Thyroid Lymphoma

Etiology

Primary thyroid lymphoma is uncommon, comprising less than 5% of all thyroid malignancies and less than 3% of all extranodal lymphomas.[2] Primary thyroid lymphoma often manifests in individuals with preexisting Hashimoto (chronic autoimmune) thyroiditis, showing a significant correlation with previous autoimmune conditions.[3] The risk of developing primary thyroid lymphoma is nearly 60 times higher in individuals with thyroiditis compared to those without, typically emerging 20 to 30 years after the initial diagnosis of thyroiditis.[4]

Epidemiology

The yearly estimated incidence of thyroid lymphoma is approximately 2 per 1 million individuals.[5] The occurrence and prevalence of primary thyroid lymphoma are elevated in regions with higher rates of thyroiditis.[6] This condition is more common in females, with a female-to-male predisposition ratio of approximately 4:1. The average diagnosis is around age 65.[7]

Pathophysiology

The chronic antigen stimulation and heightened proliferation of lymphocytes in autoimmune conditions like Hashimoto thyroiditis have been suggested as potential contributors to the malignant transformation leading to primary thyroid lymphoma.[5] Notably, there is no discernible association between conditions like Grave disease, colloid goiter, exposure to ionizing radiation, or chromosomal abnormalities and the development of primary thyroid lymphoma.[8]

Histopathology

Almost all instances (98%) of primary thyroid lymphoma belong to the category of B-cell, non-Hodgkin lymphomas.[7] Among B-cell lymphomas, the most prevalent subtype is diffuse large B-cell lymphoma (DLBCL), encompassing approximately 60% to 70% of cases. Mucosa-associated lymphoid tissue (MALT) lymphoma/extranodal marginal zone lymphoma follows, constituting 10% to 23% of cases. Follicular lymphoma represents 10% of cases, followed by small lymphocytic lymphoma and chronic lymphocytic lymphoma at around 3%. Mantle cell lymphoma constitutes less than 1% of cases.

Other rare histological types include Hodgkin lymphoma (2% of cases), T-cell lymphomas, and lymphoblastic lymphomas (<1% of cases).[5][9] Intermittent T-cell primary thyroid lymphoma cases have been reported in regions endemic to human T-lymphotropic virus (HTLV) associated adult T-cell leukemia and lymphoma.[10] If untreated, indolent histologies like MALT lymphoma and extranodal marginal zone lymphoma can transform into aggressive histologies like DLBCL. Mixed histology, ie, DLBCL and MALT occurring together, is observed in some cases.[5]

History and Physical

The aggressiveness of clinical presentation depends on histology, with DLBCL displaying a more aggressive behavior than indolent lymphomas like MALT lymphoma or follicular lymphomas. The duration of symptoms before diagnosis can range widely, ranging from a few days to a few years, with a notably shorter duration reported in DLBCL.[11]

The predominant local symptom is a rapidly enlarging thyroid gland (goiter), accompanied by obstructive symptoms resulting from the enlarged gland.[7][12] These obstructive symptoms include dyspnea, stridor due to tracheal compression, dysphagia due to esophageal compression, neck pain, facial edema due to compression of neck veins and the superior vena cava, and hoarseness of voice due to recurrent laryngeal nerve compression.

The systemic symptoms encompass B-symptoms of lymphoma, such as fever, night sweats, and weight loss, as well as symptoms of hypothyroidism, including fatigue, cold intolerance, constipation, dry skin/hair, hoarse voice, and menstrual irregularities. Hypothyroidism in these patients is commonly due to Hashimoto thyroiditis and, infrequently, to diffuse thyroid gland infiltration by the lymphoma. Rarely, some patients may exhibit symptoms of hyperthyroidism due to the destruction of the thyroid follicles by the lymphoma.[13] Patients with Hashimoto thyroiditis undergoing thyroid hormone replacement are expected to maintain euthyroid status.

Physical examination typically reveals a firm to hard, diffusely enlarged, and immobile thyroid gland, accompanied by cervical or supraclavicular lymphadenopathy.[12] Rarely, some patients may present with a large distinct nodule instead of diffuse thyroid enlargement.

