Guido Gasparri

Secondary and Tertiary Hyperparathyroidism: Causes of Recurrent Disease After 446 Parathyroidectomies

ObjectiveTo determine, in a series of patients with secondary and tertiary parathyroid hyperplasia, whether the type of parathyroidectomy (subtotal, total with autotransplantation, or total), the histologic pattern of the parathyroid tissue, or the proliferative index, as determined by Ki-67 analysis, could predispose patients to recurrent hyperparathyroidism. Summary Background DataRecurrent hyperparathyroidism appears in 10–70% of the patients undergoing surgery for secondary or tertiary hyperparathyroidism. The incidence could be related to the type of operation (Rothmund) but also depends on the histologic pattern of the glands removed (Niederle). MethodsThe retrospective investigation was performed on 446 patients undergoing parathyroid surgery. They were also studied in relation to the possibility of renal transplantation. In this population, two homogeneous groups were subsequently identified (23 patients with clear signs of recurrence and 27 patients apparently cured); they were studied from the histologic and immunohistochemical point of view using antibody to Ki-67 antigen. ResultsSubtotal parathyroidectomy, total parathyroidectomy with autotransplantation, and total parathyroidectomy produced similar results when considering the regression of osteodystrophy, pruritus, and ectopic calcification. As one could anticipate, tota1parathyroidectomy increased the incidence of hypoparathyroidism. The percentage of recurrence was 5% to 8% after subtotal parathyroidectomy, total parathyroidectomy with autotransplantation, and total parathyroidectomy, and only after incomplete parathyroidectomy did this percentage climb to 34.7%. In the recurrence group, the nodular form was more common and the proliferative fraction detected by Ki-67 was 1.9%; it was 0.81% in the control group. ConclusionsBecause more radical procedures were not more effective, the authors favor a less radical procedure such as subtotal parathyroidectomy. Histologic patterns and proliferative fraction could be useful indices of a recurrence, and these patients should be watched closely after surgery.

Proliferative activity in parathyroid tumors as detected by Ki-67 immunostaining

Clear morphological criteria for differentiating benign from malignant parathyroid tumors are not yet available and unfavorable prognosis cannot be predicted by histopathological parameters alone. A retrospective study of a series of parathyroid lesions was designed to evaluate the diagnostic role of the cell cycle-associated Ki-67 antigen detected by MIB-1 monoclonal immunocytochemistry. The mean tumor proliferative fraction (TPF), expressed as the number of Ki-67-positive nuclei per 1,000 cells, was 0.8 in normal parathyroid glands (nine specimens), 26.0 in hyperplasias (11 specimens), 32.8 in adenomas (11 specimens), and 60.5 in a group of tumors with histological features consistent with carcinoma (12 specimens). The difference between the latter two values was statistically significant (P < .05). When the five most clinically aggressive tumors were considered, the difference was even more remarkable (TPF, 78.6; P < .001). Oncocytic and pleomorphic cell components were found to proliferate with a labeling pattern similar to that of the chief cells. We conclude that proliferative activity is an additional useful parameter for evaluating parathyroid tumors diagnostically. Aggressive behavior may be expected in those tumors with a TPF greater than 6%.

Endoscopic insertion of 248 prostheses in inoperable carcinoma of the esophagus and cardia: short-term and long-term results

We present our findings after 248 endoscopic intubations with the Nottingham introducer and more recently with the Dumon-Gilliard system for inoperable carcinoma of the esophagus and cardia. Mortality within the first week was 7.6% decreasing to 4.3% with the Dumon-Gilliard method. Survival after 3 months was 61.5%, after 6 months 32.3%, after 1 year 4.8%. The quality of swallowing was very good in 51.5% of the cases, while 36.7% of the patients suffered from dysphagia for semisolids and 10.1% for semiliquids. Obstruction occurred in 36 cases; proximal and distal dislocations were found in four cases each. In 20 patients with esophagorespiratory fistula we had an operative mortality of 15%, but 6-month survival was 35.7% and 1 year survival was 7.1%.

The usefulness of preoperative dual-phase 99mTc MIBI-scintigraphy and IO-PTH assay in the treatment of secondary and tertiary hyperparathyroidism.

Background:Persistent secondary or tertiary hyperparathyroidism (HPT) results from failure to remove enough hyperfunctioning parathyroid tissue. Ectopically situated parathyroid glands and supernumerary glands make failure more likely. Recurrent HPT after subtotal Ptx is usually due to regrowth of the remaining parathyroid tissue. Recurrence may also develop from a hyperplastic supernumerary gland or rarely from parathyromatosis. Recurrent HPT after total Ptx with autotransplantation is usually due to overgrowth of the autograft or for the previously mentioned reasons. Methods:Since 1995, 464 patients with SHPT or THPT were treated surgically; intraoperative parathormone (PTH) was measured in 277 patients. Sixty-eight patients also had a preoperative MIBI scan. We compared the preoperative MIBI scan results with intraoperative findings, parathyroid gland weight and histology. We questioned whether MIBI uptake corresponded to parathyroid gland size and weight. We also correlated the number of Ki67 nuclear positive cells with MIBI uptake. For SHPT in group I with 145 patients, neither intraoperative PTH (IO-PTH) assay nor MIBI scanning was done. In group II with 163 patients IO-PTH was used and in group III with 48 patients both IO-PTH and MIBI scanning was used. For THPT in group I with 42 patients, neither IO-PTH assay nor MIBI scanning was done. In group II with 46 patients IO-PTH was used and in group III with 20 patients both IO-PTH and MIBI scanning was used. Results:Parathyroid weight correlated directly with MIBI uptake. No correlation, however, occurred between MIBI uptake and parathyroid histology or between Ki67 staining and MIBI scanning. For SHPT in group I the persistence rate was 6.2% and recurrence rate 11%; in group II the persistence rate was 4.9% and recurrence rate 4.9%; in group III the persistence rate was 2%, and recurrence 4.2% (P < 0.05 between group I and III for persistence and recurrence). We obtained similar results in THPT, but recurrence was 0 in groups II and III, also when only 3 glands were removed, probably due to asymmetric hyperplasia commonly seen in this particular population (P < 0.05 regarding recurrence between group I and II–III, no difference between group II and III). Conclusion:In conclusion our findings support that the surgeon experience is a very important factor for good results in patients with SHPT and THPT. Preoperative MIBI scanning and IO-PTH are helpful but not essential except in reoperations.

