Causative role for defective expression of mitochondria-eating protein in accumulation of mitochondria in thyroid oncocytic cell tumors.

Oncocytic cell tumor of the thyroid is composed of large polygonal cells with eosinophilic cytoplasm that is rich in mitochondria. These tumors frequently have the mutations in mitochondrial DNA encoding the mitochondrial electron transport system complex I. However, the mechanism for accumulation of abnormal mitochondria is unknown. A noncanonical mitophagy system has recently been identified, and mitochondria-eating protein (MIEAP) plays a key role in this system. We therefore hypothesized that accumulation of abnormal mitochondria could be attributed to defective MIEAP expression in these tumors. We first show that MIEAP was expressed in all the conventional thyroid follicular adenomas (FAs)/adenomatous goiters (AGs) but not in oncocytic FAs/AGs; its expression was defective not only in oncocytic thyroid cancers but also in the majority of conventional thyroid cancers. Expression of MIEAP was not correlated with methylation status of the 5'-UTR of the gene. Our functional analysis showed that exogenously induced MIEAP, but not PARK2, reduced the amounts of abnormal mitochondria, as indicated by decreased reactive oxygen species levels, mitochondrial DNA / nuclear DNA ratios, and cytoplasmic acidification. Therefore, together with previous studies showing that impaired mitochondrial function triggers compensatory mitochondrial biogenesis that causes an increase in the amounts of mitochondria, we conclude that, in oncocytic cell tumors of the thyroid, increased abnormal mitochondria cannot be efficiently eliminated because of a loss of MIEAP expression, ie impaired MIEAP-mediated noncanonical mitophagy.

Characterization of oncocytes in deep esophageal glands.

Deep esophageal glands play a vital role in the protection and regeneration of the esophageal mucosa. Conditions such as gastroesophageal reflux disease and Barrett's esophagus have been associated with a change in the usual glands by oncocytic metaplasia. However, little is known regarding the function of oncocytes or the relevance of this metaplastic change in the human esophagus. We hypothesized that oncocytes of deep esophageal glands also express markers characteristic of a ductal epithelial phenotype because similar oncocytes have been described as part of large ductal epithelial cells in salivary glands. We used immunohistochemical stains to define structural, functional, proliferative, and potential stem/progenitor characteristics of oncocytes. Oncocytes did not express mucins or lysozyme C, two molecules found in mucous cells and used for antimicrobial defense. Oncocytes did not express CK5, a cytokeratin found in myoepithelial cells and basal epithelial cells, but expressed CK7, a cytokeratin found in intralobular ductal epithelial cells and luminal epithelial cells of the main duct. Oncocytes expressed cystic fibrosis transmembrane conductance regulator and sodium/potassium ATPase, ion channels that play a role in bicarbonate secretion. Membrane-bound beta-catenin was detected in oncocytes, but these cells did not express the proliferative marker Ki67. Approximately, a third of oncocytes expressed SOX9 and p63, transcription factors expressed in epithelial progenitor cells in multiple organs. Moreover, oncocytes expressed CD44, a transmembrane Glycoprotein expressed in cancer stem cells. Taken together, our data show that oncocytes express markers of intralobular ductal epithelial cells and luminal epithelial cells of the main duct. Additionally, our observations suggest that oncocytes act as epithelial progenitor cells and play a role in bicarbonate secretion. Since oncocytic metaplasia is associated with conditions of chronic acid injury, it is possible that oncocytes replace the mucous cells in deep esophageal glands (dEG) as an adaptive change to counteract injury from acid reflux. The marker characterization suggests that oncocytes may originate from transdifferentiation of myoepithelial and mucous cells. This transdifferentiation might lead to an overall decrease of mucins production and secretion by the dEG and a subsequent reduction of the protection conferred by the viscoelastic mucous layer.

Clinicopathologic and radiopharmacokinetic factors affecting gamma probe-guided parathyroidectomy.

