False Negative Thyroid Biopsy: A Case Report Highlighting the Importance of Ultrasound Evaluation

Abstract

Introduction:

The increasing use of advanced imaging modalities has led to a growing number of Incidental thyroid nodules (ITNs). Although most ITNs are benign, dedicated evaluation with a thyroid ultrasound (US) is strongly recommended to assess malignancy risk with a dedicated.

Case Presentation:

We report a case of a 66-year-old male with large fluorodeoxyglucose (FDG)-avid right thyroid mass identified incidentally on a positron emission tomography (PET) scan. Initial fine needle aspiration (FNA) suggested benign pathology. However, subsequent thyroid US demonstrated highly suspicious features concerning for lymphoma or sarcoma, prompting a core biopsy with flow cytometry and immunohistochemistry, which confirmed a diagnosis of small lymphocytic B-cell infiltrating the thyroid gland.

Conclusion:

This case underscores the diagnostic limitation of FNA in detecting thyroid lymphoma and highlights the critical role of thyroid US in identifying concerning features. When US findings are highly suspicious for lymphoma, additional diagnostic approaches – including core biopsy with flow cytometry and immunohistochemistry – are essential to ensure accurate diagnosis and appropriate management.

Introduction

Thyroid nodules are common, with a prevalence up to 68% of the population. As cross-sectional imaging modalities like computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) have increased, the detection rate of incidental thyroid nodules (ITN) has also risen.^1,2 While these imaging techniques identify thyroid abnormalities, thyroid ultrasound (US) is the most reliable way to evaluate a thyroid nodule’s size and malignancy risk by evaluating key features such as echogenicity, margins, presence of calcification, extra-thyroidal extension, and shape (eg, taller than wide). Additionally, the US can detect abnormal lymph nodes, which may influence the diagnostic approach. Given its diagnostic value, the American College of Radiology (ACR) and American Thyroid Association (ATA) recommend thyroid US as a part of ITN evaluation. ³

Although the majority of ITNs are benign, ~12% of these nodules are malignant. Fine need aspiration (FNA) is the standard procedure for evaluating malignancy in thyroid nodules when clinically indicated, as it has a low false-negative rate. Nodules classified as benign under the Bethesda System for Reporting Thyroid Cytopathology have an estimated malignancy risk of 0% to 3%. ³ However, when rare etiologies such as thyroid lymphoma are suspected additional measures – such as core biopsy with flow cytometry and immunohistochemistry – are necessary, as FNA alone may provide a false negative.^4,5

This case serves to underscore the critical role of dedicated thyroid ultrasound for all ITN, even if initial FNA results suggest benign pathology. A thorough ultrasound assessment can identify suspicious features that warrant further investigation, ensuring appropriate diagnostic and management strategies.

Case Presentation

The case involves a 66-year-old male patient who was referred from his primary care physician to our endocrinology clinic for further evaluation and management of an ITN. His medical history also included prostate cancer, hypertension, hyperlipidemia, and atrial fibrillation.

A PET scan was performed for prostate cancer staging incidentally detected a fluorodeoxyglucose (FDG)-avid mass in the right thyroid lobe, with the most intense uptake in the superior region (max SUV 4.8). The mass exerted a mild to moderate effect on the thoracic airway, measuring 3.0 × 5.6 × 6.1 cm (Figures 1 and 2). This prompted his team to refer to interventional radiology to obtain an ultrasound-guided FNA, which yielded a benign pathology characterized by polymorphic lymphoid cells and scattered oncocytic cells; findings suggestive of chronic Hashimoto’s thyroiditis. He was referred to Endocrinology for further evaluation.

Figure 1.

PET scan of thyroid mass, coronal view.

Figure 2.

PET scan of thyroid mass, axial view.

Patient reported that over the over the past 2 years he noticed a gradually enlarging neck mass, with mild dysphagia and dry cough. Additional pertinent history included chewing tobacco use, which he discontinued 30 years ago, no prior radiation exposure before the thyroid mass was identified, and a family history of a brother with an unspecified thyroid cancer that required thyroidectomy.

On physical examination, there was anterior fullness with thyroid asymmetry. The right thyroid lobe was palpable, with laterally extending, mobile, non-adherent mass. It was non-tender, without induration, and appeared smaller than imaging suggested, indicated a posterior and low-lying position. No cervical lymphadenopathy was noted.

Thyroid function tests were within normal limits and thyroid peroxidase antibodies were mildly elevated.

Although the initial workup included the PET scan and a US-guided FNA, a dedicated thyroid ultrasound had not been performed. To adhere to the standard endocrine protocol for PET-positive thyroid nodules and complete the evaluation following the benign FNA result, the dedicated ultrasound was obtained ~8 months after the PET scan. Thyroid US revealed a highly hypoechoic, vascular, and infiltrative mass in the right thyroid measuring up to 7.9 cm, with suspected thyroid capsule invasion. The mass was not definitively of thyroid origin. The homogeneous hypoechoic echotexture raised further concern for an alternative etiology, such as lymphoma or sarcoma (Figure 3). The Endocrine Tumor Board, comprising of specialists in radiology, endocrinology, and otolaryngology, reviewed the ultrasound images and case. Given the suspicious appearance concerning for thyroid lymphoma, the consensus was to perform a core biopsy of the mass with flow cytometry.

