Thyroid lymphoma can classify as either primary or secondary thyroid lymphoma. Primary thyroid lymphoma affects the thyroid gland first followed by spread to the lymph nodes and other organs later. Secondary thyroid lymphoma affects lymph nodes and other organs first followed by subsequent spread to the thyroid. This review article focuses only on primary thyroid lymphoma.
Primary thyroid lymphoma is quite rare and accounts for less than five percent of all thyroid malignancies and less than three percent of all extranodal lymphomas. Primary thyroid lymphoma frequently occurs in patients with pre-existing Hashimoto (chronic autoimmune) thyroiditis and is the only associated risk factor. The risk is almost 60 times higher in those with thyroiditis compared to those without thyroiditis. There is no association with Grave disease, colloid goiter, exposure to ionizing radiation, chromosomal abnormalities, and the development of primary thyroid lymphoma.
Nearly all cases (98 percent) of primary thyroid lymphoma are B-cell lymphomas. Among the B-cell lymphomas, diffuse large B-cell lymphoma (DLBCL) is the most common subtype and constitutes about 70 percent of the cases. Extranodal marginal zone lymphoma is the next common subtype, followed by follicular lymphoma and extranodal small lymphocytic lymphoma. There are rare reports of T-cell primary thyroid lymphomas in human T-lymphotropic virus-associated adult T-cell leukemia/lymphoma endemic areas.
The most common local symptom is a rapidly enlarging thyroid gland (goiter) along with the obstructive symptoms caused by the enlarged gland. Obstructive symptoms include dyspnea, stridor due to tracheal compression; dysphagia due to esophageal compression; neck pain and facial edema due to neck veins/superior vena cava compression; hoarseness of voice due to recurrent laryngeal nerve compression. The common systemic symptoms include B symptoms of lymphoma - fever, night sweats, weight loss; symptoms of hypothyroidism - fatigue, cold intolerance, constipation, dry skin/hair, hoarse voice, menstrual irregularities. Hypothyroidism in these patients is commonly due to Hashimoto thyroiditis and infrequently due to diffuse thyroid gland infiltration by the lymphoma. Rarely, some patients may have symptoms of hyperthyroidism due to the destruction of the thyroid follicles by the lymphoma.
Physical examination is significant for a firm to hard, diffusely enlarged, and immobile thyroid gland along with cervical or supraclavicular lymphadenopathy. Rarely, some patients may have a large distinct nodule instead of diffuse thyroid enlargement.
The workup should include:
There is no specific laboratory finding. Laboratory findings of hypothyroidism- elevated TSH, low T3 and T4; Hashimoto’s thyroiditis - elevated antithyroglobulin or antithyroid peroxidase antibodies occur commonly.
Thyroid ultrasound is the recommended initial imaging modality. Thyroid ultrasound frequently shows multiple hypoechogenic areas appearing as pseudocysts. To determine the extent of disease, like extrathyroidal spread, tracheal invasion, lymph node involvement, computed tomography (CT), and magnetic resonance imaging (MRI) are more useful than ultrasound. Other imaging studies like 18-fluorodeoxyglucose (FDG) positron emission tomography (PET) shows increased uptake throughout the thyroid gland and is used for staging, assessing response to treatment, but not useful for diagnosis as it cannot differentiate thyroid lymphoma from other conditions like Hashimoto thyroiditis.
Fine needle aspiration (FNA) is the initial diagnostic procedure for thyroid tissue sampling. FNA alone has low sensitivity and is more likely to be diagnostic in patients with large lymphoma burden. Core biopsy is more sensitive than FNA as it yields more tissue and preserves the tissue architecture. Irrespective of FNA results, if a diagnosis of thyroid lymphoma is suspected, a core biopsy is recommended for definitive diagnosis and additional immunohistochemical studies. Additional testing like flow cytometry or immunohistochemical staining is needed to establish the monoclonality of lymphocytes and to determine the precise histological subtype of the lymphoma.
Treatment of primary thyroid lymphoma depends on the histological subtype and staging of the tumor. Combined modality treatment with chemotherapy and radiotherapy is preferred over chemotherapy alone for limited stage DLBCL as it is associated with higher five-year failure-free survival rate. Chemotherapy alone is the therapeutic choice for advanced stage DLBCL. Chemotherapy regimen used is rituximab- cyclophosphamide, doxorubicin, vincristine, prednisolone (R- CHOP). Radiotherapy alone is the option for early stage, and rituximab or chemoimmunotherapy are choices for advanced stage extranodal marginal zone lymphoma, follicular lymphoma, small lymphocytic lymphomas. Treatment failure is most commonly due to recurrence in a distant site. Surgery is generally not recommended except for diagnostic biopsy due to the potential surgical risks and no additional benefit compared to chemoradiation therapy.
