Molecular Characteristics of Large Parathyroid Adenomas

Introduction

The clinical entity of large parathyroid adenomas (LPTAs) has not been well defined. It is speculated that LPTAs would have biochemical, histological, and molecular characteristics different from small adenomas. Our study aimed to find out occurrence of atypia and carcinomas in large parathyroid lesions and the presence of distinct molecular abnormalities in LPTAs.

Materials and methods

We divided the parathyroid lesions into large (>7 g, i.e., LPTAs) and small (<7 g) adenomas. We performed parafibromin, APC (adenomatous polyposis coli), galectin 3, and PGP9.5 (protein gene product 9.5) analysis by immunohistochemistry in adenomas without atypia, atypical adenomas, and carcinomas.

Results

Mean serum calcium, alkaline phosphatase, and intact PTH were significantly higher in large parathyroid tumor group. The presence of both atypical adenoma and carcinoma was higher in large parathyroid tumor group. There was higher percentage of atypia in patients with LPTAs >10 g (33 %), and 68 % of tumors showed at least one marker suggestive of malignancy in this group. Detailed analysis of immunohistochemical features of LPTA >10 g revealed that six patients showed complete loss of parafibromin immunoreactivity (out of these four showed atypia), while seven showed partial loss. In histopathologically proven malignancy (n = 9), six patients showed complete loss of parafibromin staining, 5 (55 %) APC negativity, and 45 % showed both galectin 3 and PGP9.5 positivity. Three out of these showed all IHC markers s/o malignancy, and all of them had evidence of metastases or recurrence. 32 % of atypical adenoma and 13 % of atypical adenoma showed complete loss of parafibromin staining, however none developed metastases or recurrence in follow-up (median follow-up 40 months). Loss of parafibromin staining (complete or partial) was higher in LPTA group (56 %) than that in small adenoma (39 %); however, it was not statistically significant. APC, galectin 3, and PGP9.5 markers suggestive were higher in LPTA group but were not significant.

Conclusion

LPTAs may show some morphological and immunohistochemical features suggestive of malignancy and can be considered a separate entity. However, the immunohistochemical markers are unable to clearly segregate those LPTAs that may show premalignant potential. Further, we would like to recommend that LPTAs showing complete parafibromin loss together with atypia should be kept under close follow-up.

     

Distinguishing Parathyromatosis,Atypical Parathyroid Adenomas,and Parathyroid Carcinomas Utilizing Histologic and Clinical Features

Parathyromatosis is displaced parathyroid tissue in the neck and mediastinum related to prior surgery. Parathyromatosis can be difficult to distinguish from atypical adenoma and parathyroid carcinoma. The aim of this study is to evaluate clinical and morphologic features that may differentiate parathyromatosis, atypical adenoma, and parathyroid carcinoma. Cases of parathyromatosis, atypical adenoma, and parathyroid carcinoma were identified. Index cases were reviewed by consensus for histologic features, including stromal, cytologic/architectural, and invasive features. Ki67 was performed on index cases and scored using the Adsay method. Clinical information was gathered from the electronic medical record. 4 parathyromatosis, 17 atypical adenoma, and 6 parathyroid carcinoma were included. Parathyroid carcinomas were more likely to display coarse chromatin with nucleoli (P = 0.04), infiltrative invasion (P < 0.01), and metastasis (P < 0.01). Only parathyromatosis showed circumscribed invasion. Infiltrative invasion was more common in cases with progression (P = 0.046) and metastasis (P < 0.001). Necrosis and perineural invasion were only present in cases with progression and were more frequent in cases with metastasis (P = 0.079 and P = 0.19, respectively). There were no differences in presence of a fibrous capsule, capsular invasion, intralesional fibrous bands, random endocrine atypia, solid growth, Ki67 index, gland size/weight, serum PTH/calcium levels, and locoregional recurrence rates. There is overlap in the histologic features in parathyromatosis, atypical adenoma, and parathyroid carcinoma. While perineural, vascular, and infiltrative soft tissue invasion should remain diagnostic of malignancy, other atypical features such as solid growth, coarse chromatin with nucleoli, and necrosis should raise concern for recurrence and/or metastasis, and can be present in parathyroid lesions with and without recurrence.     

