Thyroid Lymphoma

Thyroid lymphomas are very frequently associated with Hashimoto thyroiditis.[5]  Indeed, Hashimoto thyroiditis is an identified risk factor for primary thyroid lymphoma; patients with Hashimoto thyroiditis have a 60 times higher risk of developing primary thyroid lymphoma, compared with the general population. The hypothesis is that chronic antigenic stimulation secondary to the autoimmune disorder leads to chronic proliferation of lymphoid tissue, which eventually undergoes a mutation that leads to the development of lymphoma.

It has also been reported that a mutation or deletion in A20, which is a negative regulator of NF-кB signaling pathway, plays a role in the pathogenesis of certain subsets of thyroid B-cell lymphoma, especially MALTomas.[6]

Primary thyroid lymphoma is rare. Estimates vary; primary thyroid lymphoma may constitute 1–8% of all thyroid malignancies and 1-7% of all extranodal lymphomas.[7, 8, 9] The incidence has been steadily increasing, with an annual change of 3.2%.[10]   

As with other non-Hodgkin lymphomas, the median age of presentation in patients with thyroid lymphoma is approximately 60 years.[11, 8]  Patients are rarely younger than 40 years. Most cases occur in women; the female-to-male ratio is 3-4:1.

The prognosis for patients with thyroid large-cell lymphoma usually is favorable because they typically present with localized disease, which is amenable to treatment with chemotherapy and radiation (see Treatment). A cohort study of 2215 patients with primary thyroid lymphoma from the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute reported 5- and 10-year overall survival rates of 71.61% and 55.95%, respectively. The 5- and 10-year lymphoma-specific survival rates were 85.7% and 82.2%, respectively.[10]

A study of 69 patients with primary thyroid lymphoma that evaluated prognostic factors found that the following were adverse factors for survival[12] :

• Age > 70 years
• Elevated LDH level
• Advanced clinical stage
• Aggressive histologic subtype
• High Ki-67 score
• Ultrasound elastography score > 3

A rare case of pulmonary metastasis has been reported in a 65-year-old woman diagnosed with a primary thyroid MALToma who underwent total thyroidectomy, followed by chemotherapy. After 5 years of follow-up, she was diagnosed with metastatic thyroid MALT lymphoma.[12]

The most common clinical presentation of a thyroid lymphoma is that of a rapidly growing thyroid mass, frequently in association with neck adenopathy. The enlarged cancerous gland can cause compressive symptoms such as hoarseness, dysphagia, or airway compromise. B symptoms (ie, night sweats, fever, weight loss) may be present in approximately 10% of cases.

The diagnosis of thyroid non-Hodgkin lymphoma (NHL) is established by histologic examination of a tumor sample. Laboratory and imaging studies are conducted to establish the stage and prognosis. Thyroid function must also be assessed.

Once the diagnosis of thyroid non-Hodgkin lymphoma (NHL) is established, the following laboratory studies should be obtained:

• Complete blood count (CBC)
• Serum lactate dehydrogenase (LDH) level
• Serum beta2-microglobulin level
• Bone marrow aspiration and biopsy
• Thyroid function tests
• Antithyroglobulin or antimicrosomal antibodies

The serum LDH and beta2-microglobulin levels are important because of their ability to help predict the prognosis and differentiate between indolent and aggressive lymphoma.[13] The CBC and the bone marrow studies are important as part of the staging evaluation. Evaluation of thyroid function is important because of the high incidence of hypothyroidism in these cases.[12]

It is necessary to perform chest radiography and computed tomography (CT) of the head and neck, the chest, the abdomen, and the pelvis. (See the image below.) These are critical tests for determining the stage or extent of disease.

Rapidly enlarging thyroid mass occurring in association with neck adenopathy.

In cases involving bulky disease, either gallium scanning or positron emission tomography (PET) should be performed. These modalities can be helpful later on in determining whether any residual abnormality seen on radiographic studies after treatment contains active lymphoma or just scar tissue.

In current practice, the diagnosis of thyroid lymphoma can be easily established by means of either fine-needle aspiration (FNA) or core-needle biopsy,[13] thus obviating the extensive surgery usually performed for thyroid carcinoma. With the aid of immunophenotyping, non-Hodgkin lymphoma (NHL) should be readily distinguishable from thyroid carcinoma. Furthermore, the distinction between large-cell lymphoma and follicular center-cell lymphoma can be made on the basis of cytologic and immunophenotyping criteria.

The major histologic types of thyroid NHL are as follows:

• Large-cell lymphoma
• Follicular lymphoma
• Mucosa-associated lymphoid tissue (MALT) lymphoma (MALToma)
• Burkitt lymphoma (rare)

The presence of κ and λ free light chain restriction on flow cytometry of the aspirated material has been reported as an indicator of lymphoma in suspected thyroid nodules with a 75% sensitivity and 88.4% specificity.[14]  A retrospective analysis of 26 patients reported an observation of B-cell predominance, defined as B- to T-cell ratio (CD-19 to CD-4 ratio) of more than 2.0 on flow cytometry of FNA specimens in lymphomas as opposed to other lymphoproliferative diseases.

