Follicular lymphoma of the thyroid and the role of core needle biopsy

Background

Primary thyroid lymphoma (PTL) is a rare neoplasm, accounting 2–5% of all thyroid malignancies, with an annual incidence of two cases per million people (1, 2). PTL accounts for less than 3% of all extranodal non-Hodgkin’s lymphomas (3). PTL has a female preponderance (female:male 2–8:1), with a peak incidence between 60 and 70 years (2). Patients with Hashimoto's thyroiditis have an increased risk of developing PTL (1, 4). Most PTLs are non-Hodgkin’s lymphomas and arise from B-cell. Diffuse large B-cell lymphoma is the most common subtype of PTL (>50%), followed by marginal zone lymphoma (10–23%) (2). Follicular subtype of PTL is even more rare, accounting for about 10% of all cases (2).

Treatment and prognosis of PTL depend on the histologic subtype and stage of the disease at diagnosis (1). Although rare, PTL must be considered in the differential diagnosis of a rapidly expanding thyroid mass with compressive symptoms, especially in the setting of Hashimoto’s thyroiditis (2). Early institution of treatment can reduce tumour volume and prevent airway compromise (2). We report a challenging case of a woman with a successfully treated follicular thyroid lymphoma.

Case presentation

A 64-year-old woman referred to our Endocrinology department due to a rapidly growing right neck mass associated with dysphagia developing over the last 3 months. She also complained of night sweats and weight loss. Past medical history included primary hypothyroidism due to Hashimoto’s thyroiditis, duodenal ulcer and a 52-pack-year smoking history. She was on levothyroxine 100 μg and omeprazole 20 mg. Worth to add that she had a family history of non-Hodgkin’s B cell lymphoma, with her father dying of a lymphoproliferative disease at the age of 78 years. The patient had no previous exposure to radiotherapy or a familial history of thyroid cancer. On physical examination, a nontender neck mass measuring up to 6 cm was palpated in the right thyroid lobe along with cervical lymphadenopathy on the right at levels II, III and IV.

Investigation

Neck ultrasound (US) revealed a diffuse goitre, with a solid hypoechoic nodule measuring 56 × 63 × 60 mm within the right thyroid lobe. It also showed cervical lymphadenopathies of the VII and right II–IV levels. Blood tests showed euthyroidism, with TSH 0.540 μIU/mL (0.27–4.20 μIU/mL) and free T4 17.5 pmol/L (12–22 pmol/L), with increased levels of antiperoxidase (1000 UI/mL, reference range: <53 UI/mL) and antithyroglobulin (1166 UI/mL, reference range: <115 UI/mL) antibodies. Subsequently, a US-guided percutaneous fine-needle aspiration (FNA) of the right thyroid nodule was performed which presented lymphocytic thyroiditis. Cytopathological diagnostic category was ‘benign’, according to Bethesda System. A CT scan of the neck showed a diffuse enlargement of the thyroid gland extending to the mediastinum with tracheal deviation and lymphadenopathies within levels VII (16 × 14 mm), right II (11 × 10 mm), III (14 × 14 mm) and IV (19 × 10 mm) (Figs. 1 and 2). The fine needle aspiration cytology of the lymphadenopathy (level IV) was compatible with follicular lymphoid hyperplasia. The core needle biopsy of the right thyroid nodule revealed follicular non-Hodgkin’s B cell lymphoma. On immunohistochemistry, neoplastic cells were diffusely immunoreactive to CD20, Bcl6 and CD10, and the Ki-67 index was 60%. The laboratory findings included haemoglobin 14 g/dL (reference range: 12–15 g/dL), leucocytes 5.4 × 10⁹/L (normal range (NR): 4–10 × 10⁹/L), platelets 256 × 10⁹/L (reference range: 150–400 × 10⁹/L), C-reactive protein 1.0 mg/dL (NR: <0.5 mg/dL), lactate dehydrogenase 212 U/L (NR: 135–225 U/L), B2-microglobulin 2.6 mg/L (reference range: 1.09–2.53 mg/L) and NT-proBNP 89 pg/mL (NR: <125 pg/mL). According to the histopathological and immunohistochemistry staining, she was diagnosed with follicular thyroid lymphoma and was referred to Hemato-Oncology department. The patient performed staging with chest and abdominopelvic CT scan which revealed abdominal lymphadenopathy (41 × 18 mm) between the portal vein and the inferior vena cava. The bone marrow biopsy did not show infiltration by the lymphoma. According to the Ann Arbor staging system, she was at stage IIIE and scored as a high-risk follicular lymphoma according to Follicular Lymphoma International Prognostic Index.

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Contrast-enhanced CT scan of the neck, at the infrahyoid level, depicting enlargement of the right thyroid lobe and a level IV enlarged lymph node (blue arrow).

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 1; 10.1530/EDM-21-0196

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Coronal view CT scan of the neck showing displacement of the contents of the carotid and visceral spaces of the neck by the enlarged right thyroid lobe.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 1; 10.1530/EDM-21-0196

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Treatment

The patient was discussed in the multidisciplinary meeting, and it was decided to perform chemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP). She received six cycles of R-CHOP during 4 months with significant clinical and imagiological improvement.