Evaluation

The workup for thyroid lymphoma should encompass the following:

Laboratory Evaluation

There is no specific or pathognomic laboratory finding in thyroid lymphomas. Laboratory findings associated with hypothyroidism (elevated thyroid stimulating hormone [TSH], low T3, and T4) and Hashimoto thyroiditis (elevated antithyroglobulin or antithyroid peroxidase antibodies) are common.[14] Rarely, laboratory findings indicate hyperthyroidism, characterized by low TSH and elevated T3 and T4 levels. If patients with Hashimoto thyroiditis are undergoing thyroid hormone replacement, laboratory findings of euthyroidism (normal TSH, T3, and T4) are expected. 

Imaging

Thyroid ultrasound is the recommended initial imaging modality. Although there are no specific findings, characteristic features within 1 of the 3 patterns (nodular, diffuse, or mixed) of thyroid appearance can suggest primary thyroid lymphoma. Thyroid ultrasound often reveals enhanced posterior echoes, multiple hypoechogenic areas resembling pseudocysts, and increased vascularity.[5][15] In a prospective study, 74 of 165 patients (47.9%) suspected of having malignant thyroid lymphoma based on ultrasound findings had pathologically confirmed lymphoma.[16]

To determine the extent of disease, including extrathyroidal spread, tracheal invasion, and lymph node involvement, computed tomography (CT) or magnetic resonance imaging (MRI) are more useful than ultrasound. Other imaging studies like 18-fluorodeoxyglucose (FDG) positron emission tomography (PET) show increased uptake throughout the thyroid gland. PET scans offer superior diagnostic accuracy in lymphoma for staging and assessing response to treatment but are less useful for the initial diagnosis as they cannot differentiate thyroid lymphoma from other conditions like Hashimoto thyroiditis.[17]

Pathology

The definitive diagnosis of primary thyroid lymphoma is established through histopathological analysis of tissue. Fine needle aspiration (FNA) is the initial diagnostic procedure for thyroid tissue sampling.[2][15] FNA alone has low sensitivity, diagnosing only 50% to 80% of cases depending on the study, and is more likely to be diagnostic in patients with a large lymphoma burden.[2][18] Core biopsy is more sensitive than FNA, providing larger tissue samples and preserving tissue architecture, facilitating the differentiation between thyroiditis and lymphoma, and identifying the lymphoma subtype. Although the sensitivity of FNA has improved with newer adjuncts like flow cytometry and immunohistochemical staining that help establish the monoclonality of lymphocytes, a core biopsy is still suggested for definitive diagnosis when primary thyroid lymphoma is suspected.[15][19] Open surgical biopsy is reserved for cases where less invasive techniques (like FNA or core needle biopsy) cannot definitively establish the diagnosis or identify the subtype of primary thyroid lymphoma.[2]

Treatment / Management

The management of primary thyroid lymphoma depends on the histological subtype and staging of the tumor. Given the rarity of primary thyroid lymphoma, large prospective randomized trials for optimal management are limited. Treatment recommendations primarily derive from extrapolation based on prospective, randomized studies in non-Hodgkin lymphomas. 

For DLBCL histology, combined modality treatment involving chemotherapy and radiotherapy is preferred for limited-stage (IE or IIE) DLBCL, as it is associated with a higher 5-year failure-free survival rate than chemotherapy alone.[20] For advanced stage (IIIE or IV) DLBCL, the first-line treatment involves rituximab (a monoclonal antibody selectively binding the CD20 antigen on the pre-B and mature B lymphocytes) in combination with chemotherapy (R-CHOP: rituximab in combination with cyclophosphamide, doxorubicin, vincristine, prednisolone). (B2)

For other histologies like MALT lymphoma and follicular lymphoma, treatment options for limited-stage (IE or IIE) include radiotherapy alone or combined modality treatment with chemoimmunotherapy using rituximab. For advanced-stage (IIIE or IV) indolent varieties of thyroid lymphoma, rituximab alone or in combination with chemotherapy stands as the first-line treatment option.[20][21](B2)

