Oncocytic Parathyroid Adenoma: Problem in Cytological Diagnosis Tamar Giorgadze M.D., Ph.D.,1 Berle Stratton, M.D.,2 Zubair W. Baloch, M.D., Ph.D.,1* and Virginia A. LiVolsi,
M.D.
1
Parathyroid lesions, which may occur within the thyroid, may clinically simulate thyroid nodules. Fine-needle aspiration (FNA) of these presumably “thyroid nodules” can lead to misinterpretation of cytomorphological findings because of similarities in cytological features of neoplastic and nonneoplastic parathyroid and thyroid lesions. This might be true especially for oncocytic parathyroid adenomas and parathyroid adenomas with prominent oncocytic component that, although rare, tend to be large and often are associated with minimal hyperparathyroidism. We report two cases of this type of clinically “silent” parathyroid adenomas that on FNA were diagnosed as Hurthle cell thyroid neoplasm. Diagn. Cytopathol. 2004;31: 276 –280. © 2004 Wiley-Liss, Inc.
and surgical pathology files of the Department of Pathology of the Hospital of the University of Pennsylvania (Philadelphia, PA). The air-dried and alcohol-fixed FNA slides were stained by Diff-Quik and Papanicolaou techniques, respectively. Tissue sections from parathyroid and thyroid glands were fixed in formalin, processed routinely, and stained with hematoxylin-eosin (H&E). For immunohistochemical studies, monoclonal antibodies against thyroglobulin (1: 10,000 dilution; Dako Corp., Carpinteria, CA) and parathyroid hormone (PTH; 1:50 dilution; Dako Corp.) were used. All microscopic slides were reviewed.
Key Words: oncocytic; parathyroid; adenoma; FNA
Case 1 Clinical History
Oncocytic parathyroid adenomas are rare and are clinically associated with minimal hyperparathyroidism. The cytological features of parathyroid adenomas, including that of the oncocytic ones, are well described in the literature. However, the fine-needle aspirate (FNA) from the neck mass in the anatomic vicinity of the thyroid gland that yields oncocytic cells may cause diagnostic difficulties, especially in patients without clinical evidence of hyperparathyroidism. These lesions most often are misinterpreted as Hurthle cell thyroid neoplasms. In the present study, we report two cases of oncocytic parathyroid adenomas. In one of them, arriving on a correct cytological diagnosis was even more challenging due to the intrathyroidal location of the parathyroid adenoma.
Materials and Methods The first case belongs to the personal consultation files of V.A. LiVolsi. The second case is from the cytopathology 1 Department of Pathology and Laboratory Medicine University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 2 Southwest Washington Medical Center, Vancouver, Washington *Correspondence to: Zubair W. Baloch, M.D., Ph.D., Department of Pathology and Laboratory Medicine, 3400 Spruce St., Philadelphia, PA 19104. Email:
[email protected] Received 13 January 2004; Accepted 7 April 2004 DOI 10.1002/dc.20115 Published online in Wiley InterScience (www.interscience.wiley.com).
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A 46-yr-old woman presented at the Southwest Washington Medical Center (Vancouver, WA) for evaluation and treatment of a left neck mass that was discovered on routine examination. She was otherwise asymptomatic. She had no prior history of any endocrinopathy. Her mother has had surgery for goiter and her sister had alcohol injections for hyperthyroidism. On physical examination, a faintly visible nodule in the left anterior neck was noted. Palpation of the left thyroid lobe showed a 2-cm smooth nodule. The right thyroid lobe was without nodularity. FNA of the left lobe was performed. The preoperative laboratory studies revealed that the serum PTH level was 152 pg/ml (reference range, 10 – 65 pg/ml) with a serum calcium level of 11.2 mg/dl (reference range, 8.8 –10.3mg/dl), suggestive of primary hyperparathyroidism. Thyroid function studies were normal. On ultrasound (US) examination of the thyroid gland performed by the time of FNA, the left lobe, which measured 4.0 ⫻ 0.9 ⫻ 1.6 cm and contained a hypoechoic mass contiguous with the posterior surface of the thyroid measuring 3.2 ⫻ 1.5 ⫻ 1.3 cm. The right thyroid lobe was unremarkable. Parathyroid studies with Tc-99m sestamibi scan were performed after the FNA and showed increased uptake in the entire left portion of the thyroid gland on both the immediate and the delayed images. Single proton emission © 2004
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computed tomography (SPECT) images demonstrated focal increased uptake in the left thyroid bed that corresponded to a mass seen on US in the same location. These findings were consistent with parathyroid adenoma in the region of the inferior left thyroid lobe. Clinical examination was otherwise unremarkable; there was no evidence of bone lesions secondary to hyperparathyroidism. Because the hypoechoic mass found on US examination was in continuity with the posterior surface of the thyroid, the aspirated cells were considered of the thyroid origin. Based on the foregoing studies, a left parathyroidectomy and left thyroid lobectomy were performed.
