Updated: May 17, 2007
Primary thyroid lymphoma can be defined as a lymphoma that arises from the thyroid gland. This definition excludes lymphomas that invade the thyroid gland because of either metastasis or direct extension from an adjacent lymph node. Primary thyroid lymphomas usually are of the non-Hodgkin type. Primary thyroid Hodgkin disease is extremely rare. Non-Hodgkin lymphomas (NHLs) can be further divided into aggressive and indolent cell types.
The aggressive NHLs comprise a large number of cell types, the most common of which is large-cell lymphoma. NHLs 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.
Of interest, these disorders are frequently associated with Hashimoto thyroiditis, and the incidence of primary thyroid lymphomas in patients with Hashimoto thyroiditis is markedly increased; some believe that a pathogenetic link exists between this autoimmune disorder and thyroid NHL.1 The proposed theory hypothesizes that chronic antigenic stimulation secondary to the autoimmune disorder leads to chronic proliferation of lymphoid tissue, which eventually undergoes a mutation that results in clonal proliferation, leading to the development of lymphoma. Hypothyroidism has been observed in 30-40% of patients with thyroid lymphoma.
Thyroid lymphomas constitute only 3% of all NHLs and approximately 5% of all thyroid neoplasms2,3,4 . Although thyroid NHL is not common, it is highly curable without extensive surgery; for this reason, it should be recognized early and treated correctly.
Primary thyroid lymphoma, as discussed in this article, is a highly curable malignancy if diagnosed promptly and managed correctly.
As expected, because of its association with Hashimoto thyroiditis, thyroid lymphomas are more common in women than in men, with a ratio ranging from 2:1 to as high as 14:1 in some series3,5 .
Similar to other NHLs, thyroid lymphomas usually affect patients with a median age of 60 years6 .
The most common clinical presentation is that of a rapidly enlarging thyroid mass, frequently in association with neck adenopathy6 (see Image 1). With the exception of anaplastic thyroid carcinoma, thyroid NHL usually grows faster than any other thyroid neoplasm; however, low-grade or indolent NHLs occasionally can arise in the thyroid gland, and their growth rate is slower. Hoarseness, respiratory difficulty, cough, and dysphagia also can occur as presenting symptoms.
Patients with large-cell thyroid lymphoma usually present with a rapidly growing thyroid nodule; however, those with an indolent histology (eg, those with a mucosa-associated lymphoid tissue [MALT] lymphoma) present with a slow-growing node, which can grow for months or years before it is brought to the physician's attention. Neck adenopathy can also be present in association with the thyroid nodule.
Thyroid Nodule
Thyroid, Anaplastic Carcinoma
Thyroid, Medullary Carcinoma
Thyroid, Papillary Carcinoma
Thyroid adenoma
The diagnosis of thyroid lymphoma can easily be established by using fine-needle aspiration (FNA) or needle core biopsy9 to avoid the extensive surgery usually performed for thyroid carcinoma. However, whenever possible, a biopsy specimen larger than that obtained with these techniques may be desirable to ensure that the sample is representative and that divergent histology is not missed. For example, MALT lymphoma can coexist with large-cell lymphoma. If a small sample is obtained, the aggressive component could be missed, resulting in incorrect management.
In the past, primary thyroid large-cell lymphoma was sometimes misdiagnosed as anaplastic thyroid carcinoma. With the aid of immunophenotyping, NHL should be easy to distinguish from thyroid carcinoma. Furthermore, the distinction between large-cell lymphoma and follicular center cell lymphoma is possible by using cytologic and immunophenotyping criteria.
The major histologic types of thyroid NHL are large cell, follicular, MALT, and the rare Burkitt lymphoma.6 Virtually all primary thyroid lymphomas are of B-cell origin. The most common primary thyroid lymphomas are the large-cell lymphomas. According to Isaacson, thyroid large-cell lymphomas most likely arise from a preexisting MALT lymphoma, which transforms to large-cell lymphoma.10 The large-cell type is an aggressive or high-grade lymphoma, whereas low-grade MALT is an indolent type. Similar to other low-grade MALT lymphomas (eg, those occurring in the parotid in association with Sjögren syndrome), tumors in the thyroid also occur in relationship with an autoimmune disorder (in this case, Hashimoto thyroiditis).
