AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

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• Follow-up
• Miscellaneous
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INTRODUCTION

Section 2 of 11  

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Background

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.

Pathophysiology

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.

Frequency

United States

Thyroid lymphomas constitute only 3% of all NHLs and approximately 5% of all thyroid neoplasms^{2, 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.

Mortality/Morbidity

Primary thyroid lymphoma, as discussed in this article, is a highly curable malignancy if diagnosed promptly and managed correctly.

Sex

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 series^{3, 5}.

Age

Similar to other NHLs, thyroid lymphomas usually affect patients with a median age of 60 years⁶.

CLINICAL

Section 3 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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History

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.

Physical

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.

DIFFERENTIALS

Section 4 of 11  

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Other Problems to be Considered

Thyroid adenoma

WORKUP

Section 5 of 11  

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• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Obtain the following laboratory studies after the diagnosis of thyroid NHL is established:
• • CBC count: CBC count and bone marrow are important as part of the staging evaluation.
  
  
  • Determination of serum lactate dehydrogenase (LDH) level: Serum LDH and beta2-microglobulin levels are important because of their usefulness in predicting the patient's prognosis. Serum LDH and beta2-microglobulin values are important because they are predictive of the patients' prognosis.^{7, 8}
  
  
  • Bone marrow aspiration and biopsy
  
  
  • Thyroid function tests: Evaluation of thyroid function is important because of the high incidence of hypothyroidism.
  
  
  • Test for antithyroglobulin or antimicrosomal antibodies

Imaging Studies

• To evaluate the extent of the disease, radiographs of the chest and CT scans of the head and neck, chest, abdomen, and pelvis are necessary. These are critical tests for determining the stage or extent of disease.
• Perform gallium scanning or positron emission tomography (PET) in patients with bulky disease because these can help in determining if any residual abnormality observed on posttreatment radiographs contains active lymphoma or scar tissue.
• • In patients with MALT lymphoma of the thyroid, PET scans should be interpreted cautiously because this subtype can give rise to false-negative results because of low metabolic rate.
  • The presence of an inflammatory condition, such as Hashimoto thyroiditis, can result in a false-positive PET scan. The amount of uptake, as measured by the standard uptake value (SUV), tends to be low in inflammatory conditions (SUV <6) and higher in large-cell lymphomas.

Histologic Findings

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.

Staging

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).

• In terms of predicting the prognosis, the aggressive thyroid lymphoma types (most commonly large-cell NHLs) can be classified by using the International Prognostic Index (IPI).¹¹ This prognostic system assigns 1 point to each of the following variables:
• • Age older than 60 years
  
  
  • Performance status higher than 1
  
  
  • Elevated LDH
  
  
  • Number of extranodal sites more than 1
  
  
  • Ann Arbor stage III-IV


• In a recent study, Ha et al tested the usefulness of the IPI in predicting the prognosis of patients with thyroid lymphoma. The 5-year survival rate for patients with an IPI of 0 was 86% versus 50% for patients with an IPI of greater than 0. The data included patients treated with radiation alone, chemotherapy alone, or combined-modality therapy.


• According to recent data from the MD Anderson Cancer Center, a diagnosis of thyroid MALT lymphoma should prompt gastroscopy to exclude involvement of the stomach by MALT lymphoma. MALT lymphomas tend to migrate to other areas of MALT.

TREATMENT

Section 6 of 11  

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Medical Care

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.

• MALT lymphomas
  • In theory, thyroid diffuse large-cell lymphomas arise from previously existing low-grade MALT lymphomas; however, the latter are not common in the thyroid gland. For this reason, data regarding their treatment are limited.
  
  
  • Local treatment with radiation therapy appears to be adequate.¹⁶
    
  
  
  • Patients with intermediate- or high-grade lymphoma arising from MALT lymphoma appear to have the worst prognoses, and these patients need aggressive treatment with combined-modality therapy, as discussed above.
    
  
  
  • According to recent data from our institution, a diagnosis of thyroid MALT lymphoma should prompt gastroscopy to rule out involvement of the stomach. MALT lymphomas tend to migrate to other areas with MALT.


