The use of Raman spectroscopy to identify and characterize transitional cell carcinoma in vitro

OBJECTIVE: To determine whether Raman spectroscopy can be used to differentiate between normal, inflammatory and malignant bladder pathologies in vitro, and secondly if it can used to grade and stage transitional cell carcinoma (TCC). MATERIALS AND METHODS: In all, 1525 Raman spectra were measured from 75 bladder samples comprising normal bladder, cystitis, carcinoma in situ (CIS), TCC and adenocarcinoma. Multivariate analysis was applied to the spectral dataset to construct diagnostic algorithms; these were then tested for their ability to determine the histological diagnosis of each sample from its Raman spectrum. RESULTS: The diagnostic algorithms could be used to accurately differentiate among the pathological groups, in particular, a three-group algorithm differentiated among normal bladder, cystitis and TCC/CIS with sensitivities and specificities of > 90%. Algorithms could also accurately characterize TCC in terms of splitting them into low (G1/G2) or high (G3) grade and superficial (pTa) or invasive (pT1/pT2) stage. CONCLUSION: Raman spectroscopy can be used to accurately identify and grade/stage TCC in vitro. The technique therefore shows promise for use as an objective method to assist the pathologist in assessing bladder pathologies. Raman spectroscopy also has potential to provide immediate pathological diagnoses during surgical procedures. Following the promising results of this in vitro study, in vivo cystoscopic studies are planned.     

Double parathyroid adenomas. Clinical and biochemical characteristics before and after parathyroidectomy.

OBJECTIVE: There is considerable debate about whether double parathyroid adenomas are a discrete entity or represent hyperplasia with parathyroid glands of varying sizes. This distinction is important because it impacts on the extent of parathyroid resection and the success of the parathyroid operation. SUMMARY BACKGROUND DATA: Double parathyroid adenomas have been reported to occur in 1.7% to 9% of patients with primary hyperparathyroidism (HPT). It is important for surgeons to differentiate between double adenoma and hyperplasia with glands of varying sizes using gross examination during the initial procedure because microscopic findings of a small biopsy specimen at frozen-section examination may not be diagnostic. METHODS: From 1982 to 1992, 416 unselected patients (309 women and 107 men) with primary HPT without familial HPT or multiple endocrine neoplasia (MEN) were treated by one surgeon at the University of California at San Francisco. Double adenoma occurred in 49 patients, solitary adenoma in 309 patients, and hyperplasia in 58 patients. The authors analyzed the clinical manifestations, the preoperative and postoperative serum levels of calcium, phosphate, and parathyroid hormone (PTH), and the success rate and outcome after parathyroidectomy and compared their results in 49 patients with double adenomas to the results for patients with solitary adenomas or hyperplasia. RESULTS: Ten of the patients with double adenomas (20.4%) were referred for persistent HPT after removal of one abnormal parathyroid gland. The ages of the patients with double adenoma, single adenoma, and hyperplasia were 61 +/- 14, 56 +/- 15, and 58 +/- 7 years, respectively. Fatigue, muscle weakness, and bone pain were common in patients with double adenomas, whereas nephrolithiasis occurred more frequently in patients with solitary adenoma (p = 0.0001). Serum calcium and PTH levels (per cent of upper limit of normal) fell from 11.5 +/- 1.2 mg/dL and 487% to 9.5 +/- 0.8 mg/dL and 61% for patients with double adenomas; from 11.9 +/- 0.9 mg/dL and 378% to 9.3 +/- 1.4 mg/dL and 101% for patients with single adenoma; and from 10.9 +/- 0.5 mg/dL and 418% to 9.1 +/- 0.7 mg/dL and 94% for patients with hyperplasia, respectively. There was no recurrence in the patients with double adenomas with a mean follow-up time of 5.8 years. CONCLUSIONS: Double adenomas are a discrete entity and occur more often in older patients. Patients with double adenomas can be successfully treated by removal of the two abnormal glands.     

