Signet‐ring cell differentiation in FNA cytology of a primitive thyroid carcinoma

Dear Editor, We report an exceptional case of a primary thyroid cancer with fine needle aspiration (FNA) cytology evidence of signet-ring cell (SRC) differentiation in a 76-year-old woman. The patient had previously undergone a right thyroidectomy; she presented because of progressive ideomotor slowdown. On clinical examination she was stuporous. Laboratory findings showed several alterations including high blood calcium levels: 3.80 mM (2.20–2.50). A hypercalcaemia-induced coma was suspected. Computed tomography (CT) revealed results of surgical intervention to the right thyroid lobe and a 30 · 25 mm, partially calcified mass with areas suspicious of necrosis on the left side (CTMS64, Figure 1a). Furthermore, widespread morphostructural bone alterations, with complete collapse of D10 vertebral body, probably owing to bone metastasis, and a pathological fracture of the proximal part of the sternum could be seen. Finally, CT showed masses in adrenal glands, probably metastases, and the absence of significant synchronous lung lesions. Thyroglobulin levels were 109 ng ⁄ ml (00–60). Ultrasound-guided FNA of the thyroid was carried out in order to classify the lesion, using 25-gauge needles for traditional smears and 21-gauge needles for cell block preparation. Alcohol-fixed smears from the nodule were stained using the Papanicolaou method and a periodic acid-Schiff (PAS) reaction with and without diastase. Air-dried specimens were stained with May-Grünwald–Giemsa. Material for the cell block was formalin-fixed, embedded in paraffin and haematoxylin and eosin stained. Immunocytochemistry (ICC) was performed using a Benchmark XT autostainer and monoclonal antibodies, pre-diluted by the manufacturer (Ventana Medical Systems, Inc., Tucson, AZ, USA), were thyroid transcription Factor-1 (TTF1, 8GTG3 ⁄ 1), thyroglobulin (2H11 + 6E1), galectin-3 (9C4) and cytokeratin 19 (CK19, A53-B ⁄ A2.26). Smears were highly cellular, composed of three-dimensional clusters of atypical epithelial cells in a colloid background with rare macrophages. Most of the tumour cells had a cohesive architecture, but there were also scattered individual cells. The most peculiar finding was the presence of tumour cells with eccentric nuclei with prominent PAS-positive vacuolization: that is, SRC differentiation (Figure 1b–e). ICC revealed focal nuclear expression for TTF-1 and cytoplasmic staining for thyroglobulin (Figure 1f) and reactivity for CK19 and galectin-3. A final diagnosis of thyroid carcinoma with SRC differentiation was rendered. The clinical setting contraindicated any surgical approach to the tumour. The term signet-ring is used to indicate a cell with a crescent-shaped nucleus displaced to the periphery, because of cytoplasmic accumulation of mucin, lipids, vacuoles and inclusions. The SRC appearance was classically considered as the peculiar feature of a group of adenocarcinoma of the stomach, breast, lung and other organs, but similar changes could also be seen in a variety of non-neoplastic conditions, often related to ischaemia. In the majority of cases, the presence of SRC indicates a high malignancy lesion, as this cytological finding is strongly related to a poor prognosis. However, thyroid pathology is an exception, as SRCs are more frequently found in follicular adenomas than in carcinomas. In this report, we demonstrate an unusual case of carcinoma with SRC differentiation. The first differential diagnosis was an intrathyroid metastatic lesion but ICC helped to make the correct diagnosis. Melanoma, renal cell carcinoma and lung carcinoma are the most common malignancies with possible thyroid metastases. ICC positivity for thyroid markers such as TTF-1 (which could be expressed also in lung adenocarcinomas) and thyroglobulin excluded a metastatic lesion. Another differential diagnosis was follicular adenoma with SRC features. Most thyroid SRC tumours are follicular adenomas: their malignant counterpart is rare, but it has been described, and so should be kept in mind. Our patient presented with multiple bone and adrenal gland metastases; additionally, ICC expression of CK19 and galectin-3 strongly supported the malignant nature of the tumour. In the literature, only a very small group of primary thyroid carcinoma with SRC differentiation has been described. Fellegara and Rosai described Hürtle cell carcinoma with SRC change: that tumour was characterized by classic oxyphilic differentiation with prominent nucleoli. In spite of an absence of a surgical approach, we can affirm that SRC differentiation could represent a rare example of high-grade malignancy in thyroid lesions whereas we can only hypothesize (without histological confirmation) that Correspondence: F. Pagni, Department of Pathology, Université Milano Bicocca, Via Cadore 48, Monza, 20900 Italy, Desio Hospital, Desio, Italy Tel. : +39 0362383436; Fax: +39 0362383369; E-mail: petala.83@tiscali.it Correspondence 274