The hypothesis is that chronic antigenic stimulation secondary to the autoimmune disorder leads to chronic proliferation of lymphoid tissue, which eventually undergoes mutation that leads to the development of lymphoma.
Assessment of the extent of disease in NHL is crucial in determining the prognosis and in selecting the treatment. In thyroid lymphoma, most investigators believe that only the early Ann Arbor stages (ie, I-II) can be considered as primary thyroid in origin, causing a conceptual problem. This is because advanced presentations can represent metastatic lymphoma to the thyroid rather than primary lymphoma in the thyroid.
Primary thyroid lymphomas have metastatic potential and can present with stage III-IV disease; however, because no histologic marker separate primary thyroid lymphomas metastatic thyroid lymphomas, most series include only stage I-II cases (by definition).
The treatment of thyroid large-cell lymphoma is not different from any other lymphoma occurring in a nodal site. Treatment is based on the lymphoma subtype and the extent of disease.
The trend nowadays in the management of large cell lymphoma, however, is to select treatment based on prognostic factors. Those whose IPI is favorable would be treated by most investigators with the standard CHOP regimen which consists of cyclophosphamide, doxorubicin, vincristine and prednisone followed by radiation therapy consolidation in those who present with Ann Arbor stage I-II. The number of courses of chemotherapy administered ranges from three to six.12 In cases with Ann Arbor stage I and IPI=0 with <5 cm diameter could be managed with three courses of CHOP followed by local radiation. Results from the MD Anderson Cancer Center and from Matsuzuka et al reveal that failure is avoided in about 90% of patients receiving combined therapy.13 The role of Rituximab in these very favorable presentations has not been explored but most clinicians will include it as part of the treatment. All others would receive six courses. In those with large cell lymphoma and an IPI >0, the management should consist of six courses of CHOP-Rituximab, irrespective of age. In general, the addition of Rituximab provides further benefit in survival and disease free survival and it is assumed that this also applies to primary thyroid large cell lymphoma.
At the MD Anderson Cancer Center, the present author uses the tumor-scoring system to select the treatment for aggressive lymphomas in general.14
Treatment of thyroid lymphomas is based on the same principles as those just discussed. This system is used to identify patients with favorable prognostic features with standard chemotherapeutic and/or radiotherapeutic protocols, whereas those with poor prognoses are treated with experimental protocols. This system assigns 1 point for any bulky site larger than 7.0 cm, to Ann Arbor stage III or IV, to B symptoms, to an LDH level of more than 110% of the upper normal limit, and to a beta2-microglobulin value of more than 150% of the upper normal limit. This system classifies patients into 2 prognostic groups: 1 with low risk and a tumor score of 0-2 (85% cure rate when treated with CHOP) and 1 with a tumor score of 3 or more and a poor prognosis (20% cure rate).
Radiation therapy is most commonly given after 3-6 courses of chemotherapy. The usual radiation fields are either involved fields or modified mantles, which include the thyroid, bilateral neck and supraclavicular regions, and the mediastinum.6 The importance of irradiation consolidation for patients with large-cell lymphoma was well established by 2 prospective randomized clinical trials.15,12
Overall, primary thyroid lymphoma usually occurs in women older than 55 years. Most primary thyroid lymphomas arise in the background of Hashimoto thyroiditis; this phenomenon probably is related to their pathogenesis. The most common cell type is diffuse large-cell lymphoma arising de novo or in association with MALT lymphoma. Best results for primary thyroid large-cell lymphoma are achieved with combined-modality therapy. For a primary thyroid MALT lymphoma, radiation therapy alone is probably adequate.
Managing large-cell lymphoma involves selecting treatment on the basis of prognostic factors. Most investigators treat patients whose IPI result is favorable by using the standard CHOP regimen, followed by irradiation consolidation in patients with Ann Arbor stages I-II. Three to 6 courses of chemotherapy are administered.17
Rituximab, a monoclonal antibody directed against CD20 antigen present in B-cell lymphomas, was recently combined with CHOP and compared with CHOP alone in a randomized study of patients aged >60 years with diffuse large-cell lymphoma. The combination of rituximab and CHOP improved rates of complete response, failure-free survival, and survival. 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.
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.
These agents inhibit cell growth and proliferation.
Chemically related to nitrogen mustards. Alkylating agent; mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.