• Relapsed thyroid lymphomas
  • Because of the excellent outcome related to the front-line management of MALT thyroid lymphoma, data on the salvage management of this cell type are limited. On the contrary, the management of relapsed thyroid large-cell lymphoma is based on principles similar to those applied in the salvage management of any recurrent large-cell lymphoma.
    
  
  
  • If circumstances allow, high-dose chemotherapy with autologous stem-cell transplantation is considered the treatment of choice.
    
  
  
  • Before the use of high-dose chemotherapy, a conventional dose-salvage regimen (eg, one containing Ara-C and platinum or ifosfamide and VP-16) is administered, usually for 1-2 courses. This step is typically followed by mobilization of peripheral blood stem cells with the same or another chemotherapeutic regimen. After adequate numbers of autologous hematopoietic stem cells are collected, patients receive high-dose chemotherapy, followed by autologous stem-cell transplantation for hematopoietic rescue.

MEDICATION

Section 7 of 11  

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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.

Drug Category: Antineoplastic regimens

These agents inhibit cell growth and proliferation.

Drug Name	Doxorubicin (Adriamycin, Rubex)
Description	Intercalates DNA and inhibits topoisomerase II; produces free radicals that may cause destruction of DNA and inhibit growth of neoplastic cells.
Adult Dose	50 mg/m2 IV on day 1 of each course
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; severe heart failure, cardiomyopathy, impaired cardiac function, preexisting myelosuppression
Interactions	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
Pregnancy	D - Unsafe in pregnancy
Precautions	Can cause birth defects particularly when administered during first trimester of pregnancy

Drug Name	Vincristine (Oncovin, Vincasar VFS)
Description	Mechanism of action is uncertain. May involve decrease in reticuloendothelial cell function or increase in platelet production.
Adult Dose	1.4 mg/m2 IV on day 1 of each course
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Acute pulmonary reaction may occur when taken concurrently with mitomycin-C
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in severe cardiopulmonary or hepatic impairment and preexisting neuromuscular disease; can cause birth defects particularly when administered during first trimester of pregnancy

Drug Name	Prednisone (Deltasone, Meticorten, Orasone, Sterapred)
Description	Immunosuppressant for treatment of autoimmune disorders. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.
Adult Dose	100 mg PO on days 1-5 of CHOP
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; viral infection, peptic ulcer disease, hepatic dysfunction, connective tissue infections, and fungal or tubercular skin infections; GI disease
Interactions	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
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	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

Drug Name	Rituximab (Rituxan)
Description	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.
Adult Dose	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
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in preexisting cardiac conditions; regularly obtain CBC during therapy and more frequently if cytopenia develops

FOLLOW-UP

Section 8 of 11  

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• Follow-up
• Miscellaneous
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Further Inpatient Care

• Follow-up care of patients with thyroid lymphoma is similar to the care of patients with any other lymphoma.
• In brief, see patients 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 indolent lymphoma types (ie, low-grade variants), 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 more than 90%.

Complications

• Complications are usually related to adverse effects (eg, myelosuppression) of chemotherapy, which can be associated with infections or bleeding.
• Radiation therapy can induce xerostomia, depending on the fields used.

Prognosis

• 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.
• The cure rate is usually high.
• See Medical Care for further discussion.

Patient Education

• For excellent patient education resources, visit eMedicine's Endocrine System Center. Also, see eMedicine's patient education article Thyroid Problems.

MISCELLANEOUS

Section 9 of 11  

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Medical/Legal Pitfalls

• Primary thyroid lymphoma usually occurs in women older than 55 years.
• • Most primary thyroid lymphomas arise in the background of Hashimoto thyroiditis.
  • This tumor is occasionally confused with anaplastic thyroid carcinoma, which can lead to serious mistakes in management.

• The best treatment results for primary thyroid large-cell lymphoma occur with combined-modality therapy, which can result in a high cure rate.
• • For primary thyroid MALT lymphoma, radiation therapy alone is probably adequate.
  • Patients with diffuse large-cell primary thyroid lymphoma should not be treated with radiation therapy alone.

• Thyroid function should be assessed.

