Primary thyroid lymphoma can be defined as a lymphoma that arises from the thyroid gland. This definition excludes those that invade the thyroid gland as a consequence of either metastasis or direct extension. Primary thyroid lymphomas are practically always non-Hodgkin lymphomas (NHLs). Primary thyroid Hodgkin lymphoma is extremely rare.
NHLs can be divided into aggressive and indolent cell types. Aggressive NHLs comprise a large number of cell types, the most common of which is large-cell lymphoma. They most frequently arise from lymph nodes, but an extranodal site is the primary source in approximately 30% of cases, and the thyroid gland is among the most common of these extranodal sites.
Thyroid NHL represents approximately 1.2 to 1.7% of all NHLs. It is highly curable, without the need for extensive surgery. Accordingly, early recognition and correct treatment of this condition is vital. The most common cell type is diffuse large-cell lymphoma, either associated or unassociated with mucosa-associated lymphoid tissue (MALT) lymphoma (MALToma).The best treatment results for primary thyroid large-cell lymphoma are with combined-modality therapy; for primary thyroid MALToma, radiation therapy alone is probably adequate.[2, 3] Primary T-cell lymphoma of thyroid is extremely rare, accounting for less than 2% of all primary thyroid lymphomas, and can present both diagnostic and therapeutic challenges.
Thyroid lymphomas are very frequently associated with Hashimoto thyroiditis (HT). Conversely, there is a markedly increased incidence of primary thyroid lymphomas in patients with HT. Such lesions are an aggressive or high-grade variant, whereas a low-grade MALT is an indolent type.
Like other low-grade MALTomas, such as those presenting in the parotid in association with Sjögren syndrome, those arising in the thyroid also occur in association with an autoimmune disorder (in this case, HT). 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.
Primary thyroid lymphoma is rare, constituting only 1-2% of all extranodal lymphomas and approximately 2-8% of all thyroid malignancies.[6, 5, 7, 8] As with other non-Hodgkin lymphomas, the median age of presentation in patients with thyroid lymphoma is usually close to 60 years.[8, 7] Most cases occur in women.
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. The cure rate is typically high (see Treatment). A large population-based study that evaluated prognostic factors found that older age, advanced stage, histologic subtype, and lack of radiation/surgical treatment were adverse factors for survival.
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.
The most common clinical presentation of a thyroid lymphoma is that of a rapidly enlarging thyroid mass, frequently in association with neck adenopathy. Compressive symptoms may be present. In most cases the patient is a woman, often with a history of Hashimoto thyroiditis.
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:
The serum LDH and beta2 -microglobulin levels are important because of their ability to help predict the prognosis. The CBC and the bone marrow studies are important as part of the staging evaluation. Because of the high incidence of hypothyroidism, it is important to evaluate thyroid function.
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, 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 :
In a study from Japan that evaluated 171 patients with primary thyroid lymphoma, the distribution of pathologic diagnoses was as follows :
Determining the extent of disease in NHL is crucial for helping determine 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. Although primary thyroid lymphomas have metastatic potential and can present in stages III-IV, 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). This prognostic system assigns 1 point to each of the following variables:
In a study by Ha et al that tested the ability of the IPI to predict the prognosis for patients with thyroid lymphoma, the 5-year survival rate was 86% for those presenting with an IPI of 0, compared with 50% for those with an IPI greater than 0. . These data included patients treated with radiation therapy alone, patients treated with chemotherapy alone, and patients treated with combined-modality therapy. A 2010 study evaluated prognostic factors in a large population-based study and found that older age, advanced stage, histologic subtype, and lack of radiation/surgical treatment were adverse factors for survival.
The management of thyroid lymphoma does not differ significantly from that of any other lymphoma presenting in a nodal site. Data suggest that the best results are obtained with combined-modality therapy that includes the CHOP (cyclophosphamide, doxorubicin [hydroxydoxorubicin], vincristine [Oncovin], prednisone) regimen and radiation therapy. As many as 90% of cases are failure-free after this approach. 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).
Radiation therapy is used to consolidate the response to CHOP for those receiving only three courses. Currently, rituximab is given as part of the CHOP regimen (R-CHOP). However, patients with an IPI greater than 1 should be managed with six courses of R-CHOP, based on the results discussed below.
In the LNH-98.5 study, conducted in 399 patients 60-80 years of age with diffuse large B-cell lymphoma, 10-year progression-free survival was 36.5% with R-CHOP, versus 20% for CHOP alone, and 10-year overall survival rates were 43.5% versus 27.6%. The results can be applied to primary thyroid lymphoma. Although the study did not include patients younger than 60 years, another study found that such patients have also benefitted from rituximab.
Radiation therapy is most commonly delivered after three to six courses of R-CHOP chemotherapy. The radiation fields most commonly used are either involved field or modified mantle, which includes the thyroid, the bilateral neck and supraclavicular region, and the mediastinum.
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 contrast, the risk of recurrence for the low-grade (ie, indolent) lymphoma types does not decline as sharply after 2 years of observation. After 3 years of follow-up, the probability of cure in a patient with diffuse large-cell lymphoma is greater than 90%.
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, vincristine, prednisone) regimen, followed by irradiation consolidation in patients with Ann Arbor stages I-II. Three to six courses of chemotherapy are administered.
Patients who present with Ann Arbor stage I and an IPI of 0 with tumor diameters smaller than 5 cm could be treated with three courses of CHOP followed by local irradiation. The role of rituximab in patients with these favorable presentations has not been explored, but most clinicians include it in the treatment regimen. All other patients receive six courses of CHOP and radiotherapy. Consider investigational regimens in patients with IPI scores greater than 0.
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.
Clinical Context: Cyclophosphamide is chemically related to nitrogen mustards. It is an alkylating agent; the mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.
Clinical Context: Doxorubicin intercalates DNA and inhibits topoisomerase II; it produces free radicals that may cause destruction of DNA and inhibit growth of neoplastic cells.
Clinical Context: Vincristine's mechanism of action is uncertain; it may involve a decrease in reticuloendothelial cell function or an increase in platelet production.
Antineoplastic agents inhibit cell growth and proliferation.
Clinical Context: Rituximab is a genetically engineered chimeric murine/human monoclonal antibody (immunoglobulin G1 [IgG1] kappa) against CD20 antigen on the surface of normal and malignant B cells. It is not to be administered as an intravenous bolus.
Monoclonal antibodies are genetically engineered chimeric murine-human immunoglobulins directed against proteins involved in cell cycle initiation.
Clinical Context: Prednisone is an immunosuppressant used for treatment of autoimmune disorders. It may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear leukocyte (PMN) activity.
Clinical Context: Prednisone is useful for treating inflammatory and allergic reactions; it may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear leukocyte (PMN) activity. It decreases autoimmune reactions, possibly by suppressing key components of immune system.
These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.