Figure 3.

Thyroid US showing homogeneous hypoechoic mass.

Core biopsy revealed a group of oncocytes on a background of predominant small, monomorphic lymphocytes mixed with a few intermediate-sized lymphocytes. No definite neoplastic cells were seen (Figure 4). Flow cytometry identified an abnormal B-cell population (35% of all cells) that expressed CD19 and CD20, with absent surface immunoglobulin. They were negative for CD5 and CD10. The overall morphology and immunophenotype on flow cytometry, in correlation with radiographic imaging, supported the diagnosis of small B-cell cell lymphoma within the thyroid tissue. However, due to limited tissue samples in this case, other special studies such as immunohistochemistry could not be performed. Pathologists recommend repeat tissue sampling for further characterization.

Figure 4.

Core biopsy of thyroid mass.

The patient was referred to hematology/oncology. Consistent with standard guidelines for asymptomatic, low-grade small B-cell lymphoma/chronic lymphocytic leukemia (CLL), and given the patient was clinically and biochemically euthyroid and asymptomatic, an active surveillance strategy was adopted. The decision was made to monitor for the development of constitutional “B” symptoms, worsening compressive symptoms, or evidence of disease progression on imaging before initiating systemic therapy or radiation.

A repeat PET scan remained stable compared to the initial baseline. The patient remained asymptomatic, clinically euthyroid, and has resumed regular activities in the 2 years following his diagnosis. Oncology will continue surveillance for indicators warranting treatment initiation, including, unintentional weight loss, fever, fatigue, generalized malaise, increase in neck mass or compressive symptoms. His TSH, free T4, and complete blood count have remained within normal limits throughout follow-up.

Periodic PET-CT is planned, if increased tumor burden is identified, a bone marrow biopsy is planned to assess for disseminated small B-cell lymphoma. If no extrathyroidal/neck involvement is found there is potential for surgical excision. However, the primary therapeutic option if symptoms arise is planned to be radiotherapy and/or immunochemotherapy.

Discussion

Thyroid nodules, particularly ITNs, should undergo evaluation with thyroid US, which can identify key characteristics that may suggest rare malignancies like lymphoma or sarcoma.^4,5 These cases often necessitate additional diagnostics measures beyond the standard FNA. ⁶ In this case, a PET scan identified an FDG-avid thyroid mass, prompting an FNA that yielded a false-negative result. Subsequent US evaluation revealed suspicious features – including marked hypoechogenicity, irregular borders, and infiltration – which raised suspicion for lymphoma. FNA has a significant false negative risk for lymphoma. Therefore, a core biopsy with flow cytometry was performed, that confirmed the diagnosis. Unlike routine US monitoring after a benign FNA, this patient remains under multidisciplinary surveillance for signs warning intervention.

Thyroid US, when performed by an experienced ultra-sonographers and radiologists, is essential for accurate nodule characterization. The ACR Thyroid Imaging Reporting and Data Systems (TIRADS) categorizes thyroid nodules based on their risk of malignancy, ranging from <2% in TIRADS 1 and TIRADS 2 to a high suspicion of malignancy (TIRADS 5) with a risk >20% to 35%. ¹ Thyroid lymphoma can appear more rounded, or oval compared to the irregular shape seen in papillary thyroid cancer. It is usually hypoechoic with a “pseudocyst” appearance and presence of enhanced posterior echoes. The margins in lymphoma may be less well-defined and there is usually increased vascularity. Compared to highly suspicious nodules, calcifications are less likely to be present in lymphoma. Thyroid US has a positive predictive value >60% to detect thyroid lymphoma in most suspected cases.^4,5

Although all ITNs warrant malignancy evaluation, ~65% of thyroid FDG-avid nodules on PET are benign. The overall prognosis of most patients with non-thyroid malignancy and an FDG-avid ITN are usually determined by the non-thyroid malignancy. While PET scans can identify thyroid masses with FDG-uptake, they cannot reliably distinguish benign from malignant nodules.^3,7-9 Consequently, thyroid US is crucial for identifying suspicious features such as marked hypoechogenicity, internal echoes, irregular borders, and infiltration which raised suspicion of lymphoma in this case.

While FNA is a frequent next diagnostic tool to evaluate thyroid tissue for malignancy, it has a high false negative rate for lymphoma. ⁶ FNA biopsies can be used for flow cytometry; however, optimal results are achieved when specimens are processed within 24 hours, as cell viability may decline over time. Immunohistochemistry is contingent upon both the size of the tissue block and type of tissue and usually requires a fixation period between 12 and 24 hours.^10-12 In the absence of prior requests, most thyroid FNAs are not subjected to these additional tests. Therefore, if there is not an elevated level of suspicion for lymphoma, these supplementary tests may not be performed, potentially resulting in a missed diagnosis.