Utility of intraoperative bilateral internal jugular venous sampling with rapid parathyroid hormone testing in guiding patients with a negative sestamibi scan for minimally invasive parathyroidectomy—a randomized controlled trial

Background and aims  The purpose of this study was to determine the utility of bilateral internal jugular venous sampling with rapid parathyroid hormone assay (BIJV–IOPTH) in comparison to endocrine surgeon-performed ultrasonography of the neck as an alternative localizing modality in guiding patients with primary hyperparathyroidism (pHPT) and negative sestamibi scans for minimally invasive parathyroidectomy (MIP). Patients and methods  Seventy eight consenting patients with a negative subtraction sestamibi scan planned for parathyroidectomy underwent additional ultrasound parathyroid imaging and were randomized to undergo surgery without vs. with additional BIJV–IOPTH; n = 39 in each group. The patients with a positive alternative imaging test were qualified for video-assisted MIP, whereas the others underwent open neck explorations. The primary outcome measure was the number of patients with true-positive results of alternative imaging tests. Results  Of the 78 patients, 50 (64%) had a single adenoma, eight (10.3%) had double adenomas, and 20 (25.7%) demonstrated four-gland hyperplasia. Ultrasonography alone vs. combined with BIJV–IOPTH was true positive in detecting a solitary parathyroid adenoma in 8/24 (33.3%) vs. 17/26 (65.4%) patients, respectively (p = 0.023). Curative video-assisted MIP was successfully performed in all the patients with true-positive results. The remaining individuals were cured by more extensive open neck explorations (unilateral—4/39 vs. 4/39, respectively; p = 1.0 or bilateral—27/39 vs. 18/39, respectively; p = 0.039). Conclusions  Most patients with pHPT and a negative subtraction sestamibi scan (64%) have a single adenoma. BIJV–IOPTH as an addition to a surgeon-performed ultrasound of the neck allows for more accurate guiding for MIP in patients with a solitary parathyroid adenoma and negative subtraction sestamibi scans. Presented at the 3rd Workshop of the European Society of Endocrine Surgeons (ESES), “Modern techniques in primary hyperparathyroidism surgery: An evidence based perspective”, 19-21 of March 2009, Lund, Sweden. “Best of Endocrine Surgery in Europe 2009”     

Functioning oxyphil cell adenomas of the parathyroid gland. A study of 15 cases

Parathyroid adenomas composed predominantly of chief cells are the most frequent cause of primary hyperparathyroidism. Until as recently as 1978, the rare oxyphil cell parathyroid adenoma was generally considered nonfunctioning. A retrospective review of 500 consecutive patients at the Massachusetts General Hospital with a diagnosis of hyperparathyroidism associated with parathyroid adenoma during the years 1979-1987 yielded 15 (3.0%) oxyphil cell adenomas. A total of 65 case reports of hyperparathyroidism associated with a diagnosis of oxyphil cell adenomas were reviewed, applying the same diagnostic criteria used in case selection for the present series. These criteria include: (a) at least 90% composition of the adenoma by oxyphil cells; (b) biopsy or excision of a second histologically normal parathyroid gland to help rule out hyperplasia; and (c) postoperative alleviation of hypercalcemia. More than 50% of the previously reported cases did not conform to these criteria. The findings in the present study further document the entity of hyperparathyroidism caused by oxyphil cell parathyroid adenomas and suggest criteria guidelines for this rare diagnosis.     

Indian Primary Hyperparathyroidism Patients with Parathyroid Carcinoma do not Differ in Clinicoinvestigative Characteristics from Those with Benign Parathyroid Pathology

Introduction No foolproof preoperative diagnostic indicators of parathyroid carcinoma (PC) exist in absence of nonskeletal metastases. Palpable parathyroid tumor, advanced skeletal and renal manifestations, and very high serum calcium and parathyroid hormone levels are considered strong predictors. Most of these features are common in Indian primary hyperparathyroidism (PHPT) patients although only few have PC. The aim of this study was to identify dependable clinicoinvestigative predictors of PC in Indian PHPT patients. Materials and Methods Clinical, biochemical, radiological, and densitometric attributes of 100 PHPT patients who underwent successful parathyroidectomy (1990–2004) were studied. Various parameters of patient groups with parathyroid adenoma (n = 84), primary hyperplasia (n = 12), and carcinoma (n = 4) were compared using ANOVA, with P value < 0.05 considered significant. Results Mean age of patients was 37.4 years, with no difference in the 3 groups (P = 0.92). Patients in 3 groups had comparably severe bone disease; 36 had coexistent renal disease. Two patients with PC and 27 (32%) with adenoma had palpable parathyroid tumor. None of the biochemical parameters predicted malignant pathology. Mean tumor weight (milligram) in carcinoma patients (15,080 ± 5,638.02) was significantly higher than those with adenoma (5,724 ± 1,257.9) (P = 0.002). Postoperative course and recovery in carcinoma patients were similar to those with adenoma. In follow-up (mean: 33 months), none of the adenoma patients were found to have persistent/recurrent PHPT attributable to missed PC. Conclusion Indian patients with parathyroid adenoma, hyperplasia, and carcinoma were not found to differ in their clinical, biochemical, and pathological characteristics except for significantly higher tumor weight in the carcinoma group.     