Incidence and Localization of Ectopic Parathyroid Adenomas in Previously Unexplored Patients

Background

Parathyroidectomy has a success rate of >95 % for cure of primary hyperparathyroidism. In about 6–16 % of cases, one or more hyperfunctioning parathyroid gland(s) are found in an ectopic location. Accurate preoperative imaging can aid in detecting these ectopically located glands and allow a focused surgical approach with an even higher success rate. The objective of this study was to assess the utility of ultrasonography (US) and technetium-99m-sestamibi (MIBI) scans in locating ectopic parathyroid glands in previously unexplored patients who presented with primary hyperparathyroidism.

Methods

We analyzed a total of 1,562 patients who underwent surgery for hyperparathyroidism at our institution from 2000 to 2010. Ectopic parathyroid adenomas were identified in 346 of the patients (22 %). Of the 346 patients, we excluded 144 who underwent reoperations, had four-gland hyperplasia or were missing imaging details. We carefully reviewed the data, including demographics, laboratory values, preoperative localizing imaging details, and operative findings. Preoperative US and MIBI results were compared to the intraoperative findings.

Results

We analyzed 202 patients with ectopic glands for accuracy of preoperative localization. Of these 202 patients, a single adenoma was the most common (89 %) followed by double adenoma (11 %). The ectopic parathyroid glands were predominantly located in the thymus (38 %) followed by 31 % in the retroesophageal region; 18 % were intrathyroidal. Preoperative MIBI scans had a sensitivity of 89 % (161/197), whereas US had a sensitivity of 59 % (35/63) for detecting ectopic glands. Overall, both imaging modalities had a positive predictive value of 90 %, with MIBI correctly predicting ectopic glands best in the thymus, mediastinum, or the retroesophageal space, and US was most accurate at detecting intrathyroidal glands.

Conclusions

Based on the data available at our institution, MIBI has a higher sensitivity than US in correctly localizing ectopic parathyroid adenomas, but the accuracy of detection varies based on location. Both imaging techniques have a high PPV for detecting an ectopic gland. Therefore, imaging with MIBI and US can be complementary, and positive localization of an ectopic gland with either modality is highly accurate and can facilitate a more focused surgical approach.     

Intraoperative Parathyroid Hormone Assay Remains Predictive of Cure in Renal Impairment in Patients with Single Parathyroid Adenomas

Background

Parathyroid hormone (PTH) has a short half-life and is cleared by the liver and kidneys. This study examined whether declining estimated glomerular filtration rate (eGFR) affects application of the Miami criterion for intraoperative PTH (ioPTH) decline during parathyroidectomy for primary hyperparathyroidism (pHPT).

Methods

A retrospective review of consecutive patients undergoes parathyroidectomy for pHPT. Patients with multi-gland disease, without ioPTH, failure-to-cure and those <18 years were excluded. Baseline demographics, pre-operative PTH, ioPTH and 6-month follow-up data were available. Patients were categorised into normal or chronic kidney disease (CKD stage 2–5) based on pre-operative eGFR. Nonparametric data were compared using Mann–Whitney U test/Kruskal–Wallis test. The primary outcome measure was to assess whether CKD-affected ioPTH decline in parathyroidectomy for pHPT.

Results

A total of 476 patients were included [75.4% women; median age 63.8 years (18–92)]. CKD was present in 362 (76%) (CKD2:289; CKD3:66; CKD4/5:7). Increasing CKD stage was associated with advancing age [normal 53 years (41–61); CKD2 65 (57–73); CKD3 73.5 (66–78); CKD4/5 74(63–81); p < 0.001] and higher pre-operative PTH [16.6 pmol/L (11.1–22.9); 13.1 (10.4–17.7); 22.6 (13.8–33.7); 33.8(12.4–41.7); p < 0.001]. Baseline and post-excision ioPTH were significantly higher in those with CKD4/5 (p < 0.05). The Miami criterion was met in all patients, but median fall in ioPTH at 10-min varied between groups [normal:0.78 (0.71–0.82); CKD2:0.76 (0.69–0.83); CKD3:0.75 (0.69–0.82); CKD4/5:0.69 (0.61–0.70); p = 0.048)]. It was significantly lower in those with CKD4/5 compared with the remainder of patients [0.69 (0.61–0.70) vs. 0.76 (0.70–0.82); p = 0.008].

Conclusions

Although the reduction in ioPTH after successful parathyroidectomy is lower in severe CKD, the Miami criterion remains predictive of cure. Differences in absolute levels of PTH and tumour weight suggest that renal HPT may be a confounding factor.

