Introduction

Testicular tumors are uncommon malignancies, accounting for approximately 1–2% of all male cancers and about 5% of urological tumors. The majority of testicular neoplasms occur in younger males between the ages of 15 and 35 years; germ cell tumors constitute nearly 95% of cases. In contrast, in men over the age of 60 years, the incidence and histological profile differ significantly (1, 2). Although primary testicular lymphoma (PTL) is a rare malignancy, representing nearly 1–9% of all testicular tumors and 1–2% of all non-Hodgkin lymphomas (3), it deserves special attention because of its aggressive clinical course and poor prognosis compared to other testicular malignancies.
Diffuse large B-cell lymphoma (DLBCL) represents the predominant histological subtype of PTL, comprising approximately 80–90% of cases. Rarely, high-grade B-cell lymphomas with overlapping (“gray zone”) features may be encountered, as described in the World Health Organization classification. Clinically, testicular DLBCL typically presents as a unilateral painless testicular mass, although some patients may present with scrotal pain, hydrocele, or prior trauma (4).
Unlike germ cell tumors, which commonly metastasize to retroperitoneal lymph nodes, PTL frequently spreads to extranodal sites, including the central nervous system (CNS), contralateral testis, skin, and lungs (5). This predilection for systemic dissemination underlines its aggressive nature and the need for thorough staging and systemic therapy.
Histopathological examination and immunohistochemistry (IHC) remain the cornerstone for diagnosis. On hematoxylin and eosin (H&E) staining, DLBCL, the predominant histological subtype, is typically characterized by diffuse sheets of large atypical lymphoid cells exhibiting prominent nucleoli, vesicular nuclei, frequent mitoses, and replacement of seminiferous tubules. Immunophenotypically, tumor cells express pan-B-cell markers, including CD20, CD45, and Bcl-2, and are negative for T-cell markers such as CD3. These features are essential for distinguishing PTL from other testicular tumors, especially germ cell neoplasms, which predominate in younger men (5).
The standard initial management is high inguinal orchiectomy, which serves both diagnostic and therapeutic purposes. However, unlike germ cell tumors, where orchiectomy may suffice for localized disease, PTL invariably requires multimodal therapy including systemic chemo-immunotherapy, most commonly with the R-CHOP regimen (rituximab, doxorubicin, cyclophosphamide, prednisolone, and vincristine). Given the high risk of CNS involvement, prophylactic intrathecal chemotherapy and contralateral testicular radiotherapy are also recommended. Despite advances in therapy, PTL carries a high relapse rate and poorer overall survival compared to nodal DLBCL, particularly when diagnosed at advanced stages.
In summary, PTL is a rare but important cause of testicular swelling in elderly men. Early recognition, histological confirmation, and aggressive multimodal therapy are essential for improving outcomes. Here, we report a case of primary testicular DLBCL (PT-DLBCL) in a 60-year-old male who presented with scrotal swelling and nodal involvement. This report aims to highlight the clinical presentation, diagnostic challenges, and management considerations of PT-DLBCL.

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Case Presentation

A 60-year-old male with a known history of bronchial asthma presented to the outpatient department with complaints of swelling in the right scrotum for 4 months. The swelling was associated with intermittent dull pain of sudden onset, which was non-radiating. There was a history of scrotal trauma 6 months prior, followed by the patient first noticing a gradual increase in the size of the swelling. There was no significant past medical history apart from asthma and no family history of malignancy.

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Clinical examination
The physical assessment revealed that the patient had a moderate build and adequate nourishment, with vital signs remaining stable. Local scrotal examination revealed a 7×4-cm hard, oval mass involving the right scrotum. The right testis was not separately palpable from the swelling, while the left testis was clinically normal. No transillumination or cough impulse was noted. Local examination of the right inguinal region revealed three hard, fixed, and separate palpable lymph nodes, suggesting nodal involvement. No other peripheral lymphadenopathy was detected (Figure 1).

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Figure 1.

(a) Pre-operative photograph showing right scrotal swelling before high inguinal orchiectomy. (b–e) Contrast-enhanced computed tomography scan of the abdomen and pelvis.

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Laboratory investigations
Standard blood tests, such as complete blood count, renal function, and liver function evaluations, showed no abnormalities, and serum tumor markers typically measured in testicular tumors (α-fetoprotein, β-human chorionic gonadotropin, and carcinoembryonic antigen) were all within normal limits. However, serum lactate dehydrogenase (LDH) was elevated, indicating a high tumor burden and rapid cellular turnover.

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Radiological investigations
An ultrasonography of the scrotum showed a heterogeneous echotexture of the right testis, consistent with a neoplastic process. Figure 1b–e shows contrast-enhanced computed tomography images of the abdomen and pelvis, demonstrating a relatively well-defined, heterogeneously enhancing right testicular mass. Additionally, multiple nodal deposits were noted in the right inguinal region, along the external and internal iliac vessels, and in the aortocaval region (L2–L4). These findings suggested regional as well as retroperitoneal lymph node involvement, indicating advanced disease.