Shifting Incidence of Solitary Adenomas in the Era of Minimally Invasive Parathyroidectomy. A Multi-Institutional Study

Background

Previously, when a conventional neck exploration (CNE) without preceding diagnostic imaging was the surgical treatment for patients with primary hyperparathyroidism (pHPT) solitary adenomas were observed in 69–88% of patients. The advent of minimally invasive parathyroidectomy (MIP), aiming at a preoperatively identified parathyroid abnormality may be associated with a different incidence of solitary and multiglandular parathyroid disease.

Materials and Methods

In a cohort of 467 patients with sporadic pHPT who preferentially underwent MIP in four hospitals in the same geographical region, the incidence of solitary adenomas, multiple adenomas, and multiglandular hyperplasia (MGD) was evaluated.

Results

A total of 367 patients were scheduled for MIP; 100 patients underwent a planned CNE. The overall surgical success rate of the first operation was 93%, and the cumulative success rate, including a second operative procedure, was 99%. Normocalcemia resulted from removing 1 abnormal PG in 426 patients (91%) and more than one abnormal gland in 35 patients (8%). A parathyroid carcinoma was diagnosed in four of the 426 patients with a single abnormal gland. Four gland hyperplasia was observed in 1 patient. In hospitals where diagnostic workup usually consisted of ultrasound (US) and computed tomography (CT) the incidence of solitary adenomas was 88%, compared with 96% in hospitals where MIBI, US, and CT were used preoperatively (P = 0.007).

Conclusions

A higher frequency of solitary adenomas was observed than historically reported. The extent of the preoperative workup influences the number of observed solitary adenomas.     

Diagnosis of pathological minor salivary glands in primary Sjogren’s syndrome by using Raman spectroscopy

The lip biopsy is essential for the diagnosis of primary Sjogren’s syndrome (SS) but an invasive method can cause some disadvantages. The purpose of this study is to apply Raman spectroscopy to detect the pathological minor salivary glands in primary SS and establish the diagnostic model of Raman spectra of the primary SS samples. Raman spectra from the primary samples and control samples were obtained by Raman microscope and were compared to find the differences. The principal component analysis (PCA) and discrimination function analysis (DFA) were employed to analyze the spectra and establish the diagnostic model. The differences of Raman spectra demonstrated the biochemical molecular alterations between the different samples. Compared with the control samples, the content of proteins, nucleic acids, and keratin increased in the primary SS samples but the content of lipids decreased. PCA and DFA displayed a powerful role in the classification of the Raman spectra. The sensitivity and specificity of the diagnostic model reached above 91 and 92 %, respectively. The total accuracy is 92.4 %. Raman spectroscopy combined with PCA-DFA algorithm will provide an effective and accurate technology for the diagnosis of the pathological minor salivary glands in primary SS, which may replace the lip biopsy in the future.     

The role of hyperplasia in multiple parathyroid adenomas

BACKGROUND: Parathyroid adenoma is the most common cause of primary hyperparathyroidism (pHPT). Adenomas usually involve only a single gland, and the remaining glands are normal or suppressed. Multiple parathyroid adenomas have been reported to occur in as high as 11% of patients with pHPT. The significant incidence of multiple adenomas with histologic similarities to hyperplasia has raised the possibility that adenoma is a continuation of the hyperplasia state. To test this theory, we used molecular genetics to compare clonality and proliferative activity of parathyroid adenoma with its corresponding normal glandular tissue. Furthermore, we devised a scheme to definitively distinguish between the different parathyroid states on a molecular level, because histologic distinction is unreliable. METHODS: The study included three patients with a diagnosis of singular parathyroid adenoma and three with double parathyroid adenomas. Paraffin-embedded surgical specimens of both adenomas and normal glands were retrieved from each patient. Clonal analysis of the phosphoglycerolkinase (PGK) gene has suggested that parathyroid adenomas are monoclonal. Clonality of parathyroid adenomas and normal parathyroid glands was studied by polymerase chain reaction-based restriction fragment length polymorphic analysis for the PGK gene. Proliferative activity of the specimens was also analyzed using the immunohistochemical markers PCNA and Ki-67. RESULTS: All adenomas were monoclonal and all normal parathyroid glands were polyclonal for the PGK gene in both the single and double adenoma specimens. All adenomas stained positive for proliferative activity. In the three patients with singular adenoma, proliferative activity was not detected in the normal parathyroid tissue. However, in the double adenoma group, two of the three patients showed hyperproliferative activity in the normal glands. CONCLUSION: Proliferative activity consistent with hyperplasia was present in some normal glands of multiple adenoma patients. Our observation supports the theory that multiple adenomas may be a continuation of the hyperplasia state.     