750 mg/m2 IV on day 1 of each course
Not established
Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones; chloramphenicol may increase half-life while decreasing metabolite concentrations; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase rate of metabolism and leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity
Documented hypersensitivity; severely depressed bone marrow function
D - Unsafe in pregnancy
Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis
Intercalates DNA and inhibits topoisomerase II; produces free radicals that may cause destruction of DNA and inhibit growth of neoplastic cells.
50 mg/m2 IV on day 1 of each course
Not established
May decrease phenytoin and digoxin plasma levels; phenobarbital may decrease plasma levels; cyclosporine may induce coma or seizures; mercaptopurine increases toxicity; cyclophosphamide increases cardiac toxicity
Documented hypersensitivity; severe heart failure, cardiomyopathy, impaired cardiac function, preexisting myelosuppression
D - Unsafe in pregnancy
Can cause birth defects particularly when administered during first trimester of pregnancy
Mechanism of action is uncertain. May involve decrease in reticuloendothelial cell function or increase in platelet production.
1.4 mg/m2 IV on day 1 of each course
Not established
Acute pulmonary reaction may occur when taken concurrently with mitomycin-C
Documented hypersensitivity
D - Unsafe in pregnancy
Caution in severe cardiopulmonary or hepatic impairment and preexisting neuromuscular disease; can cause birth defects particularly when administered during first trimester of pregnancy
Immunosuppressant for treatment of autoimmune disorders. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.
100 mg PO on days 1-5 of CHOP
Not established
Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity due to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministered diuretics
Documented hypersensitivity; viral infection, peptic ulcer disease, hepatic dysfunction, connective tissue infections, and fungal or tubercular skin infections; GI disease
B - Usually safe but benefits must outweigh the risks.
Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use
Genetically engineered chimeric murine/human monoclonal antibody against CD20 antigen on surface of normal and malignant B-lymphocytes. Antibody is IgG1 kappa immunoglobulin.
Not to be administered as IV bolus.
375 mg/m2 on day 1 of CHOP; start administration rate at 50 mg/h; if no reaction increase rate by 50 mg/h q30min to maximum 400 mg/h
Not established
None reported
Documented hypersensitivity
C - Safety for use during pregnancy has not been established.
Caution in preexisting cardiac conditions; regularly obtain CBC during therapy and more frequently if cytopenia develops
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thyroid MALT, thyroid large cell lymphoma, thyroid large-cell lymphoma, primary thyroid lymphomas, non-Hodgkin lymphomas, non-Hodgkin's lymphomas, NHLs, Hashimoto thyroiditis, Hashimoto's thyroiditis, thyroid cancer
Fernando Cabanillas, MD, Chairman, Professor, Department of Hematology, Division of Lymphoma/Myeloma, MD Anderson Cancer Center, University of Texas
Fernando Cabanillas, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for Cancer Research, American Association for the Advancement of Science, American College of Physicians-American Society of Internal Medicine, American Society of Clinical Oncology, American Society of Hematology, New York Academy of Sciences, and Texas Medical Association
Disclosure: Nothing to disclose.
Lodovico Balducci, MD, Professor of Oncology and Medicine, University of South Florida College of Medicine; Division Chief, Senior Adult Oncology Program, H Lee Moffitt Cancer Center and Research Institute
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.
Wendy Hu, MD, Consulting Staff, Department of Hematology/Oncology and Bone Marrow Transplantation, Huntington Memorial Medical Center
Wendy Hu, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Society for Blood and Marrow Transplantation, American Society of Clinical Oncology, American Society of Hematology, and Physicians for Social Responsibility
Disclosure: Nothing to disclose.
Rajalaxmi McKenna, MD, FACP, Consulting Staff, Department of Medicine, Southwest Medical Consultants, SC, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.
John S Macdonald, MD, Professor of Medicine, New York Medical College; Chief, St Vincent's Hospital and Medical Center; Medical Director, Division of Medical Oncology, Saint Vincent's Comprehensive Cancer Center
John S Macdonald, MD is a member of the following medical societies: American Association for Cancer Research, American Cancer Society, American College of Clinical Pharmacology, American College of Physicians, American Federation for Medical Research, American Society of Clinical Oncology, Pennsylvania Medical Society, Philadelphia County Medical Society, Sigma Xi, Southern Association for Oncology, and Southern Medical Association
Disclosure: Nothing to disclose.
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