     

Incidental Parathyroid Adenomas with Normocalcemia Discovered During Thyroid Operations: Report of Three Cases

We report three cases of parathyroid adenoma incidentally discovered during a total thyroidectomy. No patients showed any clinical or chemical features that led us to suspect a hyperparathyroidism condition before operation, but a macroscopically enlarged parathyroid was discovered during the dissection and it was removed in all three cases. All patients had a single adenoma confirmed by a histological analysis. Calcemia decreased after operation in every case but only one patient needed temporary adjunctive therapy. No permanent hypoparathyroidism or recurrent hyperparathyroidism was observed. We recommend that any enlarged parathyroid discovered during neck surgery should thus be removed in order to avoid the risks of future surgical procedures due to successive bouts of clinical hyperparathyroidism. Received: June 5, 2000 / Accepted: January 9, 2001     

Gland Size Is Associated With Changes in Gene Expression Profiles in Sporadic Parathyroid Adenomas

Background Sporadic parathyroid adenomas (SPAs) are benign neoplasms responsible for most cases of primary hyperparathyroidism (pHPT). The molecular pathways responsible for the variations in clinical severity of pHPT are unknown. We studied gene expression profiles in patients with SPAs and pHPT to determine associations between these changes and clinical parameters.Methods We selected 10 patients with solitary SPAs and nonfamilial, non-MEN1 pHPT treated with surgery from 2001 to 2003. Pathologic and clinical data were reviewed. At operation, tissues from SPAs were frozen in liquid nitrogen; total RNA was obtained from sections, and the diagnosis was confirmed with hematoxylin and eosin staining. Control normal parathyroid RNA was age- and sex-matched. RNA was amplified, labeled, and hybridized to a microarray of 22,272 human oligonucleotides. Cluster analysis of gene expression, analysis of expression ratios, and comparison of clinical parameters were performed.Results All patients were cured; all specimens were consistent with SPAs. K means clustering divided the 10 patients into 2 distinct 5-patient gene expression groups by using uncentered correlation based on gene subgrouping. Of the clinical parameters, only the mean gland volume was significantly different between group 1 (390±160 mm³) and group 2 (1080±615 mm³; P = .032 by Mann-Whitney test). Seventy-five genes were significantly upregulated or downregulated (with a ratio of <.33 or >3) compared with controls. These genes included the v-fos viral oncogene homolog and six calcium ion-binding signaling proteins.Conclusions Differential expression of a few critical genes may contribute to differences in gland volume in SPAs. A better understanding of these pathways may help to define the pathophysiology of pHPT.     

Parathyroid Adenomas versus Four-gland Hyperplasia as the Cause of Primary Hyperparathyroidism in Patients with Prolonged Lithium Therapy

Chronic lithium therapy in patients with affective psychiatric disorders has been implicated as the cause of hypercalcemia and primary hyperparathyroidism. Our objective was to evaluate whether primary hyperparathyroidism was caused by an adenoma or four-gland hyperplasia. The medical records of 15 patients with affective psychiatric disorders who were treated with chronic lithium therapy from 1982 to 1997, all of whom were operated on for primary hyperparathyroidism, were reviewed. Data on age, symptoms, duration of lithium therapy, pre- and postoperative calcium levels, and parathyroid hormone levels were collected. Parathyroid histology for each patient was independently and blindly reviewed. The mean age was 58 +/- 10 years, the mean duration of lithium therapy 10.7 +/- 6 years, and the mean preoperative calcium level 11.7 +/- 0.5 mg/dl. All patients underwent bilateral neck exploration with selective resection of enlarged glands. Of the 15 patients, 14 (92%) had adenomas (11 single, 3 double), and 1 (8%) had four-gland hyperplasia. All patients were rendered eucalcemic, with a postoperative calcium level of 9.2 +/- 0.5 mg/dl ( p < 0.005). All patients resumed their lithium therapy, with 1 of 15 patients developing recurrent hyperparathyroidism 2 years following the first operation; this patient required reexploration, at which time an adenoma was resected. In our experience hyperparathyroidism in patients who have undergone prolonged therapy with lithium is associated with a high incidence of parathyroid adenomas versus four-gland hyperplasia. This suggests that lithium selectively stimulates growth of parathyroid adenomas in susceptible patients, who are best treated with adenoma excision rather than subtotal parathyroidectomy.     