Allelic loss in parathyroid neoplasia can help characterize malignancy

Parathyroid carcinoma can be difficult to diagnose, and the final pathologic diagnosis relies on clinicopathologic correlation. Clinical features of malignancy include high preoperative calcium levels and an intraoperative impression that the gland is adherent to local structures. Histologic features of malignancy include increased mitoses, vascular invasion, and broad bands of fibrosis. This study used molecular genotyping to assess parathyroid neoplasia for loss of heterozygosity across a panel of known tumor suppressor genes that have been previously identified as being important in the pathogenesis of parathyroid diseases. Parathyroid adenomas, hyperplasia, and carcinomas were included in the study, and a fractional allelic loss was calculated for each lesion. Losses of 1q25, 7q13.3, 10q23, 13q14.3, and 11p15.5 were particularly prevalent. In addition, almost all adenomas and carcinomas had loss of the markers for 1p. The benign parathyroid diseases (adenomas and hyperplasia) had low mean fractional allelic loss (11% and 15%, respectively). The parathyroid carcinomas, in contrast, showed high mean fractional allelic loss (63%). This difference in the mutational profile suggests that this type of assay may be useful as an adjunctive diagnostic test in cases of parathyroid neoplasia.     

Multiple parathyroid adenomas: report of thirty-three cases

An increasing number of patients with primary hyperparathyroidism are found to have two or three enlarged parathyroid glands. Of 865 patients successfully operated on by one surgeon (J.N.A.), multiple enlarged parathyroid glands (adenomas) were found and resected in 33 cases (3.8%), with resulting normocalcemia lasting from 1 to 22 years (mean 5.8). Twenty-nine patients had two adenomas and four had three adenomas. In 28 patients the multiple adenomas were synchronous. Twenty-five patients underwent removal of all of the enlarged parathyroid glands in one operation; in three patients one adenoma was removed, reoperation for persistent hypercalcemia was performed, and a second adenoma was resected with cure. In five patients one adenoma was removed, normocalcemia ensued for 3 to 18 years, and a second (metachronous) adenoma occurred and was resected successfully. Although 10 of 70 enlarged parathyroid glands removed were labeled hyperplasia, cure in all but one of our patients by selective resection of only enlarged parathyroid glands emphasizes the unreliability of histologic criteria in differentiating between parathyroid adenoma and hyperplasia. Based on this study, we support the existence of multiple adenomas and advocate removal of only macroscopically enlarged parathyroid glands in patients with primary hyperparathyroidism.     

Identification of Differentially Expressed MicroRNA in Parathyroid Tumors

Background

The molecular factors that control parathyroid tumorigenesis are poorly understood. In the absence of local invasion or metastasis, distinguishing benign from malignant parathyroid neoplasm is difficult on histologic examination. We studied the microRNA (miRNA) profile in normal, hyperplastic, and benign and malignant parathyroid tumors to better understand the molecular factors that may play a role in parathyroid tumorigenesis and that may serve as diagnostic markers for parathyroid carcinoma.

Methods

miRNA arrays containing 825 human microRNAs with four duplicate probes per miRNA were used to profile parathyroid tumor (12 adenomas, 9 carcinomas, and 15 hyperplastic) samples normalized to four reference normal parathyroid glands. Differentially expressed miRNA were validated by real-time quantitative TaqMan polymerase chain reaction (PCR).

