Testicular Lymphoma

Testicular lymphoma is a lymphoid malignancy of the testis. It makes up about 5% of testicular tumours and is the commonest testicular tumour in men over 60 years, with a median age of 60 to 70.

Most are primary and are diffuse large B-cell lymphoma (about 80 to 90%). The risks that define management are relapse in the central nervous system, in the opposite testis and at other extranodal sites.

Pathophysiology. The testis is an immune privileged site, and tumour cells commonly lose HLA expression and carry mutations that allow escape from immune surveillance. Most cases are of non-germinal centre type.

Without prophylaxis, central nervous system relapse occurs in about 20 to 35% by 5 years, and opposite testis involvement in up to about 35%. Other sites are skin, lung, Waldeyer ring and soft tissue.

Other histologies: follicular lymphoma (more in boys), Burkitt lymphoma (children and HIV infection), and NK/T-cell lymphoma. Secondary testicular involvement occurs with systemic lymphoma and leukaemia, particularly acute lymphoblastic leukaemia in boys.

Risk markers: high lactate dehydrogenase, stage, age over 60, poor performance status, MYC and BCL2 rearrangement, and the International Prognostic Index.

Painless unilateral or bilateral testicular enlargement over weeks to months, in an older man, often firm and rubbery. Constitutional features (fever, night sweats, weight loss) in about 25%. Associated epididymal or cord involvement. Bilateral disease at presentation in about 5 to 10%.

Neurological symptoms (headache, cognitive change, cranial nerve palsy) suggest central nervous system disease.

• Scrotal ultrasound: diffuse or multifocal hypoechoic enlargement with increased vascularity, often with a normal internal architecture and a hypertrophied epididymis.
• AFP and beta-hCG are normal. Lactate dehydrogenase is often raised.
• Radical inguinal orchidectomy for tissue. Histology and immunostains (CD20, CD10, BCL6, MUM1, Ki-67, MYC, BCL2, Epstein-Barr virus), and cell of origin.
• Staging: PET-CT or CT of neck, chest, abdomen and pelvis, bone marrow biopsy (or PET-CT), MRI of the brain, and lumbar puncture with cerebrospinal fluid cytology and flow cytometry.
• Full blood count, creatinine, liver tests, uric acid, immunoglobulins, HIV, and hepatitis B and C serology (HBsAg, anti-HBc) before rituximab.
• Echocardiography for left ventricular ejection fraction before doxorubicin.

Differential diagnosis.

• Seminoma and other germ cell tumours
• Epididymo orchitis or abscess
• Leukaemic infiltration
• Granulomatous or IgG4-related orchitis
• Sex cord stromal tumour
• Plasmacytoma
• Metastasis

• Radical inguinal orchidectomy with high ligation of the cord, which gives the diagnosis and local control.
• Systemic treatment for all stages, since orchidectomy alone is not curative: R-CHOP every 21 days for 6 cycles.
  • Rituximab 375 mg/m2 intravenously on day 1.
  • Cyclophosphamide 750 mg/m2 intravenously on day 1.
  • Doxorubicin 50 mg/m2 intravenously on day 1 (cumulative maximum about 450 mg/m2, and avoid in left ventricular ejection fraction under 50%).
  • Vincristine 1.4 mg/m2 (maximum 2 mg) intravenously on day 1.
  • Prednisolone 100 mg orally on days 1 to 5.
  • Over 80 years or frail: R-miniCHOP with cyclophosphamide 400 mg/m2, doxorubicin 25 mg/m2, vincristine 1 mg and prednisolone 40 mg/m2 on days 1 to 5.
• Central nervous system prophylaxis for all fit patients: intrathecal methotrexate 12 mg for 4 to 8 doses. In fit patients with eGFR over 60, high dose methotrexate 3 to 3.5 g/m2 over 3 to 4 hours is added, with folinic acid rescue 15 mg/m2 every 6 hours starting 24 hours after the start until the methotrexate level is under 0.1 micromol/L, hydration and urine alkalinisation to pH over 7. Avoid trimethoprim, penicillins, NSAIDs and proton pump inhibitors on the day of methotrexate.
• Radiotherapy to the contralateral testis, 25 to 30 Gy, after chemotherapy, which lowers relapse in the other testis. It impairs spermatogenesis and may cause hypogonadism.
• Supportive care:
  • Pegfilgrastim 6 mg subcutaneously once each cycle 24 hours after chemotherapy in patients over 60.
  • Hepatitis B: entecavir 0.5 mg orally daily (adjusted to eGFR) for HBsAg or anti-HBc positive patients, until at least 12 months after rituximab.
  • Tumour lysis prevention: hydration and allopurinol 300 mg orally daily from 1 to 2 days before (reduce when eGFR is under 30).
  • Neutropenic fever needs intravenous antibiotics within 60 minutes.
• Relapse or refractory disease: salvage chemotherapy with rituximab and platinum combinations, high dose therapy with stem cell rescue where fit, and central nervous system disease needs high dose methotrexate regimens, within a haematology centre.
• Sperm banking in younger men before chemotherapy.
• Prognosis: five year survival about 60 to 85% with full treatment, with late relapses in the central nervous system and opposite testis up to 10 years or more.

Monitoring. Clinical review and blood tests every 3 months for 2 years, then every 6 months to year 5, then yearly. Imaging directed by symptoms and stage. Ultrasound of the opposite testis every 6 to 12 months if it was not irradiated. Testosterone yearly.

Referral and escalation. Refer to urology, then to haematology oncology for all patients. Urgent referral for neurological symptoms, tumour lysis, or neutropenic fever.