Preoperative Localization of Parathyroid Adenomas Using 99mTc-MIBI Scintigraphy in Patients with Hyperparathyroidism

Background Technetium (Tc) 99m methoxyisobutyl isonitrile (_99mTc-MIBI) has recently been introduced for parathyroid imaging, as well as for myocardial imaging. We studied the usefulness of _99mTc-MIBI scintigraphy for preoperative localization of abnormal parathyroid glands.
Methods The usefulness of _99mTc-MIBI scintigraphy for detection of hyperfunctional parathyroid lesions was evaluated in 5 patients with primary hyperparathyroidism. The results of localizing the abnormal glands by using _99mTc-MIBI were compared with those obtained by using thallium (Tl) 201-technetium (Tc) 99m (_2ulTI-_99mTc) subtraction scintigraphy, computed tomography, and ultrasonography.
Results The delayed (2 hours) imaging of _99mTc-MIBI scintigraphy was highly useful for accurate localization of the abnormal parathyroid lesions. The diseased glands were detected in all cases where _99mTc-MIBI scintigraphy was used, and using _99mTc-MIBI scintigraphy provided more information than did computed tomography, ultrasonography, or ₂₀₁Tl-_99mTc subtraction scintigraphy. Conclusion: This method is simple and essential for detecting hyperfunctioning parathyroid glands, especially those with small or ectopic lesions. This technique should be widely applied as a localizing diagnostic method for hyperparathyroidism.     

Weight Difference Between Double Parathyroid Adenomas Is the Cause of False-positive IOPTH Test After Resection of the First Lesion

Background  

Some patients with double parathyroid adenoma show a greater than 50% decline in intraoperative parathyroid hormone (IOPTH) after resection of the first lesion. The present study was designed to test the hypothesis that significant adenoma weight differences may explain this inappropriate decline of IOPTH.     

The Small Abnormal Parathyroid Gland is Increasingly Common and Heralds Operative Complexity

Background

Over decades, improvements in presymptomatic screening and awareness of surgical benefits have changed the presentation and management of primary hyperparathyroidism (PHPT). Unrecognized multiglandular disease (MGD) remains a major cause of operative failure. We hypothesized that during parathyroid surgery the initial finding of a mildly enlarged gland is now frequent and predicts both MGD and failure.

Methods

A prospective database was queried to examine the outcomes of initial exploration for sporadic PHPT using intraoperative PTH monitoring (IOPTH) over 15 years. All patients had follow-up ≥6 months (mean = 1.8 years). Cure was defined by normocalcemia at 6 months and microadenoma by resected weight of <200 mg.

Results

Of the 1,150 patients, 98.9 % were cured and 15 % had MGD. The highest preoperative calcium level decreased over time (p < 0.001) and varied directly with adenoma weight (p < 0.001). Over time, single adenoma weight dropped by half (p = 0.002) and microadenoma was increasingly common (p < 0.01). MGD risk varied inversely with weight of first resected abnormal gland. Microadenoma required bilateral exploration more often than macroadenoma (48 vs. 18 %, p < 0.01). When at exploration the first resected gland was <200 mg, the rates of MGD (40 vs. 11 %, p = 0.001), inadequate initial IOPTH drop (67 vs. 79 %, p = 0.002), operative failure (6.6 vs. 0.7 %, p < 0.001), and long-term recurrence (1.6 vs. 0.3 %, p = 0.007) were higher.

Conclusions

Single parathyroid adenomas are smaller than in the past and require more complex pre- and intraoperative management. During exploration for sporadic PHPT, a first abnormal gland <200 mg should heighten suspicion of MGD and presages a tenfold higher failure rate.     

Presurgical Localization of Parathyroid Adenomas with Magnetic Resonance Imaging at 3.0 T: An Adjunct Method to Supplement Traditional Imaging

Purpose  

To investigate the use of a chemical shift-based water–fat separation magnetic resonance imaging (MRI) method, and time-resolved contrast-enhanced MRI at 3 T for improved presurgical localization of parathyroid adenomas.     

Pituitary Adenomas

Opinion statement Treatment of pituitary adenomas can be pharmacologic or surgical. First-line treatment of prolactinomas is usually medical, using either bromocriptine or cabergoline. Other symptomatic pituitary adenomas typically should be treated with transsphenoidal surgery. Radiation therapy can be adjunctive for residual or recurrent tumor. The prognosis for endocrinologic and visual improvement is usually good.     

Single Gland,Ectopic Location: Adenomas are Common Causes of Primary Hyperparathyroidism in Children and Adolescents

World Journal of Surgery - Primary hyperparathyroidism (PHPT) in children and adolescents is uncommon. Data-driven guidelines for management in pediatric patients are limited. We performed a...     