Results

One hundred fifty-six miRNAs in parathyroid hyperplasia, 277 microRNAs in parathyroid adenoma, and 167 microRNAs in parathyroid carcinomas were significantly dysregulated as compared with normal parathyroid glands [false discovery rate (FDR) < 0.05]. By supervised clustering analysis, all parathyroid carcinomas clustered together. Three miRNAs (miR-26b, miR-30b, and miR-126*) were significantly dysregulated between parathyroid carcinoma and parathyroid adenoma. Receiver-operating characteristic curve analysis showed mir-126* was the best diagnostic marker, with area under the curve of 0.776.

Conclusions

Most miRNAs are downregulated in parathyroid carcinoma, while in parathyroid hyperplasia most miRNAs are upregulated. miRNA profiling shows distinct differentially expressed miRNAs by tumor type which may serve as helpful adjunct to distinguish parathyroid adenoma from carcinoma.     

Stimulating parathyroid cell proliferation and PTH release with phosphate in organ cultures obtained from patients with primary and secondary hyperparathyroidism for a prolonged period

The pathogenesis of primary hyperparathyroidism (I°-HPT) and secondary hyperparathyroidism (II°-HPT) remains to be elucidated. To characterize their pathophysiology, we investigated the effects of calcium and phosphate on cell proliferation and PTH release in an organ culture of parathyroid tissues. Dissected parathyroid tissues obtained from patients with I°-HPT (adenoma) or II°-HPT (nodular hyperplasia) were precultured on a collagen-coated membrane for 1–4 week. After changing the medium for one containing various concentrations of phosphate, PTH release and [³H]thymidine incorporation were studied. In contrast to dispersed parathyroid cells cultured in a monolayer, calcium decreased PTH release in a concentration-dependent manner in parathyroid tissues. Furthermore, when parathyroid tissues obtained from II°-HPT were precultured for 1–4 weeks, PTH release and parathyroid cell proliferation were significantly increased in high-phosphate medium. These phosphate effects were also observed to a lesser extent in parathyroid tissues obtained from I°-HPT, but there was no significant difference between I°-HPT and II°-HPT. Microarray analyses revealed that mRNA levels of PTH, CaSR, and VDR were well preserved, and several growth factors (e.g. TGF-beta1-induced protein) were abundantly expressed in II°-HPT. Using organ cultures of hyperparathyroid tissues, in which PTH release and CaSR are well preserved for a prolonged period, we have demonstrated that phosphate stimulates parathyroid cell proliferation not only in II°-HPT but also in I°-HPT. Although the mechanism responsible for phosphate-induced cell proliferation remains to be elucidated, our in vitro findings suggest that both parathyroid tissues preserve to some extent a physiological response system to hyperphosphatemia as observed in normal parathyroid cells.     

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.     

Expression of TRAIL and Fas in Primary Hyperparathyroidism

Aim: Differentiating between parathyroid lesions is still difficult and ambiguous. In cases of primary hyperparathyroidism, appropriate and prompt diagnosis is of great importance for effective treatment and follow-up. A great amount of mechanisms contribute to the pathogenesis of primary hyperparathyroidism, such as disturbance in balance between pro- and anti-apoptotic factors. Therefore, we examined whether immunohistochemical expression of apoptotic factors, TNF-related apoptosis-inducing ligand (TRAIL) and Fas, could have clinical utility as a marker of proliferative lesions of parathyroid gland. Materials and methods: Parathyroid specimens of 58 consecutive patients who had undertaken surgery due to primary hyperparathyroidism were incubated with purified mouse monoclonal antihuman antibodies: anti-TRAIL and anti-Fas. Staining was considered positive when at least 5% of the cells showed immunoreactivity. Results: The percentage of cells which were positively stained for TRAIL in parathyroid hyperplasia was 9.65%, in parathyroid adenoma 8.31%, and in normal controls 2.24%. Immunoreactivity for TRAIL was detected in 91.89% of parathyroid hyperplasias, 85.71% of parathyroid adenomas, and none in healthy glands. The percentage of cells with a positive reaction to Fas in parathyroid hyperplasia was 8.92%, in parathyroid adenoma 8.09%, and in normal tissue 1.9%. The expression of Fas was found in 94.59% of parathyroid hyperplasias, 90.48% of parathyroid adenomas, and none in healthy glands. Conclusions: In our study, hyperplasias demonstrated the highest expression of TRAIL and Fas, whereas in adenomas it was increased compared to normal tissue, but lower than in hyperplasias. These factors could be an additive tool in the differential diagnosis of parathyroid lesions.     

