Concomitant presentation of histologically distinct bilateral, synchronous testicular tumors is exceedingly rare. This study reports the case of a 45-year-old male who presented with a left testicular mass. He was found to have bilateral testicular tumors: in testicular left heterogeneous mass and in right testicular ill-defined hypoechoic pseudonodular image on ultrasound scan and underwent bilateral orchiectomy. He underwent bilateral radical orchiectomy, leaving him in a state of anorchia. Left testicular pathology revealed malignant mixed germ cell tumor consisting of immature teratoma-85%, endodermal sinus-10% and embryonal carcinoma-5%; right testicular pathology revealed Leydig cell hyperplasia (nodular and diffuse). For the right testicular tumour, he received adjuvant treatment with two cycles of BEP (bleomycin, etoposide, and cisplatin) and hormone replacement therapy with intramuscular testosterone. Our case demonstrates the rare occurrence of bilateral primary synchronous testicular tumors with different histopathology in each testis. We would like to underscore the importance of testicular tumor markers, ultrasound, computed tomography, and MRI in the diagnosis, characterization, and staging of these tumors. Despite the rarity of this condition, its treatment is based on standard management of unilateral testicular carcinoma, with the added element of prioritization of one tumor over the other. It is important for clinicians to tailor management for bilateral testicular germ cell tumors according to the most aggressive component.

Testicular germ cell tumors (TGCTs) are more common in Caucasian men than African American men [1]. Global incidence rates for TGCTs are higher in Northern Europe and lower in Northern and sub-Saharan African countries [2]. Nonseminomas account for 44% of  GCTs; they are the most common solid malignancies in young males, particularly those aged 15 to 35, with germ cell tumors (GCTs) comprising the majority of cases, with non-seminomatous germ cell tumors (NSGCTs) representing a significant subset characterized by aggressive behavior and elevated tumor markers; laboratory investigations showed significantly elevated tumor markers, including Alpha-fetoprotein (AFP) and Beta-human chorionic gonadotropin (βHCG), raising suspicion for a malignant testicular tumor, histopathological exams are importants, to define the histopathological type of tumor, these are: Sal-like protein 4 (SALL4); Placental Alkaline Phosphatase  (PLAP), celular kit (c-kit), and Vimentin [2, 3]. Bilateral primary synchronous testicular tumors (BPSGCTs) are a relatively uncommon occurrence, especially when they involve GCTs of different histology [4]. Bilateral testicular germ cell tumors (BTGCTs) occur in 1 to 4% of patients with testicular cancer and, of these, 10-15% are synchronous. Overall, BTGCTs represents less than 0.5% of all new cases of testicular cancer. There are few reports in the literature of synchronous BTGCTs with different histology [5].

Testicular teratoma is a germ cell-derived neoplasia composed of various somatic tissues and can arise from 1 or more germinal layers (endoderm, mesoderm, and ectoderm). The vast majority of adult testicular teratomas are malignant TGCTs. Teratoma accounts for about 3% to 7% of NSGCTs and about 50% of mixed TGCTs. Metastatic tumors do not respond well to chemotherapy, and the goal is to achieve a complete surgical resection [6].

Endodermal sinus tumor (EST), also known as yolk sac tumor (YST), is a rare type of germ cell cancer. It is the most common malignant testicular tumor in children under 2 to 3 years old (accounting for up to 80% of pediatric cases), although in adults it usually occurs as part of mixed tumors [7]. 

TGCTs are the most common solid malignancies in young males, NSGCTs representing a significant subset characterized by aggressive behavior and elevated tumor markers [3].

Embryonal carcinoma is the most frequent tumor component of testicular mixed GCT, present in ~80 - 90% of cases. Eighty percent or more of embryonal carcinoma component and vascular invasion are recognized predictors of occult metastasis for clinical stage I mixed GCTs [8].

Leydig cell hyperplasia is a rare benign condition characterized by small, multifo-cal testicular nodules that are frequently bilateral. Its form can be primary or secondary. The former produces precocious puberty in boys and the latter presents as a testicular mass andproduces gynecomastia in approximately 30% of the patients as a result of idiopathic supraphy-siologic hormone stimulation, and has clinical manifestations similar to those of Leydig celltumors [9]. 