HYPOTHESIS: The kinetics of technetium Tc 99m sestamibi (MIBI) in primary hyperparathyroidism are variable and affected by the cellular size of the abnormal glands, the parathyroid hormone levels, and the functional expression of P-glycoprotein (Pgp). The success of gamma probe-guided parathyroidectomy is closely related to the parathyroid-to-thyroid activity ratio at the time of surgery. Preoperative determination of maximum uptake ratio may improve the surgical outcome. DESIGN: Thirty-one patients with primary hyperparathyroidism attributed to a solitary parathyroid adenoma (27 patients) or multiglandular hyperplasia (4 patients) underwent dynamic MIBI imaging preoperatively. Maximum MIBI activity and activity elimination half-life in the abnormal parathyroid glands and thyroid glands were measured, and the maximum uptake ratio was calculated. After a second MIBI injection on the day of surgery, all patients underwent gamma probe-guided parathyroidectomy and cervical exploration. Timing of surgery after MIBI injection was individualized according to the optimal time to surgery (time to maximum uptake ratio), which was determined by preoperative scintigraphy. During surgery, the gamma probe was used to measure ex vivo counts of excised lesions and adjacent postexcision normal tissue (background). Image characteristics, MIBI kinetics, and gamma probe findings were correlated with gland volume, oxyphil cell content, Pgp expression, and serum parathyroid hormone levels. RESULTS: Probe localization of abnormal glands at maximum uptake ratio was successful in all patients. The volume of the parathyroid lesion ranged from 0.03 to 9.8 mL (median, 0.7 mL). Parathyroid maximum MIBI activity correlated with the volume of the gland (r = 0.54, P = .002) and serum parathyroid hormone level (r = 0.58, P = .001). No correlation between maximum MIBI activity and oxyphil cell content or Pgp expression could be demonstrated. Elimination half-life of MIBI from parathyroid inversely correlated with Pgp (r = -0.36, P = .05). The ex vivo lesion-background count ratio positively correlated with volume of the gland (r = 0.66, P = .001) and parathyroid hormone level (r = 0.48, P = .006). Ex vivo lesion counts and Pgp expression were negatively correlated (r = -0.37, P = .04). CONCLUSIONS: A strong relationship between volume of the parathyroid gland, serum parathyroid hormone levels, and MIBI uptake exists in primary hyperparathyroidism. Gamma probe-guided localization of abnormal gland(s) can be more successful if surgery is undertaken at maximum uptake ratio. High Pgp expression increases MIBI parathyroid clearance rate, decreases gamma probe counts, and may significantly alter the optimal time to surgery.

The meaning and predictivity of Hürthle cells in fine needle aspiration cytology for thyroid nodular disease.

AIMS: The significance of Hürthle cells in thyroid nodule fine needle aspiration cytology (FNAC) samples remains uncertain. This study aims to clarify the meaning and the predictivity of this kind of cells. METHODS: One hundred and ten patients with Hürthle cells in FNAC of thyroid nodules were reviewed. Histopathology was correlated with cytological findings. RESULTS: The density of Hürthle cells in FNACs ranged from 20 to 100%. Eighty-nine patients had benign nodular disease (Hürthle cell or follicular adenoma), and 21 patients had malignant tumours. The presence of more than 50% Hürthle cells in FNAC correlated with benign or malignant Hürthle cell neoplasm. Hürthle cell carcinomas displayed more than 90% Hürthle cells in FNAC. CONCLUSIONS: Surgery is indicated for all nodular lesions with more than 50% Hürthle cells in FNAC.

Morphometrically observable aging changes in the human tongue.

Like the outside parts of the nose and the ear but unlike most other organs, the tongue continues to grow at advanced age. Therefore, internal morphological aging processes must also proceed in a specific way. We used sectioned specimens of the radix linguae from 111 humans. The specimens were fixed in 4% formalin solution, embedded in paraffin, then cut at a thickness of 5 microm and stained with hematoxylin-eosin. The structures of interest were measured with an automatic image analyzing system (SIS, Münster, Germany). The statistical analysis package SPSS was used for correlation and regression analysis and testing of the resulting coefficients. The mean cross-sectional area of the muscle fibers increases sharply during youth, but remains at a high level into old age. After the age of seventy, it increases again. With muscles of the locomotor apparatus, this same parameter decreases after the fifth decade. We have demonstrated the process of adipose tissue formation in muscles and serous glands. Gender differences in the aging process could be clearly shown. Numerous oncocytes were visible in ducts from elder persons.

Oncocytic sialolipoma of the submandibular gland with sebaceous differentiation: a new pathological entity.

CASE REPORT: We report the case of an oncocytic sialolipoma of the submandibular gland with sebaceous differentiation in a 73-year-old man. The initial symptom was a right submandibular painless mass. Ultrasonography showed a hypoechoic oval mass posterior to the submandibular gland. The tumorectomy was performed with preservation of the salivary gland. The tumor was composed of mature adipose tissue surrounded by a thin fibrous capsule, multiple nodules of oncocytes, normal ductal-acinar units with focal ductal sebaceous differentiation. DISCUSSION: We reviewed literature of the reported cases of mixed tumors of the salivary glands composed of mature adipose tissue with oncocytosis, salivary ducts, and acini with sebaceous differentiation. CONCLUSIONS: Sialolipoma and lipoadenoma with or without oncocytosis and/or sebaceous differentiation should be considered organ-specific tumors with a distinct histological appearance and specific terminology.