Pathological Findings The FNA smears of the neck mass were cellular and showed a monotonous population of cells arranged in numerous cohesive clusters and scattered singly in the background. There also were three-dimensional tissue fragments with a perivascular arrangement of cells; rare microfollicular arrangements were noted also. Cytologically, the cells were small and uniform with abundant finely granular eosinophilic cytoplasm. The central nuclei were centrally placed and showed an even chromatin pattern and did not show prominent nucleoli. Numerous small naked nuclei (with stripped cytoplasm) with similar chromatin texture were identified also. No mitotic figures were noted. The background was composed of red blood cells, rare hemosiderin-laden macrophages, and scant light blue colloid-like material. The FNA was interpreted as Hurthle cell lesion. Because the suspicion of the aspirated lesion of thyroid origin was high, the diagnosis remained unchanged even after reviewing the radiological findings. On gross examination of the resected specimen, the left parathyroid gland measured 2 ⫻ 1.8 ⫻ 1.5 cm; the weight of the parathyroid gland was not available for our review. On histological examination, the left parathyroid gland showed a well-circumscribed hypercellular nodule that was composed predominantly of oxyphil cells. A compressed rim of normal parathyroid tissue composed of chief cells surrounded the nodule. The neoplastic cells in the nodule were arranged in solid sheets and anastomosing cords within a rich capillary network. The cells had abundant granular eosinophilic cytoplasm and centrally placed small round hyperchromatic nuclei. Some of the nuclei were larger, but prominent nucleoli were not identified. Small cystic spaces with extravasated red blood cells and hemosiderin depositions were noted also. No increased mitotic activity, thick fibrous bands, or capsular or vascular invasion were identified. The morphological findings of the resected tumor that showed the compressed rim of normal-appearing parathyroid tissue at the periphery of the hypercellular monotonous population of oncocytic cells were classic for oncocytic parathyroid adenoma, correlated well the FNA findings of
the neck mass, and eliminated the need of immunohistochemical stains to confirm the diagnosis.
Case 2 Clinical History A 73-yr-old patient presented to the Hospital of the University of Pennsylvania for evaluation of a left thyroid nodule. Medical history was remarkable for insulin-dependent diabetes mellitus, coronary artery bypass graft, and superior mediastinal mass resection in 1993, which was diagnosed as nodular goiter with retrosternal extension into the mediastinum. Three years ago, the patient presented to the hospital with symptoms of urolithiasis and left renal mass. Left radical nephrectomy was performed, and a 2-cm renal tumor was diagnosed as low-grade papillary oncocytic neoplasm. US examination of the thyroid gland showed a nodular gland with a solitary left anterior lower pole nodule that was uniformly hypoechoic compared with the more heterogeneous appearance of the other nodules. US-guided FNA of this nodule was performed. The preoperative laboratory evaluation revealed thyroid-stimulating hormone (TSH) of 0.72 IU/ml (reference range, 0.40 – 4.00 IU/ml); serum calcium level of 10.1 mg/dl (reference range, 8.5–10.5 mg/dl); PTH of 22.4 pmol/l (reference range, 1.3–7.6 pmol/l); and elevated urea nitrogen, creatinine, and glucose levels. High PTH levels were interpreted as being secondary to the patient’s kidney disease (secondary hyperparathyroidism). During the surgical neck exploration, bilateral nodularity was identified throughout the thyroid gland. There was no lymphadenopathy. Both superior parathyroid glands were grossly unremarkable, but the inferior parathyroids were not seen clearly. Because of the patient’s multiple medical problems, total thyroidectomy was performed in order to avoid a second operation. The patient’s postoperative period was uneventful. Her postoperative serum PTH was 9.5 pmol/l and the serum calcium levels were within normal limits.