In our manuscript, we describe a clinical case with rare occurrence of bilateral primary synchronous testicular tumors with different histopathology in each testis in adult patient of 45 years olg age. When reviewing literature, we found several publications describing clinical cases of testicular cancer with this presentation.

45-year-old man with a history of treatment with ciprofloxacin 500 mg every 12 hours for 7 days for acute epididymitis. In physical examination: right testicle normal, enlarged left testicle, erythematous, painful on palpation, not adherent to the skin, indurated.

He is seen in the Urology clinic after 15 days of treatment with anti-inflammatory and antibiotics for follow-up, where it is noted that after discontinuing the antibiotic, he has again developed scrotal-testicular discomfort and pain in the left inguinal region. On physical examination, the right testicle is normal; the left testicle is hard, hardened and painful, with induration extending to the spermatic cord.

A scrotal and testicular ultrasound scan is ordered (Figure. 1): Right testicle with normal morphology and size, homogeneous echotexture, with a vascularized hypoechoic nodular lesion located in posterior side of 7 mm. Right epididymis is normal. Left testicle is enlarged, with a parenchymal disorganization, heterogeneous appearance containing lobulated and anechoic areas, raising the need to rule out granulomatous orchitis, lymphoma, or a primary tumor. This is associated with thickening of the testicular coverings. At the paratesticular level, a comma-shaped hypoechoic image is observed, suggestive of an enlarged epididymis.

Figure 1: Right testicle with normal morphology and size, homogeneous echotexture, with a vascularized hypoechoic nodular lesion located in posterior side. Enlarged left testicle with a disorganized, parenchymal disorganization, heterogeneous appearance, containing lobulated and anechoic areas. Associated thickening of the testicular coverings is present.

Testicular tumor markers: Serum alpha-fetoprotein (AFP) 1.126.8 ng/mL; β-human chorionic gonadotropin (β-hCG): 452.2 mIU/mL; Lactate dehydrogenase (LDH): 382 U/L.

Based on these findings, surgical treatment consisting of a left radical orchiectomy was performed. Histopathological examination of the surgical specimen revealed a malignant mixed GCT (85% immature teratoma, 10% yolk sac tumor, and 5% embryonal carcinoma).

Thoracoabdominal-pelvic computed tomography (CT): no radiological evidence of local or distant metastases.

The patient was referred to Oncology for further treatment: left radical orchiectomy, non-seminomatous testicular tumor, pT1 N0 M0 S2. He received adjuvant treatment with two cycles of BEP (bleomycin, etoposide, and cisplatin).

After completing adjuvant chemotherapy yhe laboratory tests: serum β-hCG  <1>

The patient also remains under follow-up because of the ultrasound finding of a 7 mm nodule in the right testicle.

Scrotal and testicular ultrasound scan (Figure. 2): Compared with the previous study, no significant changes are observed. Right testicle measuring 29× 12×21 mm. Right epididymal head measuring 4×4 mm. The right testicle shows a homogeneous echotexture with a poorly defined hypoechoic pseudonodular lesion located in its posterior peripheral margin, without color Doppler flow, measuring approximately 4–5 mm, with no apparent changes compared with the reference study. The scrotal coverings are not thickened. There is no hydrocele or significantly enlarged inguinal lymph nodes.

Figure 2: Ultrasound of the right testicle: Testis with homogeneous echotexture and a poorly defined hypoechoic pseudonodular lesion located in the posterior peripheral margin, without color Doppler flow, measuring approximately 4–5 mm.

Laboratory tests: β-human chorionic gonadotropin (β-hCG) <1>

For better characterization of this lesion, a Magnetic Resonance Imaging (MRI) scan of the male genital tract was requested (Figure. 3). Contrast-enhanced study: Left orchiectomy. No nodular lesions are seen in the surgical bed to suggest local recurrence. Right testis measures 2×2.7×2.1 cm. Two small rounded intratesticular lesions are identified: one measuring 3 mm in the anterior region of the testis and another measuring 5 mm in the posterior region. Both are homogeneously hypointense on 

T2-weighted images and show marked early enhancement after intravenous contrast (IV contrast) administration. The diffusion-weighted sequence was degraded by artifacts. Given the patient's history and the above findings, malignancy cannot be ruled out. No pelvic lymph nodes of abnormal size or morphology are identified. In conclusion:

Two rounded focal lesions measuring 3 mm and 5 mm are identified in the right testis. They are hypointense on T2-weighted imaging and demonstrate enhancement after IV contrast administration; therefore, given the patient's history, malignancy cannot be ruled out.

