Synchronous clear cell renal cell carcinoma and classic Hodgkin lymphoma

Abstract

Introduction

The coexistence of renal cell carcinoma and classic Hodgkin lymphoma is exceedingly rare, with only two documented cases. Here, we present the third case diagnosed in our institution.

Case presentation

A 46‐year‐old man presented with right flank pain, fever, mild pancytopenia, and renal mass on computed tomography scan, suggesting renal malignancy. Despite intravenous antibiotics and extensive workup for recurrent fever, his condition did not improve. A bone marrow biopsy revealed rare large EBV‐positive B cells. Surprisingly, imaging only showed minimal intraabdominal lymphadenopathy in the perinephric region. Subsequent surgery confirmed clear cell renal cell carcinoma in the kidney and scattered large, atypical cells consistent with classic Hodgkin lymphoma in the suprahilar lymph node.

Conclusion

This case presents a rare case of classic Hodgkin lymphoma occurring in the perirenal region. When clinicians encounter unexplained symptoms in patients with primary tumors, additional biopsies should be considered for possible secondary malignancy.

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Keynote message

Our case reveals a rare instance where classic Hodgkin lymphoma and renal cell carcinoma occurred synchronously in a patient. This highlights the need for pathologists to carefully examine specimens for multiple lesions.

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Abbreviations & Acronyms

• ccRCC
• clear cell renal cell carcinoma
• CHL
• classic Hodgkin lymphoma
• CT
• computed tomography
• RCC
• renal cell carcinoma

Introduction

RCC comprises about 2% of adult malignancies.¹ Although its incidence has risen in recent years, 5-year cancer-specific survival rates have significantly improved.² Most RCCs are the clear cell subtype.

CHL often presents with lymphadenopathy. Advanced CHL can affect multiple sites, including bone marrow, liver, and spleen; however, extra-nodal involvement is rare.³ The coexistence of RCC and CHL is exceptionally rare. Only two cases have been reported where both cancers presented concurrently.^4,5 Herein, we describe a case where both CHL and ccRCC were diagnosed simultaneously, with findings suggestive of lymphadenopathy mimicking metastatic lymph node involvement of ccRCC, posing a diagnostic challenge.

Case presentation

A 46-year-old Hispanic man presented with fever, night sweats, chills, and right flank pain. His lab workup was notable for pancytopenia. CT scan showed a 3.5 × 2.8 × 2.7 cm enhancing heterogeneous right renal mass with pericaval and para-aortic/suprahilar lymphadenopathy, as well as splenomegaly (Fig. 1). Due to recurrent fever, he was started on intravenous antibiotics and underwent an extensive infectious workup, which showed positivity for Epstein–Barr Virus (EBV). Bone marrow and renal biopsies were performed to work up the cause for the patient's pancytopenia and recurrent fever. While ccRCC was confirmed on the biopsy, the bone marrow showed patchy involvement by a mixed inflammatory infiltrate with rare large, EBV-positive B-cells with an atypical immunophenotype [PAX5 dim, CD30(+), rare cells CD15(+), OCT2(+), BOB1(−), CD20(−)], consistent with bone marrow involvement by an EBV-positive lymphoproliferative disorder, concerning for CHL (Fig. 2).

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A comprehensive radical right nephrectomy was performed, along with the removal of a suprahilar lymph node. Urology preferred radical nephrectomy over partial nephrectomy with the intention to address the refractory fevers and other unexplained symptoms. The suprahilar lymph node examination revealed scattered large, atypical cells consistent with mononuclear Hodgkin cells and Reed–Sternberg cells amidst a background of small lymphocytes, plasma cells, neutrophils, and histiocytes (Fig. 3b). Immunostaining demonstrated positivity of the large, atypical cells for CD30, MUM1, PAX-5 (weak), and EBER ISH (in a subset of the large cells), while CD3, CD15, and CD20 were negative (Fig. 3c–h). This confirmed the diagnosis of CHL, stage IV, with bone marrow involvement. A PET-CT scan was performed for staging, showing hypermetabolic activity in the right supraclavicular and upper abdominal lymph nodes, splenomegaly with multiple hypermetabolic foci, and numerous hypermetabolic foci throughout the skeleton including the bone marrow.

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The histological examination of the renal mass was consistent with ccRCC with International Society of Urological Pathology (ISUP) nuclear grade 2, confined solely to the right kidney without extension into adjacent structures (Fig. 3a). The RCC tumor cells exhibited positivity for PAX-8 but were negative for CK7, AMACR, and CD117. Staging according to AJCC 8^th Edition is pT1aN0.