Pathological Findings The Diff-Quik-stained FNA smears were cellular and showed cohesive clusters of monotonous cells with abundant granular cytoplasm and indistinct cell borders (Fig. 1A, B). The cells had centrally placed small nuclei without nucleoli. The smear background contained numerous bare nuclei with similar morphology and blood. The Papanicolaou-stained smears showed epithelial fragments with oncocytic granular cytoplasm and centrally placed small nuclei with even chromatin distribution (Fig. 1C). Immunohistochemical stains for thyroglobulin performed on a destained alcohol-fixed smear with appropriate controls were negative. No other immunohistochemical stains have been performed due to limited cytological material. Based on the cytological findings, a diagnosis of oncocytic neoDiagnostic Cytopathology, Vol 31, No 4
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Fig. 1. (A) Diff-Quik-stained FNA smears showing a monotonous population of oncocytic cells arranged in pseudopapillary clusters and singly scattered cells (Diff-Quik stain, ⫻100). (B) High-power view showing cells with eosinophilic cytoplasm and round nuclei (Diff-Quik stain, ⫻200). (C) High-power view of Papanicolaou-stained smears highlighting granular cytoplasm and round nuclei with prominent nucleoli (Papanicolaou stain, ⫻200). (D) H&E-stained histological section showing and intrathyroidal (notice the rim of normal thyroid at the periphery) hypercellular oncocytic parathyroid nodule (H&E stain, ⫻50).
plasm was rendered. Given the patient’s prior history of oncocytic renal neoplasm, it was noted that although the nodule in the thyroid may represent a primary thyroid neoplasm, the possibility of a metastatic lesion from the kidney could not be excluded entirely. Recommendation for surgical excision was given. On gross examination, the left lobe of the thyroidectomy specimen measured 6.5 ⫻ 4.5 ⫻ 2.5 cm. On serial sectioning, a slightly firm circumscribed white ovoid nodule was noted measuring 1.0 ⫻ 0.7 ⫻ 0.5 cm. The right thyroid lobe measured 6.0 ⫻ 3.5 ⫻ 3. 0 cm and on sectioning revealed three discrete nodules measuring in greatest dimension from 0.6 to 1.6 cm. The gland otherwise was remarkable for multiple minute cysts, some with focal calcification. Histological examination of the left thyroid lobe revealed a hypercellular intrathyroidal parathyroid gland that was 278
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well demarcated from surrounding thyroid tissue. It was composed of a mixed population of chief cells and oncocytic cells arranged in a solid pattern (Fig. 1D). The oncocytic cells constituted approximately 40% of the gland, showed eosinophilic granular cytoplasm, and centrally placed small nuclei without nucleoli. Morphologically, they were similar to the cells in FNA. Changes consistent with the previous FNA were present also. No cellular atypia, thick fibrous bands, necrosis, or increased mitotic activity were identified. At the periphery of the nodule, there was a small compressed rim of normalappearing parathyroid tissue. An unremarkable normocellular parathyroid was noted also within the right lobe of the thyroid. Immunohistochemical stains showed focal positivity for PTH and absence of staining for thyroglobulin in the left thyroid nodule, confirming the diagnosis of intrathyroidal parathyroid adenoma.