Surgery is generally not recommended for the treatment of primary thyroid lymphoma. It holds no role beyond diagnostic biopsy due to potential surgical risks and the absence of additional benefits compared to chemoradiation therapy.[2] Obstructive symptoms usually improve within days of chemotherapy (R-CHOP) initiation due to the steroid in the regimen. The rapid alleviation of symptoms allows for the safe and successful medical management of severe airway compromise due to tracheal compression, often avoiding the need for tracheostomy or thyroidectomy.[2](B3)

The management strategy for hypothyroidism symptoms, whether arising from Hashimoto thyroiditis, diffuse thyroid gland infiltration by the lymphoma, or radiation-associated hypothyroidism, involves thyroid hormone replacement. A study at the Mayo Clinic demonstrated that diagnostic biopsy followed by definitive chemotherapy alone was more effective in complete remission rates than undergoing surgical debulking followed by adjuvant therapies.[22]

Treatment failures, categorized as refractory lymphoma (no response to initial treatment or reoccurrence shortly after completing treatment) or relapsed lymphoma (responds to treatment and enters remission but recurs after a period), can occur. Subsequent treatment options for refractory and relapsed cases vary, contingent on histology and time taken for relapse following initial treatment. These options are primarily informed by evidence from non-Hodgkin lymphoma trials and studies.

Differential Diagnosis

The primary differential diagnosis for primary thyroid lymphoma is anaplastic thyroid carcinoma, given its clinical resemblance characterized by the presentation of a rapidly growing thyroid mass that is firm and fixed to surrounding structures. Other differentials include primary thyroid carcinomas like papillary thyroid carcinoma, follicular thyroid carcinoma, and medullary thyroid carcinoma, and benign conditions like simple colloid goiter and benign thyroid nodules.

Despite its rarity, primary thyroid lymphoma should always be considered in the list of potential diagnoses for any rapidly growing thyroid nodules or goiter. Early diagnosis and appropriate management play a crucial role in impacting the prognosis. 

Staging

The Lugano staging system or modified Ann Arbor staging classification determines the staging of primary thyroid lymphomas.[23] Imaging for lymphoma staging includes imaging the whole body with either FDG PET/ CT for FDG avid lymphomas or CT scans (of the head, neck, chest, abdomen, and pelvis) for FDG non-avid lymphomas like MALT lymphoma and small lymphocytic lymphoma. Almost 80% of patients present with limited disease (stage IE: thyroid only or IIE: thyroid with regional lymph nodes involvement), while about 20% of patients have advanced disease (stage IIIE: thyroid with lymph nodes and organs involvement on both sides of the diaphragm or stage IV: disseminated lymphoma).[7][24] Accurate staging at the time of presentation is crucial for assessing prognosis, determining the appropriate treatment, and evaluating treatment response.

Prognosis

The prognosis of primary thyroid lymphoma depends on various factors such as histology, tumor burden, stage, age, performance status, treatment modality, and type. Histology-specific disease-free survival rates from the Surveillance Epidemiology and End Result (SEER) database estimate a 5-year disease-free survival rate of 96% for MALT lymphoma, 87% for follicular lymphoma, 86% for small lymphocytic lymphoma, and 75% for DLBCL.[2] Histology-specific overall survival rates from the UK lymphoma treatment center experience estimate a 5-year survival rate of 75% for indolent B-cell lymphoma not otherwise specified, 62% for MALT lymphoma, and 45% for DLBCL, with a median overall survival of all histological subtypes being 5.7 years.[25]

Complications

Complications arising from thyroid lymphoma include life-threatening issues like airway compromise due to tracheal compression, superior vena cava syndrome due to superior vena cava compression, and dysphagia due to esophageal compression. Additionally, complications stemming from lymphoma treatment include radiation-associated hypothyroidism, radiation-associated malignancies of the thyroid or other exposed organs, chemotherapy-related side effects like peripheral neuropathy due to vincristine, congestive heart failure due to doxorubicin, conditions such as hemorrhagic cystitis or bladder cancer due to cyclophosphamide.