Figure 3: MRI of the male genital tract. Two rounded focal lesions measuring 3 mm and 5 mm are observed in the right testis. They are hypointense on T2-weighted imaging and show enhancement after intravenous contrast administration (IV contrast); therefore, given the patient's medical history, malignancy cannot be ruled out.

The staging thoracoabdominal CT scan showed: true bilateral gynecomastia. No masses or hilar or mediastinal lymphadenopathy were observed. No masses, nodules, consolidations, or other pathological findings were seen in the lung parenchyma. No pleural effusion was identified. Diffuse hepatic steatosis, with no findings suggestive of metastatic disease. Postsurgical changes in the left inguinal canal, with no lymphadenopathy observed.

Based on these findings, a right radical orchiectomy was performed. The pathological examination of the surgical specimen revealed nodular and diffuse Leydig cell hyperplasia of the right testis.

The patient remains anorchic (hypergonadotropic hypogonadism), under follow-up by Oncology and in the specialized Testicular Cancer (Urology) clinic. The patient is a candidate for testosterone replacement therapy with intramuscular testosterone. Free and total testosterone levels, as well as prostate serum antigen (PSA) levels, should be determined before initiating hormone replacement therapy. Treatment with testosterone 1,000 mg every 3 months was prescribed.

Bilateral synchronous primary testicular germ cell tumors (BSPGCTs) are a relatively uncommon occurrence, especially when they involve TGCTs of different histology. The case of a 20-year-old male who presented with a left testicular mass has been published. He was found to have bilateral testicular masses on ultrasound and underwent bilateral orchiectomy. Left testicular pathology revealed a mixed germ cell tumor consisting of teratoma, seminoma, and germ cell neoplasia in situ; right testicular pathology revealed two foci of pure seminomas. He is currently on active surveillance and remains in remission at 18-month follow-up. The BSPGCTs with different histopathology in each testis is the rare occurrence. Despite the rarity of this condition, its treatment is based on standard management of unilateral testicular carcinoma, with the added element of prioritization of one tumor over the other. It is important for clinicians to tailor management for bilateral BPSGCTs according to the most aggressive component [10].

Others authors described a case of a male patient who was diagnosed with BPSGCTs, with one being a seminoma and the other a NSGCT. The coexistence of two distinct histological types, seminoma and NSGCT, necessitates a comprehensive diagnostic approach to accurately identify and characterize each tumor. This underscores the importance of clinical history, physical examination, imaging techniques, and histopathological analysis to establish an appropriate diagnosis. Careful consideration must be given to factors such as tumor stage, histological subtype, and individual patient characteristics to determine the most suitable treatment strategy. Treatment options may encompass a combination of surgery, chemotherapy, and radiation therapy, tailored to each tumor's specific characteristics and the patient's overall health [4].

In the study of Talerman (1980) [7], in which the cases of pure seminoma were excluded, the results indicate that EST elements occur quite frequently in testicular germ-cell neoplasms in adults and provide an explanation for the raised levels of serum AFP found in many adults with TGCTs. The results emphasize the importance of a thorough and careful pathologic examination of TGCTs, and the value of AFP as a tumor marker in patients with EST (YST). The results also provide further support for the view that EST (YST) elements found in testicular germ-cell tumors in adults are homologous with infantile EST (YST) and that EST (YST) is a distinctive and specific type of germ-cell neoplasm and should be included as such in the classification of testicular tumors. 