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Discussion In recent years, there has been an increased interest in the cytomorphology of the FNAs of parathyroid lesions. With the advent of the imaging-guided FNA technique, the number of FNAs of neck masses is increasing, and so is the number of aspirated normal and/or neoplastic parathyroid tissue. Data published in the literature emphasize the difficulties in differentiating the parathyroid lesions from other types of lesions in the head and neck, especially from the neoplastic and nonneoplastic diseases of the thyroid. The possibility of the ectopic location of the parathyroid gland, including intrathyroidal location, clinical similarity between the parathyroid, and thyroid lesions, overlap in their cytomorphology and coexistence of pathology in both glands undoubtedly contribute to the misinterpretation of the FNAs. Parathyroid lesions in the FNAs are confused most commonly with the thyroid neoplasms; papillary, follicular or Hurthle cell; adenomatous thyroid nodules; or lymphocytic thyroiditis. This is caused by the presence of tissue fragments with papillary architecture, epithelial cells arranged in microfollicular pattern, colloid-like material in the background, and the presence of oxyphil cells and naked nuclei of chief cells resembling Hurthle cells and lymphocytes, respectively.1–5 Although the literature dealing with the parathyroid FNA is sparse, most authors emphasize that there is no single diagnostic criterion that helps to differentiate reliably parathyroid lesions from those of the thyroid, but rather a combination of the cytomorphological features should be used.2,4,6,7 Most helpful might be the presence in the parathyroid aspirates of three-dimensional fragments, naked nuclei admixed with cohesive cell clusters, nuclear overlapping, nuclear molding, and the presence of mast cells.2,6 Special techniques, such as immunoperoxidase staining for the PTH and thyroglobulin, chromogranin, and assays of the PTH level of the aspirated fluid might be helpful.2,8,9 We report two cases of parathyroid adenomas that on FNA specimens due to the fact that the presence of monotonous proliferation of oncocytic cells were misinterpreted as Hurthle cell thyroid neoplasm. In both cases, parathyroid adenomas were oncocytic, intrathyroidally located, and associated with normal or mildly increased calcium levels. Because all oncocytic cells have a common feature—increased number of mitochondria in the cytoplasm—the morphology of oncocytic tumors in different organs can be very similar. In the parathyroid gland oncocytes increase in number with age and are considered to reflect degenerative processes associated with aging. This might explain the fact that most oncocytic parathyroid adenomas and parathyroid adenomas with prominent oncocytic component are nonfunctional and clinically quiescent, reflecting structurefunction alterations. Although the oncocytic change in the
parathyroid gland is quite common, oncocytic adenomas of the parathyroid gland are considered relatively rare. According to the literature, they constitute 4.4 – 8.4% of all parathyroid adenomas.10 Among the 306 cases of parathyroid adenomas resected at the Hospital of the University of Pennsylvania during the period 1992–2002, 25 cases were diagnosed as oncocytic and 7 additional lesions had prominent oncocytic components (unpublished findings). Hence, the oncocytic parathyroid adenomas and oncocytic change in parathyroid adenomas and/or normal parathyroid tissue are common enough to be considered as another potential source of the diagnostic pitfall in the FNA of neck masses, particularly in elderly patients. This is especially important to realize because the oncocytic adenomas may reach a large size, and most of the patients are clinically asymptomatic or have mildy elevated serum calcium levels. Although in the first presented case, even in retrospect it would be very difficult to diagnose an oncocytic parathyroid adenoma based solely on the cytomorphological findings without clinical evidence of hyperparathyroidism; the nuclear features of the neoplastic cells in the aspirate were different from those of classic Hurthle cells. The presence of bare nuclei in the background (an unusual feature for Hurthle cell thyroid neoplasm) and absence of a definitive thyroid tumor could have been helpful in suspecting this possibility. In the second case, arriving at the correct diagnosis was complicated by four factors: the patient’s known history of low-grade renal oncocytic neoplasm, intrathyroidal location of the parathyroid adenoma, presence of prominent oncocytic component, and absence of clinical signs of primary hyperparathyroidism. In both cases, the monotonous proliferation of oncocytic cells could represent oncocytic parathyroid adenoma or Hurthle cell neoplasm of the thyroid. Even on review of the slides, it was felt that differential diagnosis of these two entities based only on cytological smears, is extremely difficult. Nevertheless, subtle peculiarities in the nuclear morphology of the oncocytic cells that are different from those of the classic Hurthle cell thyroid neoplasms (small and dark vs. large with prominent nucleoli in Hurthle cell neoplasms) and presence of numerous naked nuclei in the background might be helpful in considering the existence of parathyroid neoplasm. In conclusion, although the oncocytic parathyroid adenomas and parathyroid adenomas with prominent oncocytic component are comparatively uncommon, they should be considered in the differential diagnosis while evaluating the FNAs of the neck masses even in patients without clinical evidence of hyperparathyroidism. It is extremely important to correlate carefully the cytological diagnosis with clinical, radiological, and laboratory findings. Only in cases when clinical and morphological suspicion is strong, a panel of immunohistochemical stains for thyroglobulin, thyroid tranDiagnostic Cytopathology, Vol 31, No 4
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scription factor (TTF-1), and PTH should be performed to rule out a lesion of parathyroid origin.
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