | 22 (9.1%) |
| Chemotherapy | 125 (52%) |
| BEP | 108 |
| BEP + other | 8 |
| TIP or VIP | 4 |
| Other | 5 |
| Chemo radiation | 6 (2.5%) |
| BEP | 4 |
| Other | 2 |
| Recurrence | 22 |
| No recurrence | 173 |
| Loss to follow-up | 46 (19%) |
Table 6.
Adjuvant treatment, recurrence, and survival of testicular germ cell tumors divided by stages and histology.
| Histology |
||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Seminoma | Non-seminoma | Ia | Ib | Is | IIa | IIb | IIc | III (IIIa-IIIc) |
Unknown stage |
|
| Seminoma | 56 (53.8%) |
18 (17.3%) | 2 (1.9%) |
9 (8.7%) |
4 (3.8%) |
8 (7.7%) |
7 (6.7%) |
4 | ||
| Non-seminoma | 23 (17.7%) |
23 (17.7%) |
8 (6.2%) |
18 (13.8%) |
11 (8.5%) |
9 (6.9%) |
38 (29.2%) |
3 | ||
| No adjuvant treatment | 50 (46.3%) |
38 (28.6%) | 48 (60.8%) |
21 (51.2%) |
7 (70%) |
2 (7.4%) |
2 (13.3%) | 2 (11.8%) | 2 (4.4%) |
4 (57.1%) |
| Chemotherapy | 32 (29.6%) |
93 (69.9%) | 18 (22.8%) | 15 (36.6%) |
3 (30%) |
22 (81.5%) |
10 (66.7%) | 14 (82.4%) |
42 (93.3%) | 1 (14.3%) |
| Radiation | 22 (20.4%) |
0 | 12 (15.2%) |
5 (12.2%) |
0 | 2 (7.4%) |
2 (13.3%) |
0 | 0 | 1 (14.3%) |
| Chemo radiation | 4 (3.7%) |
2 (1.5%) |
1 (1.3%) |
0 | 0 | 1 (3.7%) |
1 (6.7%) |
1 (5.9%) | 1 (2.2%) |
1 (14.3%) |
| RPLND | 6 (5.6%) |
19 (14.3%) | ||||||||
| Death | 3 (2.8%) |
8 (6%) |
||||||||
| Survival | 105 (97.2%) |
125 (94%) |
||||||||
Figure 1.
Overall survival of patients with GCT by stage.
Figure 2.
Recurrence-free survival of GCT tumor patients by stage.
Discussion
Testicular GCT represents a heterogeneous group of neoplasms with different pathologies, incidences, prognosis, and management. While the demographics of GCT and treatment outcomes are well studied in developed countries, there are minimal data about GCT in the Middle East. There are few retrospective cohorts with a limited sample population from Lebanon, Egypt, Turkey, and Saudi Arabia [9–11,13–16]. We herein present the largest single-center series in the Middle East, presenting epidemiologic and treatment outcomes of a total of 241 patients with GCT of which 108 (44.8%) were diagnosed with seminoma and 133 (55.2%) with NSGCT.
Data from western developed countries revealed that the majority of GCT are seminoma tumors (range 50–57%) [17–20]. Similarly, Surveilance, Epidimiology and End Results (SEER) data also show a higher percentage of seminoma to NSGCT [10,15], whereas our series had a higher percentage of NSGCT (55.2%) compared to seminoma (44.8%). This was also different to the already published literature from the Middle Eastern region where data from Lebanon and Saudi Arabia revealed a higher percentage of seminoma compared to non-seminoma. One plausible explanation lies in the nature of our cohort that fails to capture the incidence of testicular cancer on a national level but rather limits its registry to those patients that have been referred to our tertiary referral cancer center; hence, a biased referral of the more complex NSGCT cases could have swayed the incidence rate in favor of NSGCT. Interestingly, data from other referral centers in under-developed countries such as Pakistan and Morocco revealed similar higher rates of NSGCT [21,22]. The median age (IQR) for all GCT was 31 (25–36) years. For seminoma, the median age (IQR) at diagnosis was 32 (28–38) years, while the median age (IQR) for NSGCT was 30 (25–34.5) years. While both groups reveal a high incidence of diagnosis in young adults, NSGCT patients presented earlier with an average age of 32 compared to 30, P = 0.003 (Table 2). The age of presentation of GCT patients along with the presentation age of the two different subtypes was similar to the already published data from around the globe [11,23]. Nevertheless, several cohorts report various ranges of age presentation specially with NSGCT. For instance, the mean age of NSGCT in Pakistan and the US was reported to be 23 and 25 years, respectively, whereas in Germany, it was 31 years [21,23].