MULTIMEDIA

Section 10 of 11  

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Media file 1:  Rapidly enlarging thyroid mass occurring in association with neck adenopathy.
	View Full Size Image
Media type:  CT

REFERENCES

Section 11 of 11

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1. Holm LE, Blomgren H, Lowhagen T. Cancer risks in patients with chronic lymphocytic thyroiditis. N Engl J Med. Mar 7 1985;312(10):601-4. [Medline].
2. Ansell SM, Grant CS, Habermann TM. Primary thyroid lymphoma. Semin Oncol. Jun 1999;26(3):316-23. [Medline].
3. Austin JR, el-Naggar AK, Goepfert H. Thyroid cancers. II. Medullary, anaplastic, lymphoma, sarcoma, squamous cell. Otolaryngol Clin North Am. Aug 1996;29(4):611-27. [Medline].
4. Pasieka JL. Anaplastic cancer, lymphoma, and metastases of the thyroid gland. Surg Oncol Clin N Am. Oct 1998;7(4):707-20. [Medline].
5. Tupchong L, Hughes F, Harmer CL. Primary lymphoma of the thyroid: clinical features, prognostic factors, and results of treatment. Int J Radiat Oncol Biol Phys. Oct 1986;12(10):1813-21. [Medline].
6. Ha CS, Shadle KM, Medeiros LJ, et al. Localized non-Hodgkin lymphoma involving the thyroid gland. Cancer. Feb 15 2001;91(4):629-35. [Medline].
7. Velasquez WS, Jagannath S, Tucker SL, et al. Risk classification as the basis for clinical staging of diffuse large- cell lymphoma derived from 10-year survival data. Blood. Aug 1 1989;74(2):551-7. [Medline].
8. Swan F Jr, Velasquez WS, Tucker S, et al. A new serologic staging system for large-cell lymphomas based on initial beta 2-microglobulin and lactate dehydrogenase levels. J Clin Oncol. Oct 1989;7(10):1518-27. [Medline].
9. Pappa VI, Hussain HK, Reznek RH, et al. Role of image-guided core-needle biopsy in the management of patients with lymphoma. J Clin Oncol. Sep 1996;14(9):2427-30. [Medline].
10. Isaacson PG. Lymphoma of the thyroid gland. Curr Top Pathol. 1997;91:1-14. [Medline].
11. International Non-Hodgkin Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin's lymphoma. The International Non-Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med. Sep 30 1993;329(14):987-94. [Medline].
12. Miller TP, Dahlberg S, Cassady JR, et al. Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin's lymphoma. N Engl J Med. Jul 2 1998;339(1):21-6. [Medline].
13. Matsuzuka F, Miyauchi A, Katayama S, et al. Clinical aspects of primary thyroid lymphoma: diagnosis and treatment based on our experience of 119 cases. Thyroid. Summer 1993;3(2):93-9. [Medline].
14. Rodriguez J, Cabanillas F, McLaughlin P, et al. A proposal for a simple staging system for intermediate grade lymphoma and immunoblastic lymphoma based on the 'tumor score'. Ann Oncol. Nov 1992;3(9):711-7. [Medline].
15. Glick JH, Kim K, Earle J, et al. An ECOG randomized phase III trial of CHOP vs. CHOP + radiotherapy (XRT) for intermediate grade early stage non-Hodgkin's lymphoma (NHL) [abstract]. Proceedings of the American Society of Clinical Oncology. 1995;14 (A-1221):391.
16. Laing RW, Hoskin P, Hudson BV, et al. The significance of MALT histology in thyroid lymphoma: a review of patients from the BNLI and Royal Marsden Hospital. Clin Oncol (R Coll Radiol). 1994;6(5):300-4. [Medline].
17. Miller TP, Dahlberg S, Cassidy JR, et al. Three cycles of CHOP (CHOP-3) plus radiotherapy (RT) is superior to eight cycles of CHOP (CHOP-8) alone for localized intermediate grade non-Hodgkin's lymphoma (NHL). A Southwest Oncology Group study. Proc Ann Meet Am Soc Clin Oncol. 1996;15 (A1257):411.
18. Ito Y, Yoshida H, Matsuzuka F, et al. Cdc25A and cdc25B expression in malignant lymphoma of the thyroid: Correlation with histological subtypes and cell proliferation. Int J Mol Med. Mar 2004;13(3):431-5. [Medline].
19. Macchiarini P, Ostertag H. Uncommon primary mediastinal tumours. Lancet Oncol. Feb 2004;5(2):107-18. [Medline].

Article Last Updated: May 17, 2007