The use of radioiodinated toluidine blue for preoperative localization of parathyroid pathology

The efficiency of preoperative radioactive toluidine blue (RTB) scintigraphy for the localization of parathyroid pathology was evaluated prospectively in 69 patients (age range, 15 to 81 years; mean, 56 years) with primary hyperparathyroidism. Four patients have previously undergone negative exploratory surgery. Patients underwent preoperative dual radionuclide parathyroid-RTB/technetium 99m (Tc 99m)-thyroid scintigraphies with a computer-interfaced gamma-camera with a pinhole collimator. Computer-acquired scintigraphic data were analyzed for parathyroid localizations by an RTB-parathyroid/thyroid superposition technique. At surgery, parathyroid adenomas were found in 64 patients (single adenomas in 60 patients; two adenomas in four patients), nine of these adenomas were mediastinal. Four patients had parathyroid hyperplasia. One patient had no parathyroid pathology (negative exploratory surgery). Correlation between the surgical-pathologic findings and the scintigraphic RTB localization studies disclosed a sensitivity of 87%, with a specificity of 94%, and an overall accuracy of 92%. The routine use of preoperative scintigraphic parathyroid-RTB/Tc 99m-thyroid localization has proved to be highly effective, enabling detection of small hyperfunctioning parathyroid glands in normal and ectopic locations in a wide range of weights. In this series a success rate of 98% was achieved on initial and reexploratory surgery for primary hyperparathyroidism.     

Intraoperative Parathyroid Aspiration and Parathyroid Hormone Assay as an Alternative to Frozen Section for Tissue Identification

Most people would agree that successful parathyroidectomy depends on two important variables: the surgeon's recognition and excision of the abnormal parathyroid gland(s) and the pathologist's confirmation that the removed tissue is parathyroid tissue. Frozen section is usually employed to confirm the identity of parathyroid tissue, but occasionally confirmation cannot be made without a permanent section, as with intrathyroidal glands. This study proposes a new method of expeditious and easy confirmation of parathyroid tissue utilizing the immunoassay for quick measurement of intraoperative parathyroid hormone (IOPTH). By directly aspirating the suspected adenoma, the assay becomes a rapid diagnostic tool that can be used as an alternative to frozen section. In cases where the surgeon is already planning to employ the assay, the elimination of frozen section is cost-effective. Intraoperative aspiration of histologically confirmed parathyroid adenomas was performed on 12 consecutive patients undergoing parathyroid surgery. Parathyroid glands were aspirated with a 22-gauge syringe after gland excision. Aspirates were placed in 1 to 3 ml of buffered saline. A similar process was performed on 12 thyroid controls. Specimens were centrifuged, aliquotted, and stored at −70°C. The parathyroid hormone value was analyzed electively by rapid assay and the values recorded. For all parathyroid aspirates, the rapid assay value was > 1500 pg/ml, exceeding the uppermost limit of the diagnostic chart. Values for thyroid aspirates ranged from 58 to 85 pg/ml (mean 75.7 pg/ml). In all cases tissue confirmation was achieved with permanent section. Values were 100% sensitive and specific. Measurement of PTH from intraoperative aspiration of suspected parathyroid adenomas is clinically useful in patients for whom frozen section would routinely be employed. Values > 1500 pg/ml secure the tissue diagnosis. There is no additional cost in cases where IOPTH monitoring is already being utilized to confirm cure. The elimination of frozen section could be cost-effective and, for some institutions, actually decrease the operating time as the IOPTH assay takes only 15 minutes. PTH assay is an accurate diagnostic technique and to date is 100% sensitive and specific for differentiating between parathyroid tumors and thyroid nodules.     

Relation of biochemical, cytologic, and morphologic parameters to the result of gammagraphy with technetium 99m sestamibi in primary hyperparathyroidism

The aim of this study was to analyze the possible relation of biochemical, cytologic, and morphologic parameters to the results of parathyroid gammagraphy with Tc 99m sestamibi in primary hyperparathyroidism. We studied 46 consecutive patients with primary hyperparathyroidism who were undergoing surgery. All the patients were given a preoperative parathyroid gammagraphy with Tc 99m sestamibi and a complete preoperative biochemical study. During the surgical intervention we recorded the weight and size of the pathologic glands to calculate the volume of each. We also determined the percentage of the chief and oxyphil cells in the pathologic glands. Tc 99m sestamibi sensitivity is higher in adenomas (91%) than in hyperplasia (67%) or double adenomas (50%). No relation was found between biochemical or cytologic parameters and gammagraphic results. Weight and gland volume were significantly greater for adenomas than for hyperplasia (P < 0.0014 and P < 0.0004, respectively), and statistically significant differences in both of them were observed between the glands with positive and negative sestamibi.     