Obstructive symptoms usually improve within hours of chemotherapy (R- CHOP) initiation due to the steroid (prednisolone) in the regimen. Due to this rapid effect, even patients with severe airway compromise due to tracheal compression can be safely and successfully managed medically avoiding the need for tracheotomy or thyroidectomy. Thyroid hormone replacement is the management strategy for hypothyroidism symptoms (due to Hashimoto thyroiditis or diffuse thyroid gland infiltration by the lymphoma or radiation associated).
The principal differential diagnosis is anaplastic thyroid carcinoma as it clinically resembles primary thyroid lymphoma by presenting as a rapidly growing thyroid mass, which is firm and fixed to the surrounding structures. The other differentials include primary thyroid carcinomas like papillary thyroid carcinoma, follicular thyroid carcinoma, and medullary thyroid carcinoma; benign conditions like simple colloid goiter, and a benign thyroid nodule.
Lugano staging system (modified Ann Arbor staging classification) is the means for staging primary thyroid lymphoma. Imaging for lymphoma staging includes FDG PET/ CT for FDG avid lymphomas and CT alone for FDG non-avid lymphomas like small lymphocytic lymphoma, marginal zone lymphoma. Almost 80 percent of patients have limited disease, i.e., stage IE – thyroid only or IIE- thyroid + regional lymph nodes. Only about 20 percent of patients have advanced disease, i.e., stage IIIE -thyroid + lymph nodes/organs on either side of diaphragm or IV- generalized disease.
Prognosis depends on the histology, tumor burden, stage, age, performance status, treatment type. The five-year failure-free survival rate is 91 percent, in patients with limited stage (IE, IIE) disease who received combined modality (chemotherapy and radiotherapy) treatment, implying an excellent prognosis for thyroid lymphoma in general.
Complications due to lymphoma include life-threatening complications like airway compromise due to tracheal compression, superior vena cava syndrome due to superior vena cava compression, dysphagia due to esophageal compression. Complications due to lymphoma treatment include radiation associated hypothyroidism, radiation-associated malignancies of the thyroid or other exposed organs, peripheral neuropathy due to vincristine, congestive heart failure due to doxorubicin, hemorrhagic cystitis/bladder cancer due to cyclophosphamide.
Lymphoma is a solid, cohesive cancer of the lymphatic cells. In thyroid lymphoma, these lymphoid cancer cells in the thyroid cause the gland to enlarge. The patient may experience various symptoms due to thyroid gland dysfunction and enlargement; or symptoms like fever, night sweats, and weight loss due to the lymphoma itself. Multiple laboratory investigations, imaging, and biopsy of the thyroid gland are needed to establish the diagnosis and stage the lymphoma. Good treatment options are available depending on the specific subtype and stage of the lymphoma. Usually, multiple specialists like the medical oncologist, radiation oncologist, chemo pharmacist, chemo nurse are involved in healthcare. Prognosis depends on several factors like age, functional status, tumor type, and stage; but overall, primary thyroid lymphoma has an excellent prognosis if promptly identified and treated.
In patients presenting with a rapidly enlarging goiter, especially in the setting of Hashimoto’s thyroiditis, the diagnosis of primary thyroid lymphoma should always be considered.
Management of primary thyroid lymphoma requires the involvement of an interprofessional team of specialists from different departments that includes a medical oncologist, radiation oncologist, ENT surgeon, primary care physician, endocrinologist, and pathologist. Patients usually present to their primary care physician, nurse practitioner or endocrinologist with an enlarged neck mass and obstructive symptoms, and it is the responsibility of the initial physician to have a high degree of suspicion for thyroid lymphoma and involve the ENT surgeon and the pathologist for establishing a diagnosis with a core biopsy of the thyroid. Once the diagnosis is confirmed, the medical oncologist, radiation oncologist, and an endocrinologist should all have involvement in the case; additional workup and treatment should commence immediately. Primary thyroid lymphoma has a good prognosis if the patient receives well-coordinated care from all the specialists promptly. As can be seen, thyroid lymphoma diagnosis and management require an interprofessional team approach, including physicians, specialists, specialty-trained nurses, and pharmacists, all collaborating across disciplines to achieve optimal patient results. [Level V]
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