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 represents approximately 1.2 to 1.7% of all NHLs.[1] 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]

Pathophysiology
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.[3]
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
Sjgren 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.

Epidemiology and Prognosis

Primary thyroid lymphoma is rare, constituting only 1-2% of all extranodal lymphomas and
approximately 2-8% of all thyroid malignancies.[4, 3, 6, 5] As with other non-Hodgkin lymphomas,
the median age of presentation in patients with thyroid lymphoma is usually close to 60 years.[5, 6]
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.[7]
History and Physical Examination

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.
Differential Diagnoses

Anaplastic Thyroid Carcinoma

Medullary Thyroid Carcinoma

Papillary Thyroid Carcinoma

Thyroid Nodule

Laboratory Studies
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 beta 2 -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.[8] 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.

Plain Radiography, CT, Gallium Scanning, and PET

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.

Histologic Findings
In current practice, the diagnosis of thyroid lymphoma can be easily established by means of
either fine-needle aspiration (FNA) or core-needle biopsy,[8] 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[9] :

Large-cell lymphoma

Follicular lymphoma

Mucosa-associated lymphoid tissue (MALT) lymphoma (MALToma)

Burkitt lymphoma (rare)

In a study from Japan that evaluated 171 patients with primary thyroid lymphoma, the
distribution of pathologic diagnoses was as follows[10] :

Diffuse large B-cell lymphoma (DLBCL) - 43%

DLBCL with MALToma - 8%

MALToma - 47%

Other - 2%

Staging
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).[11] This
prognostic system assigns 1 point to each of the following variables:

Age older than 60 years

Performance status greater than 1

Elevated lactic dehydrogenase (LDH) level

Number of extranodal sites greater than 1

Ann Arbor stage III-IV

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.[9] . 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 populationbased study and found that older age, advanced stage, histologic subtype, and lack of
radiation/surgical treatment were adverse factors for survival.[7]

Chemotherapy and Radiation Therapy

Large-cell lymphoma
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,
vincristine, prednisone) regimen and radiation therapy. As many as 90% of cases are failure-free
after this approach.[12] 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%.[13] 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.[14]
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.[15]
Long-Term Monitoring

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%.
Medication Summary

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.
Antineoplastic Agents

Class Summary
Antineoplastic agents inhibit cell growth and proliferation.
View full drug information

Cyclophosphamide
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.
View full drug information

Doxorubicin (Adriamycin)
Doxorubicin intercalates DNA and inhibits topoisomerase II; it produces free radicals that may
cause destruction of DNA and inhibit growth of neoplastic cells.
View full drug information

Vincristine (Vincasar VFS)

Vincristine's mechanism of action is uncertain; it may involve a decrease in reticuloendothelial
cell function or an increase in platelet production.
Antineoplastics, Monoclonal Antibody

Class Summary
Monoclonal antibodies are genetically engineered chimeric murine-human immunoglobulins
directed against proteins involved in cell cycle initiation.
View full drug information

Rituximab (Rituxan)
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.
Corticosteroids

Class Summary
These agents have anti-inflammatory properties and cause profound and varied metabolic effects.
Corticosteroids modify the body's immune response to diverse stimuli.
View full drug information

Prednisone
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.
View full drug information

Prednisolone (Millipred, Pediapred)

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.

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