He was started on chemotherapy with the A-AVD regimen (Brentuximab vedotin, Doxorubicin, Vinblastine, and Dacarbazine). He completed the treatment without significant complications. A follow-up PET-CT revealed no definite evidence of active lymphoma. At the 1-year follow-up since the incidental diagnosis of CHL following the renal mass, there was no evidence of disease recurrence.

Discussion

This case highlights the rare concurrent diagnosis of ccRCC and CHL, a combination that adds significant complexity to the diagnostic process. The overlapping presentation of lymphadenopathy initially suggested metastatic RCC, a common metastatic pattern for advanced renal tumors. This underscores the need for a comprehensive differential diagnosis. In cases with unexpected or ambiguous lymphadenopathy, considering a second primary malignancy and obtaining a tissue diagnosis are essential steps to avoid potential misdiagnosis.

Although the exact cause of CHL is unknown, EBV has been implicated in its pathogenesis, particularly in EBV-positive CHL cases, which account for about one-third of CHL cases.⁶ EBV-positive CHL is closely associated with the HLA-A01 allele, which cannot present EBV antigens effectively, whereas the HLA-A02 allele, which supports anti-EBV immune responses, appears protective.⁷ In infected B cells, proteins such as EBV nuclear antigen (EBNA) and latent membrane proteins (LMP1 and LMP2) are expressed, promoting the survival of Hodgkin Reed–Sternberg (HRS) cells through mechanisms that mimic CD40 signaling and interfere with B-cell receptor signaling. The HRS cells exhibit a “latency II” EBV gene expression pattern, primarily involving LMP1 and LMP2A, which aids cell survival despite their lack of surface immunoglobulin and apoptosis-prone characteristics.^8,9 LMP2A's specific function in CHL remains to be clarified, given the absence of some necessary signaling molecules.

In addition to its role in CHL, EBV has also been detected in RCC across all stages and histological types, with expression levels correlating with tumor grade, suggesting an oncogenic role in RCC pathophysiology.¹⁰ Shimakage et al. found that RCC cells express high levels of EBV proteins, including LMP1 and EBNA-2, indicating a tumor-promoting role for EBV in RCC.¹¹ This complex interaction may create an immunosuppressive environment that theoretically fosters secondary malignancies such as CHL. Further research is needed to understand the underlying mechanisms.

The lymphadenopathy in this case initially resembled metastatic ccRCC but was ultimately found to be due to CHL, with a distinctive presentation involving minimal lymph node involvement and more pronounced infiltration of the bone marrow, spleen, and skeleton. This pattern highlights the need for broader diagnostic evaluations in cases of concurrent malignancies, particularly when systemic symptoms or imaging findings deviate from expected patterns. Comprehensive assessments, including tissue biopsies, are critical to ensure accurate diagnosis and treatment planning in such complex scenarios.

While previous studies have noted associations between lymphoid neoplasms and solid tumors, these typically involve secondary malignancies resulting from chemotherapy. In this patient, the simultaneous occurrence of CHL and ccRCC was unrelated to prior treatment, representing a unique case of synchronous primary malignancies. This underscores the importance of maintaining a high index of suspicion for second malignancies, particularly in the presence of unexplained findings or atypical clinical presentations. Additional biopsies and thorough diagnostic workups remain essential for accurate identification and management of such cases.

Acknowledgments

We sincerely thank Dr. Joseph P. Hasapes for their expert assistance in interpreting the radiologic imaging, which was essential to this case report.

Author contributions

Phuoc Christie-Nguyen: Conceptualization; data curation; formal analysis; investigation; methodology; project administration; resources; software; supervision; validation; visualization; writing – original draft; writing – review and editing. Ahmed A Ahmed: Conceptualization; data curation; investigation; methodology; resources; software; validation; visualization; writing – original draft; writing – review and editing. Nourhan Ibrahim: Data curation; investigation; methodology; resources; software. Jacob Armstrong: Conceptualization; data curation; formal analysis; investigation; methodology; resources; validation. Brenda Mai: Conceptualization; data curation; formal analysis; investigation; methodology; project administration; resources; software; supervision; validation; visualization; writing – review and editing.

Conflict of interest

The authors declare no conflict of interest that might be relevant to the contents of this manuscript.

Approval of the research protocol by an Institutional Reviewer Board

Not Applicable.

Informed Consent

Not Applicable.

Registry and the Registration No. of the study/trial

N/A.

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