Clear Cell Follicular Adenoma of the Thyroid: A Case Report Torill Sauer, M.D., F.I.A.C., and Reidar Olsholt, M.D., Ph.D.

A case of clear cell follicular adenoma of the thyroid is presented. The patient presented with a single, hyperactive nodule in the right lobe. The cytologic features include cellular smears with numer- ous disrupted cells and a granular background. The cytoplasm was abundant, pale grayblue vacuolated or granulated, but not clear. Thyreoglobulin was demonstrated both histologically and ultras~ructurally, confirming the follicular-cell derivation of the tumor. Ultrastructurally, the cytoplasm was filled with empty, membrane bound vacuoles. The clear cell change might represent an artifact of formalin fixation and/or the parafin embedding procedure. Diagn Cytopathol 1996 15: 124- 126. @) 1996 Wiley-Lib\, Inc

Key Words: Clear cell; Thyroid; FNAC

Follicular lesions are common findings when investigating thyroid nodules by fine-needle aspiration cytology (FNAC). Histologically they may represent a cellular nodule in a goiter, a follicular adenoma, or a carcinoma. Several variants exist as to growth pattern (follicular, tra- becular, solid) and cell types (common, oxyphilic, and clear cell type).

Clear cell changes of the cytoplasm may occur in areas of both follicular and papillary tumors, but pure clear cell differentiation is unusual. Chronic TSH overstimula- tion has been suggested as a cause for this change due to hypertrophy and dilation of mitochondria or hypertrophy of the Golgi apparatuses.

Accumulation of glycogen, lipid, and thyr~globul in~-~ has also been described. Other clear cell tumors such as metastatic renal cell cancer, parathyroid tumors and hyperplasias, and clear cell variant of medullary carci- noma may mimic a primary follicular-derived tumor, both cytologically and histologically, and demonstration of in- tracellular thyroglobulin is essential for diagnosis.

Received September 14, 1994. Accepted March 23, 1995. From the Department of Pathology and the ENT Department, Ullev-

Address reprint requests to Torill Sauer, M.D., Department of Pathol- aal University Hospital, Oslo, Norway.

ogy, Ullevaal University Hospital, N-0407 Oslo, Norway.

We present a case of clear cell follicular adenoma of the thyroid and demonstrate the cytologic features of this tumor.

Clinical History A 47-yr-old female presented at the ENT outpatient clinic of Ullevaal Hospital with an asymptomatic, palpable nod- ule in the right thyroid lobe. The lesion was aspirated. The cytologic findings were consistent with a follicular tumor.

A scintigramm (using the isotope 99mTc-pertecnetat) of the thyroid revealed an enlarged right lobe with a hy- peractive nodule occupying most of the lobe. The sur- rounding thyroid tissue and the left lobe was partly sup- pressed. The patient had normal thyroid function with FT4 and TSH within normal range.

Because the cytologic diagnosis was consistent with a neoplasm, a right thyroidectomy was performed. Histol- ogy showed a clear cell follicular adenoma. Follow-up has been uneventful.

Cytologic Findings The smears were cellular with partly disrupted cells, nu- merous naked nuclei, and a finely granular background. Sheets and follicular clusters were loosely cohesive with occasional overlapping of nuclei (Fig. 1). Stromal frag- ments containing branching blood vessels and attached epithelial cells were seen. Nuclei were uniformly round and 2-3X the size of an erythrocyte. The chromatin structure was homogenous. A single, round and medium- sized nucleolus was apparent. The cytoplasm was abun- dant, pale grayblue, with different sized vacuoles in the Giemsa-stained smears and finely granulated in the Papanicolaou-stained smears (Fig. 2). Colloid material was not seen. Based on these findings, a primary diagnosis of follicular tumor of the thyroid was given.

Histologic Findings Thyroidectomy specimen revealed a 2.2 cm diameter tumor. A thin rim of compressed, normal thyroid tissue

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THYROID FOLLICULAR ADENOMA

surrounded the lesion. The tumor was well circumscribed with a smooth, thin capsule and a rather soft consistency. The cut surface was pale brown and homogeneous. Micro- scopically the pattern was mostly solid, but with areas of follicular growth. The cells were large with a clear cyto- plasm (Fig. 3). There was no evidence of vascular or cap- sular invasion. The tumor cells stained positive for in- tracytoplasmic thyroglobulin (Fig. 4) (APAAP method with a fast red substrate).