In one of the largest studies of primary thyroid lymphoma, which included 2215 patients, the distribution of pathological diagnoses was as follows:[10]

• Diffuse large B-cell lymphoma (DLBCL) - 58.8% 43%
• DLBCL with MALToma - 15.5% 8%
• Follicular lymphoma - 10.2%
• NHL not otherwise specified (NHL-NOS) - 6.3%
• Hodgkin lymphoma - 1.2%
• T-cell NHL - 0.5%
• MALToma - 47%
• Other - 2%

Determining the extent of disease in NHL is crucial for helping establish the prognosis and select treatment. In thyroid lymphoma, however, a conceptual problem arises in that most investigators have tended to believe that only thyroid lymphomas that are in the early Ann Arbor stages (ie, I-II) can be considered as being of primary thyroid origin.

The explanation for this view is that advanced presentations can represent a lymphoma metastasizing to the thyroid rather than a primary thyroid lymphoma. Primary thyroid lymphomas have metastatic potential and can present in stages III-IV in 2-7% of cases. However, there is no histologic marker that can be used to separate those that are primary in the thyroid from those that are metastatic to the thyroid; thus, most literature series, by definition, include only stage I-II cases.

For the purposes of prognosis, the aggressive thyroid cell types (most commonly the large-cell NHLs) can be classified on the basis of the International Prognostic Index (IPI).[15] This prognostic system assigns 1 point to each of the following variables:

• Age older than 60 years
• Performance status > 1
• Lactate dehydrogenase (LDH) level > 1 times normal
• Number of extranodal sites > 1
• Ann Arbor stage III-IV

Point totals and risk grouping in IPI are as follows:

• 0 or 1: Low risk
• 2: Low intermediate risk
• 3: High intermediate risk
• 4 or 5, high risk

In 2020, a study by Ha et al tested the ability of the IPI to predict the prognosis for patients with thyroid lymphoma. A 5-year overall survival and 5-year progression-free survival PFS for patient Patients with a low IPI score of 0–1 were 80.6% and 68.9%respectively. while for patients with an IPI score of 2–3, the 5-year OS and 5-year PFS were 51.1 and 47.3%, respectively.[16]

The management of thyroid lymphoma does not differ significantly from that of any other lymphoma presenting in a nodal site, and is similarly sensitive to combined-modality therapy of chemotherapy and radiation therapy (RT). The number of courses of chemotherapy administered can be limited to three for patients with localized stage I-II, especially those with good prognostic features (ie, an International Prognostic Index [IPI] of 0 and tumor less than 5 cm in diameter).

In a multicentric retrospective study of 58 patients with primary DLBCL of the thyroid, Yi et al reported that the patients who received chemotherapy with RT had better survival than those treated with chemotherapy only or surgical excision alone; 5-year overall survival (OS) and progression-free survival rates (PFS) were 81.2% and 77.8%, respectively, for the 25 patients who received chemotherapy plus RT, 60.9% and 53.9% for the 18 patients who received chemotherapy alone, and 35.3% and 31.6% for the 15 patients who underwent surgical excision. In addition, OS and PFS rates were higher in patients whose chemotherapy regimens included rituximab (R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone] versus CHOP).[16]

Follow-up care for patients with thyroid lymphoma is similar to that for patients with any other lymphoma. In brief, patients should be seen approximately every 3 months during the first year and every 4 months during the second year. After the second year, the risk of relapse diminishes substantially for patients with tumors of the large-cell (ie, aggressive) types. In the aforementioned study of 58 patients with primary thyroid DLBCL, only 10 patients experienced relapse of disease and had to receive different lines of chemotherapy.[16]

After 3 years of follow-up, the probability of cure in a patient with diffuse large-cell lymphoma is greater than 90%. In contrast, the risk of recurrence for the low-grade (ie, indolent) lymphoma types does not decline as sharply after 2 years of observation. 

Treatment for large-cell lymphoma is selected on the basis of prognostic factors. Most investigators treat patients whose International Prognostic Index (IPI) result is favorable by using the standard CHOP (cyclophosphamide, doxorubicin [hydroxydaunorubicin], vincristine [Oncovin], prednisone) regimen or rituximab plus CHOP (R-CHOP), followed by irradiation consolidation in patients with Ann Arbor stages I-II. Three to six courses of chemotherapy are administered.

In general, the addition of rituximab provides benefit in survival and disease-free survival rates, and the results are also assumed to apply to primary thyroid large-cell lymphomas.

Intrathecal methotrexate is also used in patients with central nervous system involvement.

Regimens used in refractory or recurrent cases include the following:

• GEMOX (gemcitabine and oxaliplatin)
• MINE (mesna, ifosfamide, mitoxantrone, etoposide)
• ESHAP (etoposide, methylprednisolone, cisplatin, cytarabine)