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Surgical management
Following pre-operative optimization and cardiac assessment, the patient underwent a right high inguinal orchiectomy. In addition, enlarged inguinal lymph nodes were surgically excised and sent for histopathological evaluation. The procedure was uncomplicated, and the patient had an unremarkable post-operative recovery. The pre-operative field is shown in Figure 1, while the excised gross specimen is depicted in Figure 2.

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Figure 2.

(a) Gross specimen of the right testis with attached spermatic cord after high inguinal orchiectomy (b) Hematoxylin and eosin staining (40×) demonstrating diffuse sheets of large neoplastic lymphoid cells with vesicular nuclei and prominent nucleoli.

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Gross pathology
The specimen consisted of a right testis with attached spermatic cord, measuring 11.5×5×4 cm. The external surface appeared capsulated, exhibiting a gray–white to gray–brown appearance and focal areas of necrosis and fibrosis. In the cut section, the testicular parenchyma was largely replaced by tumor tissue. The epididymis and spermatic cord were infiltrated by the tumor (Figure 2a).

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Microscopic features
Histopathological sections (H&E) revealed diffuse sheets of large atypical lymphoid cells infiltrating the testicular parenchyma and largely obliterating the normal seminiferous tubules. The tumor cells were round to oval with irregular and multilobulated prominent nucleoli, vesicular nuclei, and scant to moderate eosinophilic cytoplasm. High mitotic activity was noted, with 8–10 mitoses per high-power field. Areas of necrosis, hyalinized blood vessels, and stromal sclerosis were also seen. Sections from the spermatic cord and resected margins showed tumor infiltration (Figure 2b).

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Immunohistochemistry
Immunohistochemical staining confirmed the diagnosis. The tumor cells showed diffuse positivity for CD20, CD45, and Bcl-2, while CD3 was negative, confirming a B-cell phenotype. The combined histological and immunohistochemical profile was consistent with a diagnosis of PT-DLBCL, not otherwise specified.

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Lymph node involvement
All six excised right inguinal lymph nodes submitted for histopathological examination showed tumor infiltration.

