Thyroid Lymphoma

Thyroid lymphoma is a lymphoma arising in the thyroid gland, usually in a background of Hashimoto thyroiditis. Most cases are diffuse large B-cell lymphoma or extranodal marginal zone (MALT) lymphoma, and both are potentially curable with chemotherapy and radiotherapy.

It forms about 1% to 5% of thyroid malignancies and under 2% of extranodal lymphomas, with an incidence of about 2 cases in 1,000,000 people each year. Median age at diagnosis is 60 to 70, and women are affected about 3 to 4 times more often than men.

Hashimoto thyroiditis raises risk by 40 to 80 times, with the lymphoma arising after years of chronic stimulation. Sjögren syndrome and other autoimmune diseases are associated.

Pathophysiology. Chronic antigenic stimulation by thyroiditis leads to clonal B-cell proliferation. MALT lymphoma may transform to diffuse large B-cell lymphoma, and the two often coexist. Common changes are MYC, BCL6 and BCL2 rearrangements, and NF-kB signalling alterations in MALT lymphoma.

Staging and prognosis. Most cases are stage IE or IIE at diagnosis. Five year survival is about 90% for MALT lymphoma and about 60% to 80% for diffuse large B-cell lymphoma, depending on stage and age.

• Rapidly enlarging, painless neck mass (weeks to months) in an older woman with known Hashimoto thyroiditis.
• Compressive symptoms: dysphagia, dyspnoea, stridor, hoarseness, and facial swelling from superior vena cava compression.
• B symptoms (fever, night sweats, weight loss) in a minority, and hypothyroidism.

Red flags.

• Stridor or airway compromise from rapid growth.
• Superior vena cava obstruction.
• Features of tumour lysis (rarely, after treatment starts).

• Neck ultrasound: diffusely hypoechoic or nodular gland with posterior acoustic enhancement and pseudocystic change. Fine needle aspiration with flow cytometry, but core needle or open biopsy is needed for histological subtyping.
• Immunohistochemistry: CD20, CD79a, CD10, BCL6, MUM1, Ki-67 and cytogenetics (MYC, BCL2, BCL6).
• Thyroid function, thyroid peroxidase antibodies, LDH, FBC, beta-2 microglobulin, creatinine, liver tests and HIV, hepatitis B and C serology.
• Staging with FDG-PET-CT (or CT of the neck, chest, abdomen and pelvis), and bone marrow biopsy when PET is not definitive.
• Laryngoscopy and airway assessment, and echocardiography before doxorubicin.

Differential diagnosis.

• Anaplastic thyroid carcinoma and poorly differentiated thyroid carcinoma
• Hashimoto thyroiditis and Riedel thyroiditis
• Medullary carcinoma, metastasis to the thyroid and sarcoma

Treatment depends on histology and stage, and is delivered by a haematologist and radiation oncologist. Surgery is limited to biopsy and airway relief, since lymphoma is curable by non-surgical therapy.

Diffuse large B-cell lymphoma. Combination immunochemotherapy, then involved site radiotherapy for limited stage disease.

• Rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone, every 21 days for 3 to 6 cycles:
  • Rituximab 375 mg/m2 IV on day 1.
  • Cyclophosphamide 750 mg/m2 IV on day 1.
  • Doxorubicin 50 mg/m2 IV on day 1.
  • Vincristine 1.4 mg/m2 IV (maximum 2 mg) on day 1.
  • Prednisolone 100 mg orally on days 1 to 5.
  • Maximum doxorubicin cumulative 450 mg/m2 and vincristine 2 mg each dose.
  • Monitoring: FBC before each cycle, hepatitis B serology before the first dose, echocardiography, creatinine, urate, infusion reactions, neuropathy, hydration for tumour lysis risk.
  • Adjustment: reduce doxorubicin by 50% when bilirubin is 26 to 51 micromol/L and avoid it over 51 micromol/L.
  • Reduce vincristine by 50% for bilirubin 26 to 51 micromol/L.
  • Reduce cyclophosphamide when eGFR is under 30 mL/min/1.73 m2.
  • Give pegfilgrastim 6 mg subcutaneously 24 to 72 hours after each cycle in older adults.
  • Start antiviral prophylaxis for hepatitis B core antibody positivity.
• Involved site radiotherapy 30 to 36 Gy in 15 to 20 fractions follows 3 cycles (limited stage) or after 6 cycles for bulky disease.

MALT lymphoma. Localised disease is treated with involved site radiotherapy (24 to 30 Gy), or by observation in a minority with asymptomatic disease. Advanced disease is treated with rituximab based therapy.

Airway and tumour lysis. Short course corticosteroid and early chemotherapy relieve airway compression, with hydration and urate lowering therapy before the first cycle when tumour bulk is high. Tracheostomy is rarely needed.

Thyroid replacement. Levothyroxine for hypothyroidism after treatment:

• 1.6 micrograms/kg orally once daily on an empty stomach, titrated to TSH, with start doses of 25 to 50 micrograms daily in older adults or coronary disease.
• Monitoring: TSH every 6 to 8 weeks after each change, heart rate.
• Adjustment: separate from calcium and iron by 4 hours; maximum 2.5 micrograms/kg daily.

Monitoring. Clinical review and imaging at end of treatment (PET-CT), then every 3 to 6 months for 2 years and every 6 to 12 months to year 5. Thyroid function every 3 to 6 months.

Referral and escalation.

• Urgent referral to a haematology centre on suspicion.
• Same day airway assessment for stridor.

Special groups.

• Older adults: reduced intensity regimens and growth factor support.
• Cardiac disease: replace doxorubicin with a non-anthracycline regimen after cardiology review.
• Hepatitis B carriers: antiviral prophylaxis before rituximab.
• Pregnancy: individualised treatment with the obstetric team.