Three-Dimensional Metabolic and Radiologic Gathered Evaluation Using VR-RENDER Fusion: A Novel Tool to Enhance Accuracy in the Localization of Parathyroid Adenomas

Background

The aim of this study was to assess the accuracy of a novel imaging modality, three-dimensional (3D) metabolic and radiologic gathered evaluation (MeRGE), for localizing parathyroid adenomas (PAs).

Methods

Consecutive patients presenting with primary hyperparathyroidism who underwent both thin-slice cervical computed tomography (CT) and ^99mTc-sestamibi (MIBI) scanning were included. 3D-CT reconstruction was obtained using VR-RENDER, which was used to perform 3D virtual neck exploration (3D-VNE). The MIBI scan was then fused with the 3D reconstruction to obtain 3D-MeRGE. Sensitivity, specificity, and accuracy were assessed. Parathyroid gland volume and preoperative parathormone (PTH) levels were analyzed as predictive factors of correct localization (i.e., correct quadrant).

Results

A total of 108 cervical quadrants (27 patients) were analyzed. Sensitivities were 79.31, 75.86, 65.51, and 58.61 % with 3D-MeRGE, 3D-VNE, MIBI, and CT, respectively. Specificity was highest with CT (94.93 %) followed by 3D-VNE (92.4 %). MIBI and 3D-MeRGE had the same specificity (88.6 %). 3D-MeRGE and 3D-VNE achieved higher accuracy than MIBI or CT alone. Mean PTH values were significantly higher in patients with lesions that were correctly identified (true positive, TP) than in those whose lesions were missed (false negative, FN) with 3D-VNE (219.60 ± 212.77 vs. 98.75 ± 12.76 pg/ml; p = 0.01) and 3D-MeRGE (217.69 ± 213.76 vs. 09.75 ± 20.48 pg/ml; p = 0.02). The mean parathyroid gland volume difference between TP and FN was statistically significant with all modalities except CT.

Conclusions

3D-MeRGE and 3D-VNE showed high accuracy for localization of PAs. 3D-MeRGE performed better than MIBI or CT alone for detecting small adenomas and those with a low PTH level.     

Adenomas of the nipple

A case of adenoma of the nipple is reported. Although this is a comparatively rare condition, knowledge of it is extremely important because clinically it simulates Paget's disease. A failure to recognise the pathology could therefore lead to mistaken diagnosis and consequent surgery which would create serious damage to the patient. According to almost all authors, it is a benign pathology and can therefore be treated with an intervention limited to removing the complete tumour. This for two reasons: the first is that if the tumour grows it can become painful, create a sense of tension and bleed in the erosive phase; the second, more important, is that malignant degeneration has been hypothesised. For these reasons it is essential to examine the other breast immediately and follow the patient over time to prevent unpleasant surprises.     

Intraoperative Secretion of Intact Parathyroid Hormone and Amino-Terminal Parathyroid Hormone Fragments from Normal Parathyroid Glands Associated with Solitary Parathyroid Adenoma

p < 0.05 for both). Because the reduction was more pronounced for i-PTH than for N-PTH, the N/i ratio increased from 0.54 ± 0.33 to 3.76 ± 1.62 ( p < 0.05). Furthermore, the levels of i-PTH and N-PTH were higher centrally than peripherally both before and after adenoma excision ( p < 0.05). The results therefore suggest that the secretion of i-PTH and N-PTH in the remaining normal-size parathyroid glands is not completely suppressed. Furthermore, in these parathyroid glands the secretion of amino-terminal PTH fragments is relatively predominant when compared to the release of the intact PTH. The findings underscore the importance of the N-terminal PTH fragment for maintaining calcium homeostasis during the early postoperative period after surgery for pHPT and may explain the rarity of prolonged hypocalcemia after parathyroidectomy.     

Synchronous Multifocal Canalicular Adenomas

Canalicular adenoma (CAD) is an uncommon benign tumor of minor salivary glands with predilection for the upper labial mucosa. An 80-year-old female presented with nine submucosal nodules of the upper labial mucosa and bilateral buccal mucosa. Histopathologic examination revealed multifocal circumscribed tumor islands with a tubular growth pattern within a loose hypocellular myxoid background stroma. Interconnecting rows of columnar tumor cells imparted a canalicular morphology. In addition to the characteristic histopathologic findings, a comprehensive immunohistochemical panel supported a final diagnosis of multifocal CAD. Synchronous multifocality in CAD is an infrequent finding and this sine qua non clinicopathologic correlation article exemplifies such a case.