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Discussion

PT-DLBCL is a rare and aggressive extranodal lymphoma that predominantly affects elderly men, accounting for 1–2% of all non-Hodgkin lymphomas and approximately 5% of testicular tumors (1). Our patient, a 60-year-old male presenting with unilateral testicular swelling, regional nodal involvement, and histopathology consistent with DLBCL, aligns well with the classical epidemiological and pathological features reported in the literature. The immune-privileged nature of the testis contributes to delayed diagnosis, aggressive behavior, and a high propensity for extranodal dissemination.
Clinically, PT-DLBCL commonly presents as a painless unilateral testicular mass, sometimes associated with nodal involvement and elevated serum LDH levels (2, 3). In our case, retroperitoneal nodal deposits extending up to the L2–L4 level indicated advanced disease at presentation, which is considered an adverse prognostic factor (1). Elevated LDH further reflected increased tumor burden and disease aggressiveness. Histopathologically, our case demonstrated diffuse sheets of large atypical lymphoid cells with obliteration of seminiferous tubules, vascular invasion, and stromal sclerosis, consistent with classical morphological descriptions of PT-DLBCL (1, 2). IHC revealed positivity for CD45, CD20, and Bcl-2 with negativity for CD3, thereby confirming a B-cell phenotype, as is observed in the majority of cases (3).
The genetic landscape of PT-DLBCL has been increasingly studied in recent years. Guo et al. demonstrated recurrent mutations in PIM1, MYD88, KMT2D, BTG2, and ETV6, with BTG2 mutations being strongly associated with a poor prognosis (4). These findings indicate that PT-DLBCL shares molecular similarities with primary CNS lymphoma, another immune-privileged site lymphoma, which explains its high risk of relapse in extranodal locations such as the CNS and contralateral testis (4). Our case, although lacking molecular analysis, clinically resembled these aggressive variants given the extent of nodal dissemination at diagnosis.
The importance of cell-of-origin classification in PT-DLBCL has been repeatedly emphasized. Pollari et al. described that 60–96% of cases represent the activated B-cell-like or non-germinal center B-cell-like (non-GCB) phenotype, which is associated with a worse prognosis (5). Similarly, Zhou et al. reported that the majority of patients in their Chinese cohort were classified as the non-GCB subtype, with high Ki-67 proliferation indices that correlated with an aggressive clinical course (6). The immunophenotypic profile in our patient, with Bcl-2 positivity and CD3 negativity, strongly supports a non-GCB subtype, consistent with these reports.
Therapeutically, orchiectomy remains the first-line surgical intervention for diagnosis and local control, as performed in our patient (3). However, as highlighted across multiple studies, surgery alone is insufficient due to the high risk of systemic relapse (1, 2). Standard management includes systemic chemoimmunotherapy, typically R-CHOP, with CNS prophylaxis and prophylactic irradiation to the contralateral testis. The IELSG30 trial demonstrated that combined intravenous high-dose methotrexate and intrathecal cytarabine, along with R-CHOP and contralateral testis irradiation, achieved excellent outcomes with 5-year overall survival and progression-free survival exceeding 90%, and no CNS relapses during follow-up (7). This finding underscores the need for aggressive multimodal therapy, particularly in patients like ours with extensive disease.
Nevertheless, despite advances in therapy, the prognosis of PT-DLBCL remains guarded. In Zhou et al.’s study of 37 patients, the 3-year overall survival was 57%, with CNS relapse occurring in 5 patients and contralateral testis relapse in 3 patients (6). Intrathecal prophylaxis alone did not prevent CNS relapse, emphasizing the necessity of combined intravenous and intrathecal prophylaxis (7). Wang et al. similarly noted that although some patients achieved remission with surgery and R-CHOP, relapses were common, often in extranodal sites, and prognosis remained poor for advanced disease (2). Our patient, with retroperitoneal nodal involvement, would be considered at high risk for such relapses, necessitating comprehensive systemic therapy beyond orchiectomy.
The role of the tumor microenvironment and immune escape mechanisms has also been increasingly recognized. Pollari et al. discussed how aberrations such as 9p24.1 alterations and programmed death-ligand 1 expression contribute to immune evasion in PT-DLBCL, distinguishing it from nodal DLBCL. These features have therapeutic implications, as immune checkpoint inhibitors may offer benefit in relapsed or refractory disease, though clinical data are still preliminary. This immune-privileged niche biology is consistent with the frequent extranodal relapses observed in PT-DLBCL, including the CNS, contralateral testis, and other extranodal sites (5).
A comparison of our case with the Romanian report by Rotaru et al. highlights differences in disease stage and prognosis (1). Their patient was diagnosed at stage IIB with a low International Prognostic Index (IPI) risk and achieved complete remission following multimodal therapy, remaining disease-free for 36 months. In contrast, our patient presented with extensive nodal spread at baseline, elevated LDH, and spermatic cord infiltration, all of which are poor prognostic markers (2, 4). Similarly, the case reported by Sadiq et al. described a younger patient (47 years) with localized disease who was managed with CHOP chemotherapy and intrathecal methotrexate, achieving good disease control (3). These cases highlight that earlier-stage disease often responds better to therapy, whereas advanced disease, as in our patient, carries a higher relapse risk and poorer outcomes.
From a prognostic perspective, Guo et al. identified age ≥60 years, high IPI score, BTG2 mutation, and extranodal involvement as independent predictors of poor survival (4). Our patient meets at least three of these adverse criteria, indicating a high-risk profile. In addition, Zhou et al. showed that prophylactic radiotherapy to the contralateral testis prevented local relapse in their cohort, suggesting that this should be part of our patient’s treatment plan (6). The integration of CNS prophylaxis, as advocated in the IELSG30 study, would also be essential to minimize relapse risk (7).
In summary, our case illustrates the aggressive clinical course and high-risk features of PT-DLBCL, consistent with the existing literature. The combination of advanced stage at presentation, elevated LDH, and regional as well as retroperitoneal nodal involvement indicates a poor prognosis. Comparative analysis with reported cases highlights the importance of early detection and aggressive multimodal treatment, including systemic R-CHOP chemotherapy, contralateral testis irradiation, and CNS prophylaxis. Molecular and immunological studies continue to refine our understanding of PT-DLBCL pathogenesis, with emerging targeted therapies offering potential future avenues for management.

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Conclusion

PT-DLBCL is an aggressive malignancy that should be considered in elderly patients presenting with testicular swelling. Early histopathological diagnosis and prompt multimodal therapy are essential to improve outcomes.

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Acknowledgments
The authors would like to acknowledge the contributions of the surgical department of SRM Medical College Hospital and Research Institute for their technical support in conducting this study.

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Author Contributions
MVD: Writing of the original draft, methodology, investigation. RJM: Formal analysis, methodology, data curation, conceptualization. VBS and AI: Formal analysis and data curation. VS: Supervision, project administration.

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Ethical Consideration
Declaration of Use of Generative AI
In this study, artificial general intelligence (AGI) was utilized to enhance the readability of the paper.

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References​​

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4. Guo D, Hong L, Ji H, et al. The mutation of BTG2 gene predicts a poor outcome in primary testicular diffuse large B-cell lymphoma. J Inflamm Res. 2022; 15: 1757-69.

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7. Conconi A, Chiappella A, Ferreri AJ, et al. IELSG30 phase 2 trial: intravenous and intrathecal CNS prophylaxis in primary testicular diffuse large B-cell lymphoma. Blood Adv. 2024; 8(6): 1541-9.