Burkitt-Like Lymphoma Infiltrating a Hyperfunctioning Thyroid Adenoma and Presenting as a Hot Nodule

Introduction

T hyroid nodules are one of the most frequent findings in clinical endocrinology. Thyroid ultrasonography (US), fine-needle aspiration cytology (FNAC), and scintigraphy are recommended in some patients to evaluate these lesions. Less than 5% of all thyroid nodules are malignant. Of these, lymphomas account for only 1%–5% of all thyroid cancers (1). Most thyroid lymphomas arise in a clinical and histological background of chronic autoimmune thyroiditis, usually characterized by hypothyroidism, and most frequently present as cold nodules on thyroid scintiscan. Here we report an unusual thyrotoxic patient with a thyroid lymphoma that was hidden in an hyperfunctioning thyroid nodule.

Patient

A 56-year-old man was referred to our Endocrine Unit in May 2009 for evaluation of a thyroid nodule that was noted on computed tomography as part of the workup of a suspected underlying neoplasm. In January 2009 he suffered a pathological fracture of the right femoral diaphysis due to a lytic lesion of unknown origin. A computed tomography scan of the thoracic and abdominal districts revealed two small nodules in the right kidney, an abnormal mass in the anterior mediastinum corresponding to the thymic area and a large nodule of the left thyroid lobe. In April 2009 the patient underwent an osteosynthesis of the right femoral diaphysis. At histology, the resected bone fragment was found to be extensively necrotic and to contain a neoplastic cell population, which was not further defined.

When first seen in our outpatient clinic, the patient appeared slightly thyrotoxic with fine tremors and sinus tachycardia, but no evidence of inflammatory eye disease. Neck palpation revealed a firm, 5-cm nodule in the left thyroid lobe. The right thyroid lobe was barely palpable and there was no evidence of lymphoadenopathy. Thyroid function tests indicated overt thyrotoxicosis (thyrotropin < 0.004 mU/L, range 0.4–4 mU/L; free thyroxine = 31.2 pg/mL, range 8.0–19.0 pg/mL; free triiodothyronine = 7.8 pg/mL, range 1.8–4.2 pg/mL). Tests for anti-thyroglobulin, anti-thyroid peroxidase, and anti-thyrotropin-receptor antibodies were negative. Serum thyroglobulin was high (434 ng/mL), and serum calcitonin was undetectable (<2 pg/mL).

Neck US showed an asymmetrical thyroid with a huge left lobe (estimated volume = 70 mL), which was almost completely occupied by a large nodule measuring 46 × 49 × 60 mm. The nodule was not homogenous but contained multiple hypo and anechogenic areas, intralesional vascular spots, and calcifications (Fig. 1a). A rightward tracheal dislocation was evident. Due to the thyrotoxic state, a (99m)-technetium scintiscan was ordered, which revealed a large hot nodule of the left thyroid lobe. No radioisotope uptake was evident in the right lobe. Thus, the nuclear medicine imaging was consistent with a hyperfunctioning thyroid nodule with suppression of the contralateral lobe (Fig. 1b). FNAC of the left nodule was performed, which yielded a population of neoplastic cells that were not considered of thyroid origin (Fig. 2a). The patient was started on methimazole (20 mg/day), with remission of hyperthyroidism within 3 weeks. In June 2009, an 18-fluorodeoxyglucose positron emission tomography was performed, which showed a pathological uptake of the radioisotope corresponding to the left thyroid nodule, as well as in the mediastinum and right femur. Considering the malignant cytological findings and the surgical accessibility of the thyroid nodule, a left lobe thyroidectomy and istmectomy were performed. The thyroid nodule was easily resectable, with no evidence of adherence to the trachea or to other neck structures. Histological analysis led to the diagnosis of diffuse large B-cell lymphoma (DLBCL) (1), with an high proliferation index (Ki-67 > 95%) and a CD20/CD79a positivity. Given the high proliferation rate, it was classified as a Burkitt-like lymphoma (Fig. 2b, c). The surgical specimen of the nodule also contained thyroid tissue with a macrofollicular appearance, marked fibrosis, and dystrophic calcifications. A nuclear magnetic resonance of the brain excluded cerebral metastases. Further investigations involved the assay of serum lactate dehydrogenase (1585 U/L, range 240–480 U/L) and β2-microglobulin (2310 mg/L, range 609–2366 mg/L). A bone marrow biopsy did not show malignant cells. The final diagnosis was stage IV E Burkitt-like lymphoma according to the WHO classification. According to the recent revision of the 2008 WHO Classification (2), this lymphoma may alternately be included in the provisional category termed B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma. The patient was treated with eight cycles of intensive chemotherapy (hyperfractionated cyclophosphamide, vincristine, doxorubicine, and dexamethasone), and had dramatic reduction of all lesions with improvement of symptoms.