It is without doubt that for GCT patients, age at presentation is of utmost importance when it comes to survival rates. The sooner the age of presentation, the higher chances of survival [7,24]. In fact, testicular cancer mortality doubles in those diagnosed at age 40+ [24]. In our data, 18% of seminoma patients initially presented at 40 years of age or above, whereas less than 9% of patients with NSGCT initially presented at 40 years of age or above (Table 3).
High levels of awareness play a major role in early detection of testicular tumor [25]. Reports in the region reveal that the majority of GCT patients present for treatment early in their disease with the majority revealing that most initially present with localized disease [11,15,16]. Compared with seminoma patients, a higher percentage of patients with NSGCT are diagnosed with regional or distant disease on presentation. Our cohort revealed that 17% of seminoma patients presenting at age 40 or above had metastatic disease, whereas 24% of NSGCT aged 40 or older had metastatic disease. This further strengthens the association between age of presentation and OS.
Our cohort demonstrated a slightly higher incidence of left-sided testicular involvement (52%). As cryptorchidism is more common on the right side, several studies revealed a side discrepancy favoring the development of testicular cancer on the right side [10, 26]. Such discrepancy could be explained by our relatively small sample size. Furthermore, the rate of bilateral testicular cancer in our series was low encompassing to 0.4% of patients. This was in line with previously published series revealing a rate as low as 0.6% [27,28].
Our institutional protocol mandates a confirmatory pathology review by an experienced genitourinary pathologist if orchiectomy was done outside, prior to the initiation of any treatment modality. Our data revealed a 19.8% discrepancy rate between original pathology reports and those reread by the specialized pathologist. Fifteen (7%) patients who were initially read as seminoma were reread as NSGCT, while seven patients who were initially read as NSGCT were reread as seminoma. In addition, seven patients read as mixed were reread as embryonal and teratoma tumors. Nason et al. reported that among specimens from the Ontario Cancer Registry who underwent a second pathology review, 40% yielded significant changes in pathological parameters such as T stage and lymphovascular invasion (LVI), whereas the rate of histopathological subtype change was 5.4% [29]. Another study by Harari et al. in 2017 showed a histopathological discrepancy rate of 31% [30]. These significant levels of histopathological discrepancies strengthen the role of a secondary confirmatory review by genitourinary specialist pathologist, especially that treatment strategies in testicular cancer are highly influenced by stage of disease and pathological subtype.
GCT management protocols involve post-surgical staging upon which adjuvant treatment versus rigorous active surveillance is decided. In our cohort, 64% of patients received adjuvant treatment including chemotherapy (52%), radiation (9.1%), and chemoradiation (2.5%), with 5-year OS of 97% (Figure 1). In other countries such as Spain, adjuvant chemotherapy is at an almost similar rate of 50% [31]. For stages Ia and Ib, 39.2% and 48.8% of patients underwent adjuvant treatment, respectively. For those with stage I seminoma, 43% underwent adjuvant treatment with a recurrence rate of 2.6%, whereas those with stage I non-seminoma, 42% underwent adjuvant chemotherapy with a recurrence rate of 4.7%. Compared to other series, ours revealed a slightly higher percentage of stage I patients receiving adjuvant treatment, and lower recurrence rate. In other series, this increased tendency for adjuvant chemotherapy in stage I is prevalent in third world countries where there is significant cost for meticulous follow-up and low compliance in active surveillance [11,32]. Another reason might be the higher presence of LVI in our sample population which we did not account for in our series.
This study has several limitations. The retrospective nature of the study limits short interval follow-up. Although this is the largest series in the Middle East, the sample size is still small compared to some of the larger series in North America and Europe. In addition, our loss to follow-up rate is relatively high at 19%; nevertheless, we believe this study is noteworthy with good inputs on treatment of GCT in the Middle East; however, this region needs larger multicenter studies to further understand the nuances of treatment of GCTs according to stage, especially in areas with limited access to adjuvant treatment.
Our histopathologic, demographic, and survival data are commensurate with those from around the world. This reinforces the fact that GCT remains a curable solid tumor disease of the young with excellent survival rates if diagnosed promptly and treated accordingly. As such, it is of utmost importance that genitourinary pathologists, when available, confirm subtype classification of testicular tumors prior to initiation of treatment modalities.
Authors contributions
Study conception and design: M. Shahait, El-Achkar
Data collection: Al asadi, R. Abu-Hijlih, F. Abu-Hijle, A. Al-ibraheem, J. Khzouz
Analysis and interpretation of results: El-Achkar, M. Shahait
Draft manuscript preparation: El-Achkar, J. el Asmar A. Armach
All authors reviewed the results and approved the final version of the manuscript.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Data availability statement
All the data generated or analyzed during this study are not publically avaialbe; however, they are availabe upon editor / reviewer request.
Statement of ethics
An ethics statement is not applicable because this study is based exclusively on published literature.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
All the data generated or analyzed during this study are not publically avaialbe; however, they are availabe upon editor / reviewer request.