Symeonidis et als. (2023) [11] describe a case of a 20-year-old male complaining of a palpable painless right testicular mass incidentally noticed during sexual intercourse. Ultrasoud  and IMR of the scrotum demonstrated bilateral testicular lesions, while staging with contrast-enhanced CT scan exhibited normal findings. Right radical orchiectomy and left testis-sparing surgery with concomitant onco-testicular sperm extraction (onco-TESE) were initially performed. Histology of the right testis revealed a mixed germ-cell tumor, consisting of seminoma and embryonal carcinoma, while that from the left testis disclosed embryonal carcinoma and intratubular germ-cell neoplasia unclassified (IGCNU) infiltrating the surgical margins. Left orchiectomy was subsequently scheduled with histology unveiling IGCNU in the greatest part of the remaining testicular parenchyma. Following adjuvant chemotherapy with BEP, the patient received testosterone replacement therapy and remained free of recurrence at an 18-month follow-up. The authors conclude that this case highlights both the rarity of a bilateral testicular tumor's synchronous appearance and its extremely uncommon discordant histopathology.

10 to 15% of BTGCTs are synchronous, it is reported a case of a 30-year-old male patient who presented with a bilateral increase in testicular volumen. A testicular ultrasound showed the presence of solid tumors in both testes. Staging studies were negative for metastatic disease.  It is subjected to bilateral radical orchiectomy. The histopathology evaluation revealed a right-sided mixed germ cell tumor and a left-sided testicular seminoma. Suffers a recurrence it is subjected to adjuvant chemotherapy one cycle BEP was favored. After four years of follow up, the patient shows no evidence of relapse [5].

Others authors propose that testicular cancer, accounting for 1-1.5% of male malignancies, rarely presents bilaterally, with only 2-3% of cases being bilateral and a mere 10?ing synchronous, typically sharing histological patterns in both testes. Discordant histological presentation is exceedingly rare, with few reported cases. In this report, we detail a case involving a 35-year-old infertile male with bilateral synchronous testicular tumors, each exhibiting different histopathologies (embryonal carcinoma; seminoma; testicular germ cell tumor). This case highlights the diagnostic intricacies and the necessity for tailored management with regard to such uncommon presentations. The implications of oncological treatment and fertility preservation significantly affect the patient's overall quality of life [12].

Özen et als. (2024) [13] claim that most bilateral tumors are observed metachronously. Synchronous tumors usually present with the similar histological pattern. Bilateral synchronous testicular tumors with discordant pathology are extremely rare. Only 56 cases have been documented since Bidard first described synchronous testicular tumors with discordant pathology in 1853. 

It has also been published a rare case of synchronous bilateral testicular spermatocytic tumor, typically presents as a unilateral, slow-growing mass in older men. A case has been presented in patient of a 54-year-old man with painless bilateral scrotal swelling. Imaging revealed heterogeneous masses in both testes, and laboratory findings were within normal limits. Left high orchiectomy revealed polygonal cells with clear cytoplasm, initially suggesting seminoma. Given the patient's age and histological features, immunohistochemistry was performed. A right high orchiectomy was subsequently conducted. Both tumors were diagnosed as spermatocytic tumors based on Sal-like protein 4 (SALL4) positivity; Placental Alkaline Phosphatase (PLAP), celular kit (c-kit), and Vimentin negativity. Developed postoperative hypogonadism and began testosterone replacement therapy. No recurrence was observed during 1-year follow-up. These authors conclude that the immunohistochemistry is essential for accurate identification of spermatocytic tumor [14, 15, 16].

Metachronous BTGCT with different histopathology is a rare disease. The treatment depends on histology of second tumor and its stage. The treatment of choice is bilateral orchiectomy. The positron emission tomography (PET)/computerized tomography CT scan post-operative imaging and testicular tumor marker are important for identify metastases. Digital rectal examination should be measured three to six weeks after initiation is mandatory for patient undergoing bilateral orchidectomy to address lack if testosterone. The treatment includes BEP chemotherapy, testosterone replacement therapy. For further management in this patient controls with complete blood count, PSA and digital rectal examination should be measured three to six weeks after initiation [17].

Ginting et als (2023) [18] in their publication, they emphasize that the combined treatment of surgery and chemotherapy was well tolerated by the patient and offered an excellent clinical outcome. The study highlights the rarity of these cases and mentions that investigating the mechanisms of cell communication (through chemokines) between different types of tumor cells in bilateral presentations could open new frontiers in the study of response to chemotherapy. The authors point out that there is currently no single consensus or standardized guideline for the management of bilateral synchronous testicular cancer, so these cases often require a personalized approach.