When thyroid lymphoma is suspected, a core biopsy accompanied by immunophenotypic assays such as flow cytometry and immunohistochemistry is recommended, as these methods enhance the sensitivity and specificity of FNA cytology. ⁶ In this case, core biopsy confirmed small lymphocytic B cell lymphoma after initial FNA yielded a false negative. Unlike FNA, core biopsy provides a larger tissue sample with preserved architecture, which is often necessary to differentiate between various conditions with overlapping histologic features, such as Hashimoto’s thyroiditis – commonly coexisting with thyroid lymphoma – and anaplastic thyroid cancer. Core biopsy is especially valuable in cases where FNA cytology results are inconclusive or when an insufficient amount of tissue is obtained.^4-6

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a single disease spectrum; thus, small lymphocytic lymphoma (SLL) of the thyroid is considered the local tissue manifestation of CLL. Primary thyroid lymphoma is rare, representing ~2.5% of all lymphoma cases and 2% to 5% of all thyroid malignancies. This rarity is generally attributed to the natural absence of lymphoid tissue, except in conditions like autoimmune thyroiditis. Consequently, the coexistence of autoimmune thyroiditis and suspicious US features should raise the suspicion of thyroid lymphoma.^4,5,13

About 5 similar cases have been reported in the literature.^14-18 One such case involves a female patient in her 50s with underlying chronic B-cell leukemia who developed an infiltrating small B-cell lymphoma in the thyroid while undergoing chemotherapy. CT showed an irregular area in the left thyroid lobe along with generalized lymphadenopathy. A dedicated thyroid ultrasound with Doppler depicted suspicious characteristics of lymphoma. Standard FNA biopsy with additional measure of flow cytometry and immunohistochemistry confirmed the rare diagnosis of infiltrating small B-cell lymphoma in the thyroid. This comprehensive approach led to the decision to start immunochemotherapy. However, contrary to our case, the patient demonstrated severe symptoms and progression of her underlying malignancy culminating in a fatal outcome. ¹⁸ Because of its indolent nature, chemotherapy is not indicated for asymptomatic or minimally affected patients with small B-cell lymphoma, and observation is the generally accepted approach. ¹⁹ Because the rate of progression may vary, with long periods of stability and sometimes spontaneous regressions, frequent and careful observation is required to monitor the clinical course.

Management of primary thyroid lymphoma is dictated by histological subtype and stage. For low-grade lymphomas like SLL confined to the thyroid (Stage 1E), involved site radiation therapy is often curative. For more advanced stages, immunochemotherapy is the standard of care. While surgical resection was historically performed, current guidelines do not support thyroidectomy as a therapeutic intervention for thyroid lymphoma, reserving it primarily for diagnostic purposes or rare cases of severe airway obstruction unresponsive to initial modalities. The active surveillance approach chosen for this patient is a valid and widely accepted strategy for asymptomatic, low-grade SLL, aiming to avoid treatment-related toxicity until clinically indicated.^12,19

A primary strength of this case report is the comprehensive diagnostic workup, which illustrates the comparative utility of FNA versus core biopsy in the workup of PET-detected thyroid incidentalomas. Additionally, the multidisciplinary management approach highlights the viability of active surveillance for asymptomatic SLL of the thyroid. Limitations include the limited tissue yield from the core biopsy which precluded the full immunohistochemical profiling, although flow cytometry was sufficient for diagnosis.

In summary, thorough evaluation of ITNs or masses with a dedicated thyroid US is essential, especially when rare malignancies, such as thyroid lymphoma, are suspected. Relying solely on FNA may result in delayed or missed diagnosis due to its limited sensitivity in detecting lymphoma. When thyroid lymphoma is a concern, comprehensive cytopathologic assessment – including flow cytometry, immunohistochemistry, and possibly core biopsy – is essential to reduce the risk of false negatives and ensure an accurate diagnosis.

Learning Points

• Imaging: A dedicated thyroid ultrasound after incidentaloma on PET-CT scans plays a crucial role in identifying and characterizing thyroid nodules. Incidental thyroid nodules detected on PET scans often have a higher risk of being malignant due to increased glucose uptake, but standardized uptake value values alone are not sufficient for distinguishing between benign and malignant nodules.

• Comprehensive Cytological Analysis: Fine-needle aspiration cytology alone can lead to a false-negative results, potentially delaying the diagnosis of thyroid lymphoma. Flow cytometry, immunohistochemistry, and PCR can enhance the sensitivity and specificity of FNA cytology. In certain cases, a core biopsy may be necessary for a definitive diagnosis, especially when FNA results are inconclusive or insufficient.

• Early Detection: A high index of suspicion and prompt investigation are essential for early diagnosis of lymphoma involving the thyroid.

• Multidisciplinary Approach: Effective management of thyroid lymphoma often requires a multidisciplinary team of specialists, such as radiology, endocrinology, and oncology. Treatment for thyroid lymphoma is based on clinical presentation and often involves a combination of chemotherapy, radiotherapy, surgery, and immunochemotherapy.

• Favorable Prognosis: The overall prognosis for small lymphocytic B-cell lymphoma is generally favorable, especially in patients with minimal or no symptoms.