Surgery for sporadic primary hyperparathyroidism: controversies and evidence-based approach

Introduction Sporadic primary hyperparathyroidism is due to single adenoma in over 90–95% of instances. Careful medical history and precise preoperative identification of the enlarged gland by parathyroid Tc-mibi scintigraphy and neck ultrasound allow selecting patients for minimally invasive parathyroidectomy, a focused intervention with minimal skin opening and tissue dissection. Small (<300 mg) adenomas continue to challenge preoperative imaging, and most of them will still require a bilateral exploration. Conclusion Surgery should never be indicated on the basis of positive or negative preoperative localization studies. Intraoperative quick parathyroid hormone measurements seem particularly helpful for cases with equivocal localization studies. The best minimal access approach is still a matter of debate, and options include small central incision, video-assisted parathyroidectomy, minimal lateral open approach, and purely endoscopic access via lateral approach. Radioguided surgery does not seem to have a role in routine cases but may be useful to find adenomas during reintervention on scarred difficult surgical fields.     

Nonautonomy of parathyroid hormone and urinary cyclic AMP in primary hyperparathyroidism.

This study demonstrates that appreciable changes in serum parathyroid hormone and urinary cyclic AMP occur during experimentally induced hyper- and hypocalcemia in almost all patients with primary hyperparathyroidism regardless of histology. A single patient with tertiary hyperparathyroidism also demonstrated a significant elevation of serum parathyroid hormone and urinary cyclic AMP in response to EDTA induced reduction in ionized calcium. Thus, total autonomy of hormone secretion was not present in the great majority of the patients with a parathyroid adenoma, parathyroid hyperplasia, or the single patient with tertiary hyperparathyroidism. Therefore, preoperative evaluation of the rsponse of urinary cyclic AMP and serum parapthyroid hormone to EDTA or calcium infusion will not distinguish parathyroid adenomas from hyperplasia on the basis of total autonomy of hormone secretion. If a difference in secretory control is present between parathyroid adenomas and parathyroid hyperplasia, it is more subtle than total autonomy for adenomas and nonautonomy for hyperplasia.     

Parathyroid hyperplasia, adenomas, and carcinomas: differential expression of p27Kip1 protein

The histologic spectrum of proliferative parathyroid lesions (hyperplasia, adenoma, and carcinoma) often overlap, and differentiation between these lesions may at times be difficult. p27kip1 (p27) is a cyclin-dependent kinase inhibitor that helps regulate the transition from the G1 to the S phase of the cell cycle. Significantly higher levels of p27 expression have been detected in some normal tissues than in their neoplastic counterparts. The authors analyzed a series of parathyroid lesions to determine if expression of this cell cycle protein may be useful in distinguishing between parathyroid hyperplasia, adenomas, and carcinomas. Formalin-fixed paraffin-embedded tissues from randomly selected patients (22 histologically normal parathyroid glands, 33 cases of hyperplasia, 43 adenomas, and 17 carcinomas) were analyzed for expression of p27 by immunostaining. All cases were also immunostained for Ki67 with antibody MIB-1. The distribution of immunoreactivity was analyzed by quantifying the percentage of positive nuclei that was expressed as the labeling index (LI). In situ hybridization (ISH) for p27 mRNA was done using a cRNA probe with 30 of these cases. Normal parathyroid glands had the highest p27 LI (89.6 +/- 1.4), followed by hyperplasia (69.6 +/- 7.5), adenomas (56.8 +/- 3.4), and carcinomas (13.9 +/- 2.6). ISH showed no differences in p27 mRNA, indicating that the expression of the p27 gene was controlled at a posttranslational level in parathyroid tissues. Ki67 expression was significantly higher in carcinomas (LI = 8.4 +/- 1.9) than in adenomas (LI = 2.7 +/- 0.2) and hyperplasia (LI = 3.3 +/- 0.4). These results suggest that both p27 and Ki67 may be helpful in the diagnosis of histologically difficult parathyroid lesions.