Testicular germ cell tumors (TGCTs) can be treated with cisplatin-based therapy. However, a clinically significant number of cisplatin-resistant patients die from progressive disease as no effective alternatives exist. Curative cisplatin therapy results in acute and life-long toxicities in the young TGCT patient population providing a rationale to decrease cisplatin exposure. In contrast to genetic alterations, recent evidence suggests that epigenetics is a major driving factor for TGCT formation, progression, and response to chemotherapy. Hence, targeting epigenetic pathways with "epidrugs" is one potential relatively unexplored strategy to advance TGCT treatment beyond cisplatin. In this report, we demonstrate for the first time that targeting polycomb demethylases KDM6A and KDM6B with epidrug GSK-J4 can treat both cisplatin-sensitive and -resistant TGCTs. While GSK-J4 had minimal effects alone on TGCT tumor growth in vivo, it dramatically sensitized cisplatin-sensitive and -resistant TGCTs to cisplatin. We validated KDM6A/KDM6B as the target of GSK-J4 since KDM6A/KDM6B genetic depletion had a similar effect to GSK-J4 on cisplatin-mediated anti-tumor activity and transcriptome alterations. Pharmacologic and genetic targeting of KDM6A/KDM6B potentiated or primed the p53-dominant transcriptional response to cisplatin, with also evidence for basal activation of p53. Further, several chromatin modifier genes, including BRD4, lysine demethylases, chromodomain helicase DNA binding proteins, and lysine methyltransferases, were repressed with cisplatin only in KDM6A/KDM6B-targeted cells, implying that KDM6A/KDM6B inhibition sets the stage for extensive chromatin remodeling of TGCT cells upon cisplatin treatment. Targeting polycomb demethylases has been shown to be a potent new pharmacologic strategy for treating cisplatin-resistant TGCTs that warrants clinical development [19].

According to various studies several biomarkers are usefully utilized to discriminate among different histotypes. Moreover, we found new patents regarding testicular germ cell tumor treatments such as the expression of claudin 6, monoclonal antibody (Brentuximab Vedotin), immune checkpoint blockade (ICB) with the FDA-approved drugs pembrolizumab and nivolumab or the oncolytic virus Pelareorep, the combination of selective inhibitors of Aurora kinase. The pathogenesis of testicular germ cell tumor needs to be deeply understood so that it will improve data on stem cells, tumorigenesis and disease tumor management by more selective treatment [20].

BTGCT occur in 1 to 4% of patients with testicular cancer and of these, 10-15% are synchronous. Overall, BTGCT represents less than 0.5% of all new cases of testicular cancer. There are few reports in the literature of synchronous BTGCT with different histology.

Bilateral synchronous testicular tumors are a relatively uncommon occurrence, especially when they involve germ cell tumors of different histology.

GCTs are the most common solid malignancies in young males, NSGCTs representing a significant subset characterized by aggressive behavior and elevated tumor markers (AFP, βHCG). The Clinical history, physical examination, imaging techniques (ultrasound, CT, PET CT, IMR), and histopathological and and immunohistochemistry analysis are essential to establish an appropriate diagnosis. It is important for clinicians to tailor management for BTGCT according to the most aggressive component. Embryonal carcinoma is the most frequent tumor component of testicular mixed GCT, present in ~80 - 90% of the cases. In patients with EST (YST), the most appropriate tumor marker is AFP. Leydig cell hyperplasia is a rare benign condition characterized by small, multifo-cal testicular nodules.  The gold standard of treatment in these cases is bilateral radical orchiectomy complemented with chemotherapy (BEP), radiotherapy according to the histological type and stage, with testosterone replacement therapy being necessary in many patients to treat the effects of postoperative hypogonadism.  A clinically significant number of cisplatin-resistant patients die from progressive disease as no effective alternatives exist. Modulating epigenetic pathways with epigenetic drugs is a potential, relatively unexplored strategy to advance the treatment of TGCT beyond cisplatin. Targeting polycomb demethylases has been shown to be a potent new pharmacologic strategy for treating cisplatin-resistant TGCTs that warrants clinical development. Other therapies that are being established include monoclonal antibodies (Brentuximab Vedotin), immune checkpoint blockade (ICB) with the FDA-approved drugs pembrolizumab and nivolumab, or the oncolytic virus Pelareorep, a combination of selective inhibitors of Aurora kinase.

The authors declare no competing interests.