Outcome and follow-up

The neck, chest and abdominopelvic CT scan 6 weeks after the sixth cycle of R-CHOP showed regression of the thyroid gland volume and disappearance of the abdominal and cervical lymphadenopathies (Fig. 3). Two years after chemotherapy, the patient remains asymptomatic and free of disease.

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CT scan of the neck showed regression of the thyroid gland volume and disappearance of the cervical lymphadenopathies.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 1; 10.1530/EDM-21-0196

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Discussion

PTL is a rare neoplasm and represents less than 5% of all thyroid neoplasms (2). PTL has a female preponderance, usually developing in the sixth and seventh decades of life (1, 2). Normally, the thyroid gland does not contain native lymphoid tissue, unless there is a pathological condition like autoimmune thyroiditis (5, 6). In fact, most of PTLs arise in the setting of Hashimoto’s thyroiditis (60%), as in the present clinical case (5). Patients with Hashimoto's thyroiditis have a 60-fold increased risk of PTL probably due to chronic antigenic stimulation and reactive lymphoid proliferation, with possible acquisition of genetic mutations which can potentially lead to malignant transformation (4, 5).

Most of PTLs are non-Hodgkin lymphomas and arise from B-cell. Diffuse large B-cell lymphoma (>50%) and marginal zone lymphoma are the most frequent subtypes (10–23%). (2, 6). Rarer subtypes include follicular (10%), small lymphocytic (3%), Burkitt’s lymphoma (<1%) and Hodgkin’s lymphoma (2%) (2).

Thyroid lymphomas usually present with a rapidly enlarging goitre leading to compressive symptoms such as dysphagia, dyspnoea, stridor and hoarseness (7). Constitutional B symptoms including fever, weight loss and night sweats are reported in 10% of patients with PTL (2, 6). FNA has limited accuracy in PTL diagnosis due to cytomorphological similarities between PTL and Hashimoto’s thyroiditis and the possible overlapping of these two entities within the same gland, leading to false-negative results as exemplified in the present clinical case (6, 7). Furthermore, when FNA is combined with flow cytometry and immunohistochemistry, it can give a complete diagnosis in 82% of cases (3). However, tissue biopsy remains the gold standard for PTL diagnosis and core needle biopsy should be a first-line investigation in the presence of a growing thyroid mass. The core needle biopsy diagnoses and classifies more than 95% of thyroid lymphomas (6, 8). After the diagnosis is established, staging of the disease should be performed using the Ann Arbor system. Most patients present at diagnosis with locoregional disease (stages IE and IIE), and only 2–7% of patients with stages IIIE (involvement of lymph nodes on both sides of the diaphragm) and IVE (systemic dissemination) (2). ¹⁸F-fluorodeoxyglucose positron emission tomography (¹⁸F-FDG/CT PET) can be useful in staging and monitoring response to therapy in patients with PTL. However, ¹⁸F-FDG/CT PET has some limitations as diffuse thyroid uptake can also be found in Hashimoto's thyroiditis. The differential diagnosis of a rapidly expanding goitre should include anaplastic thyroid cancer, PTL, haemorrhagic thyroid cyst, subclinical variants of subacute thyroiditis and metastatic cancer (3). Differentiation of PTL from anaplastic thyroid cancer is important with both prognosis and treatment implications. Treatment of PTL depends on the histological subtype and staging of the lymphoma (5). Chemotherapy and radiotherapy remain the standard treatment of PTL (3). The indolent forms of PTL stage IE can be managed with radiotherapy alone, whereas disseminated indolent lymphoma or aggressive histological subtypes should be treated with chemotherapy (3). The standard chemotherapeutic regimen for follicular thyroid lymphoma includes R-CHOP. (3, 9). The 5-year disease-specific survival was 86, 81 and 64% for Ann Arbor stages IE, IIE and IIIE/IVE, respectively (2). Poor prognostic factors for PTL include advanced age, tumour dimension greater than 5 cm, lymph node involvement, advanced stage and presence of B symptoms (2, 10).

In conclusion, we described a challenging case of a woman with follicular thyroid lymphoma successfully treated with R-CHOP, reinforcing the importance of early diagnosis of this potentially treatable malignancy. This case also highlights the importance of considering the diagnosis of PTL in patients with rapidly growing goitre in the setting of Hashimoto’s thyroiditis, emphasizes the importance of warning the cytopathologist of the clinical context and the role of core needle biopsy in PTL diagnosis.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This study did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Patient consent

Written informed consent for publication of clinical details was obtained from the patient.

Author contribution statement

C C drafted the manuscript. C C, C S, F M and S D reviewed and edited the manuscript prior to submission. C C, C S and F M were the physicians who contributed to the care of the patient. S D also performed final editing of the manuscript and gave the approval to submit the manuscript for publication.