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FIG. 1.

(a) Neck ultrasonography showing the left thyroid lobe almost completely occupied by a large nodule (46 × 49 × 60 mm), dyshomogeneous, with multiple hypo-anechogenic areas and calcifications. (b) (99m)-Technetium scintiscan consistent with an hyperfunctioning thyroid nodule in the left thyroid lobe, with suppression of the contralateral lobe.

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FIG. 2.

(a) Fine-needle aspiration cytology of the left nodule showing a population of neoplastic cells of no thyroid origin (indicated by arrows) and necrotic fragments (magnification 40 ×, hematoxylin–eosin). (b) Histological analysis (magnification 10 ×, hematoxylin–eosin): diffuse pattern of growth of the neoplastic cells consistent with the diagnosis of diffuse large B-cell lymphoma [1], thyroid follicles with marked fibrosis and dystrophic calcifications [2], and nodule's capsule not invaded by the tumor [3]. (c) Histological analysis (magnification 60 ×, Giemsa): Burkitt-like lymphoma containing cells with scant cytoplasm, large nuclei with open chromatin pattern, and evidence of nucleoli (Starry-sky pattern).

Discussion

Lymphoma within the thyroid gland is a rare and heterogeneous disease, accounting for 1%–5% of all thyroid cancers and occurring in 1%–2.5% of all lymphomas (3). Lymphomas more commonly spread to lymph nodes, bone marrow, central nervous system, liver, and gastrointestinal tract. As noted, systemic lymphoma does not commonly spread to the thyroid gland (4). Primary thyroid lymphoma is a rare disease, almost always arising in the lymphocytic infiltrate of chronic autoimmune thyroiditis (4). Epidemiological studies indicate that patients with chronic lymphocytic thyroiditis have a 67- to 80-fold increased risk of developing thyroid lymphoma (5). In a large series of primary thyroid lymphomas (3), the most prevalent histotype was DLBCL (50%). Mucosa-associated lymphoid tissue lymphoma, follicular lymphoma, Hodgkin disease, Burkitt lymphoma, and small cell leukemia accounted for 23%, 12%, 7%, 4%, and 4%, respectively. Most patients affected by this type of neoplasia are middle-aged or elderly people, who develop a rapidly growing nodule (6), producing compressive symptoms such as hoarseness, dysphagia, and dyspnea (7 –9). A consistent proportion of these patients are hypothyroid, due to coexistent autoimmune thyroiditis, and the lymphomatous nodule appears as a cold area at thyroid scintiscan (10,11).

Thyrotoxicosis associated with thyroid lymphoma is exceedingly rare with only a few case reports (12) or brief comments in large series. The etiology of thyrotoxicosis in one case was thought to be Graves' disease (13), while in another there was a low radioiodine uptake consistent with thyroiditis (14). A patient with acquired immunodeficiency syndrome was reported in whom severe thyrotoxicosis was caused by the extensive destruction of normal thyroid tissue by an infiltrating anaplastic large cell lymphoma (4). In other patients the causes of thyrotoxicosis were not elucidated.

Our patient presented with a pathological fracture of the bone, a rare localization for lymphomas. Because of his diffuse disease, which also involved the thymus, it is not possible to determine whether he had primary thyroid lymphoma or spread of lymphoma from another site. He did not have a history of autoimmune thyroiditis, his tests for anti-thyroid antibodies were negative, and there was no inflammatory infiltrate of the thyroid. Laboratory and scintigraphic findings were consistent with the diagnosis of toxic adenoma. The remission of hyperthyroidism after methimazole treatment further confirms the diagnosis of a hyperfunctioning thyroid nodule that had been selectively infiltrated by a Burkitt-like lymphoma.

Burkitt-like lymphoma is a rare entity accounting for about 5% of all lymphomas. The onset of the disease is frequently characterized by a massive extranodal involvement (15) with high-grade behavior. To our knowledge, there has been only one case of Burkitt-like lymphoma of the thyroid, which was previously described in a three decades series of thyroid lymphomas (16).

In summary, this is the first description of an aggressive Burkitt-like lymphoma that infiltrated a hyperfunctioning thyroid adenoma, thus presenting as a hot nodule at thyroid scintiscan. In our patient there was no humoral or histological evidence of thyroid autoimmunity, thus suggesting a metastatic seeding of the lymphoma within the hyperfunctioning thyroid nodule. According to the recently delivered American Thyroid Association management guidelines for patients with thyroid nodules, hyperfunctioning thyroid nodules do not deserve FNAC (17). However, as highlighted by the present case report, performing FNAC of a thyroid nodule should be always considered in the clinical context of a metastatic disease of unknown origin or when, in spite of the hot appearance of the nodule, there are US signs suggesting malignancy.

Disclosure Statement

The authors declare that they have nothing to disclose.