Ultrastructurally, the cells were dominated by closely lying, membrane bound, empty vacuoles (Fig. 5) . Neuro- endocrine granules were not found. EM immunostaining for thyroglobulin showed positivity in moderate electron- dense globules of the common follicular cell type. Acinic

tive granules within the colloid (Fig, 6). Fig. 1. Loosely cohesive epithelial cell clusters; abortive f o k u l a r struc- ture (arrowheads) and fragile cytoplasm (PAP stain; magnification X 250).

structures containing thyroglobulin POsi-

Fig. 4. Positive cytoplasmic staining for thyroglobulin (APAAP stain with fast red substrate; magnification X 250).

Fig. 2. Finely vacuolated cytoplasm (Giemsa stain; magnification x 500).

Fig. 3. Mainly follicular growth pattern; abundant clear cytoplasm (H%E stain; magnification x 250).

Fig. 5. Ultrastructural empty membrane bound cytoplasmic vacuole; in between normal appearing mitochondria (magnification X 5,700).

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Fig. 6. Thyroglobulin positivity within colloidal material in a follicular lumen (magnification x 9,100; EM immunostaining with colloidal gold).

Discussion Cytomorphologically this lesion was a follicular tumor, and except for the consistency of the cytoplasm, was remi- niscent of an oxyphilic cell variant. Instead of the dense, granulated cytoplasm of oxyphilic cells, the cytoplasm was pale granulated or vacuolated. These features are the same as reported by Jayaram’ in two cases of clear cell follicular carcinomas. Here also, the cytoplasm was vacu- olated and not clear. The clear cell appearance of histo- logic specimens might therefore represent an artifact of formalin fixation and/or the paraffin embedding proce- dure.

Ultrastructurally, empty vacuoles were found, consist- ent with degenerative changes. The specific nature of the vacuoles could thus not be established. Glycogen or lipid accumulation was not present. Thyroglobulin was demon- strated both histologically and ultrastructurally, though not accumulated. In addition, the scintigraphic finding of a hyperactive nodule, confirmed the follicular-derived ori- gin of the tumor cells.

Parathyroid lesions, medullary carcinoma of the thy- roid, and metastatic renal cell carcinoma may all present

with a dominant clear cell pattern. They may show several cytologic characteristics reminiscent of follicular thyroid lesions, such as microfollicular pattern, colloid-like struc- tures and tissue fragments with branching vessels. Usually they have a much coarser and irregular nuclear chromatin pattern, 8-1 but demonstration of thyroglobulin is essen- tial in order to differentiate a follicular cell derived tumor from these lesions. This might mainly represent a problem in histologic specimens, though, as the clear cell changes are not appreciated in cytolologic smears.

Acknowledgments The authors are grateful to Dr. Fredrik Skjgwten for sup- plying the ultrastructural pictures, and Dr. Vibeke Engh for reviewing the manuscript.

References 1.

2.

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8.

9.

10.

1 I .

LiVolsi VA. Surgical pathology of the thyroid. Philadelphia: WB Saunders Company, 323-328. Rosai J, Carcangui ML. Pathology of thyroid tumors: some recent and old questions. Hum Pathol 1984;15:1008-1012. Civantos F, Nadji M, Albores-Saavedra J, Morales AR. Clear cell variant of thyroid carcinoma. Am J Surg Pathol 1984;8:135-136. Dickerson GR, Vickery AL, Smith SB. Papillary carcinoma of the thyroid, oxyphil cell type, “clear cell” variant. Am J Surg Pathol

Valenta LJ, Michel-Bechet M. Electron microscopy of clear cell thyroid carcinoma. Arch Pathol Lab Med 1977; 101: 140- 144. Johannessen JV, Egould V, Faria V, Goncalves L, Soares J, So- brinho-Simoes M. Electron microscopy in diagnostic pathology. Portuguese Society of Pathology: 84-93. Jayaram G. Cytology of clear cell carcinoma of the thyroid. Acta

Lasser A, Rothman JG, Calamia VJ. Renal cell carcinoma meta- static to the thyroid, Aspiration cytology and histologic findings. Acta Cytol 1985;29:856-858. Gritsman AY, Popok SM, Ro JY, Dekmezian RH, Weber RS. Renal-cell carcinoma with intranuclear inclusions metastatic to thy- roid: a diagnostic problem in aspiration cytology. Diagn Cytopathol 1988;4: 125- 129. Davey DD, Grant MD, Berger EK. Parathyroid cytopathology. Diagn Cytopathol 1986;2:76-80. Glenth$j A, Karstrup S. Parathyroid identification by ultrasono- graphically guided aspiration cytology. APMIS 1989;97:497-502.

1988;4:501-509.

Cytol 1989;33: 135- 136.

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