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 disease 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 can be the primary source in approximately 30% of cases, and the thyroid gland is among the most common of these extranodal sites.
Thyroid NHL, though not especially common, is highly curable, without the need for extensive surgery. Accordingly, it is vital that this condition be recognized early and treated correctly. 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.
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, and a pathogenetic link between this autoimmune disorder and thyroid NHL is considered very likely. Hypothyroidism has been observed in 30-40% of patients with thyroid lymphoma.
Virtually all primary thyroid lymphomas are of B-cell origin. The most common are the large-cell lymphomas. It has been suggested that thyroid large-cell lymphomas most likely arise from a previously existing MALToma that undergoes transformation to a large-cell lymphoma. Such a lesion is 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 seen 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.
Thyroid lymphomas constitute only 1-2% of all extranodal lymphomas and approximately 2-8% of all thyroid malignancies.[4, 5, 6, 7] As with other NHLs, the median age is usually close to 60 years. As expected because of its association with HT, thyroid lymphomas occur more commonly in females, with a female-to-male ratio ranging from 2:1 and as high as 14:1 in some series.[6, 9]
The prognosis for patients with thyroid large-cell lymphoma usually is favorable because this condition typically presents with localized disease, which is amenable to treatment with chemotherapy and radiation. Patient age, stage, histologic subtype, and treatment modality have prognostic implications. The cure rate is typically high (see Treatment). Complications are usually related to adverse effects of chemotherapy (eg, myelosuppression), which can be associated with infections or bleeding. Radiation therapy can induce xerostomia, depending on the fields used.
The most common clinical presentation of a thyroid lymphoma is that of a rapidly enlarging thyroid mass, frequently in association with neck adenopathy (see the image below). Thyroid non-Hodgkin lymphoma (NHL) usually grows faster than any other thyroid neoplasm, with the exception of anaplastic thyroid carcinoma. However, low-grade or indolent NHLs can occasionally arise in the thyroid gland, and their growth rate is slower. Hoarseness, respiratory difficulty, cough, and dysphagia may also be noted as presenting symptoms at diagnosis.
Rapidly enlarging thyroid mass occurring in association with neck adenopathy.
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.[10, 11] 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. These are critical tests for determining the stage or extent of disease.
In cases involving bulky disease, either gallium scanning or positron emission tomography (PET) should be performed because these modalities can be helpful later on in determining whether any residual abnormality seen on radiographic studies after treatment contains active lymphoma or 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 need for the extensive surgery usually performed for thyroid carcinoma. With the aid of immunophenotyping, 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 large-cell lymphoma, follicular lymphoma, mucosa-associated lymphoid tissue (MALT) lymphoma (MALToma), and, rarely, Burkitt lymphoma. In a study from Japan that evaluated 171 patients with primary thyroid lymphoma, the pathologic diagnoses were diffuse large B-cell lymphoma (DLBCL) in 43%, DLBCL with MALToma in 8%, MALToma in 47%, and others in the remaining 2%.
Determining the extent of disease in NHL is crucial for helping predict 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 is not significantly different 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, vincristine, prednisone) regimen and radiation therapy. As many as 90% of cases are failure-free after this approach.
Treatment approaches to large-cell lymphoma are commonly selected on the basis of prognostic factors. For cases where the International Prognostic Index (IPI) is favorable, most investigators would use the standard CHOP regimen followed by radiation therapy consolidation in patients who present with Ann Arbor stage I-II disease. The number of courses of chemotherapy administered ranges from 3 to 6.
Patients with Ann Arbor stage I disease, an IPI of 0, and a tumor less than 5 cm in diameter could be managed with 3 courses of CHOP followed by local irradiation; all others would receive 6 courses. Patients with an IPI greater than 0 should be managed with experimental regimens whenever possible; however, the addition of rituximab (a monoclonal antibody directed against the CD20 antigen present in B-cell lymphomas) for large-cell lymphoma patients older than 60 years provides further benefit with respect to survival and disease-free survival.
The LNH-98.5 study compared CHOP with rituximab plus CHOP (R-CHOP) in 399 patients with diffuse large B-cell lymphoma aged 60-80 years after a median follow-up of 10 years. Survival end points were improved with R-CHOP: 10-year progression-free survival was 36.5%, compared with 20% for CHOP alone, and 10-year overall survival was 43.5%, compared with 27.6%. The results can be applied to primary thyroid lymphoma. Although the study did not include patients younger than 60 years, younger patients have received rituximab.
At the M.D. Anderson Cancer Center, the tumor-score system has been used to select the treatment for aggressive lymphomas in general. Management of thyroid lymphomas is based on the same principles. With this system, patients with favorable prognostic features are identified and are treated with standard chemotherapy/radiotherapy protocols, whereas those with unfavorable prognostic features are treated with experimental protocols. In this system, 1 point is assigned for each of the following:
The point totals are used to classify patients into 2 prognostic groups as follows:
Radiation therapy is most commonly delivered after 3-6 courses of 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. The importance of radiation therapy consolidation for patients with large-cell lymphoma was well established by 2 prospective randomized clinical trials.[19, 20]
The management of relapsed thyroid large-cell lymphoma is based on essentially the same principles as the salvage management of any recurrent large-cell lymphoma. If circumstances allow, high-dose chemotherapy with stem-cell transplantation would be considered the treatment of choice.
Although in theory thyroid diffuse large-cell lymphomas arise from previously existing low-grade mucosa-associated lymphoid tissue (MALT) lymphomas (MALTomas), the latter are relatively uncommon in the thyroid gland; consequently, data on the management of these lesions are sparse.
In most cases, local management with radiation therapy appears to be adequate. However, patients with intermediate- or high-grade lymphoma arising from MALToma appear to have a worse prognosis and thus require more aggressive treatment with combined-modality therapy. Data from the M.D. Anderson Cancer Center suggest that a diagnosis of thyroid MALToma should prompt a gastroscopy to rule out involvement of the stomach. MALTomas tend to be found in other areas of MALT.
Because of the typically excellent outcome of front-line management of thyroid MALToma, there are very few data on the salvage management of this cell type.
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%.
Managing large-cell lymphoma involves selecting treatment 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 6 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 3 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 6 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.