Comparative evaluation of cancer stem cell markers in normal pancreas and pancreatic ductal adenocarcinoma

Chemoresistance and self-renewal of cancer stem cells (CSC), found in many tumors including pancreatic ductal adenocarcinoma (PDAC), are believed to underlie tumor mass regrowth. The distribution of cells carrying the putative stem-cell markers CD133, Nestin, Notch1-4, Jagged1 and 2, ABCG2 and aldehyde dehydrogenase (ALDH1) was assessed immunohistochemically using PDAC and normal pancreas tissue microarrays. The immunoreactivity was semi-quantitatively graded against the normal pancreas and was correlated with the differentiation grade and disease stage. No statistical significant differences were found between normal pancreas and PDAC in the expression of Nestin, Notch1, 3 and 4, ABCG2 or ALDH1. Notch2 and Jagged1 and 2 expression were increased in PDAC. CD133-positive cells were above-normal in PDAC, but the difference was not statistically significant. Nestin, Notch1-4, Jagged1, ABCG2 and ALDH1 immunostaining scores were not correlated with tumor grade or disease stage. CD133 and Notch2 expression was significantly inversely correlated with tumor grade, but not disease stage. Notch3 immunostaining positively correlated with tumor stage, but not with differentiation grade. Jagged2 protein expression correlated inversely with disease stage, but not with tumor grade. From the clinical standpoint, improved delineation of the tumor CSC signature, putatively responsible for tumor initiation and recurrence after initial response to chemotherapy, may offer novel therapeutic targets for this highly lethal cancer.

Galectin-3 and Ki-67 expression in multiglandular parathyroid lesions

Hyperplastic and neoplastic parathyroid lesions may present overlapping morphologic features, and several markers have been proposed to distinguish benign from malignant growths. Recently, it was reported that galectin-3 is a useful marker of malignancy in uniglandular parathyroid diseases. To investigate galectin-3 and Ki-67 immunoexpression in parathyroid hyperplastic disease, 63 multiglandular lesions (13 primary, 40 secondary, and 10 tertiary hyperplasia cases) were analyzed and compared with 45 control cases of parathyroid adenomas and 24 carcinomas. Our data showed that hyperplastic lesions responsible for primary nonfamilial or tertiary hyperparathyroidism, as well as parathyroid adenomas, were negative for galectin-3, as opposed to carcinomas. In addition, secondary and familial primary hyperplasia cases were surprisingly positive for galectin-3 in approximately two thirds of cases. All hyperplastic lesions (positive or negative for galectin-3) had a low Ki-67 index. Based on these findings, secondary hyperplasia has a low proliferative potential but an unexplained galectin-3 reactivity, which reduces its diagnostic role in differentiating benign from malignant nodules in the context of multiglandular parathyroid diseases.

AgNOR quantity as a prognostic tool in hyperplastic and neoplastic parathyroid glands

Abstract Prediction of evolution of secondary hyperplasia and tumours of the parathyroid glands is still a problem in histopathology. To assess whether the quantity of silver-stained nucleolar organiser region (AgNOR) proteins might be used as a prognostic tool in parathyroid pathology, a standardised AgNOR analysis has been performed on 19 cases of parathyroid hyperplasia caused by secondary hyperparathyroidism (PH), 8 cases of adenoma (PA) and 10 cases of carcinoma (PC). Clinico-pathological data and follow-up information were available. On formalin-fixed and paraffin-embedded sections, the visualisation and quantification of AgNORs were achieved according to the 1995 guidelines of the Committee on AgNOR Quantification. Then, the mean area (square micrometres) of AgNORs per nucleus (NORA) was evaluated by means of an image analyser and specific softwares. After testing the normal distribution of NORA values, statistical parametric tests were utilised; Kaplan-Meier and Cox multivariate analyses were also performed. In parathyroid lesions, a progressive increase of mean NORA values was observed from PH (2.895 µm2; SE 0.171) through PA (3.638 µm2; SE 0.125) to PC (4.701 µm2; SE 0.179); these differences were highly significant (P<0.001), although some degree of overlap was found among single NORA values. A significantly higher mean NORA value was revealed in PC with distant metastases than was noted in cases with no current clinical evidence of disease progression. Furthermore, a significantly (P<0.001) higher mean NORA value was encountered in the group of PH with recurrences (3.600 µm2; SE 0.106) than in nonrecurrent PH (2.261 µm2; SE 0.087). Multivariate analyses indicated that the NORA value was an independent prognostic parameter determining the risk of recurrence in PH. We suggest that AgNOR quantity may be a promising additional tool for predicting the biological behaviour of parathyroid lesions.

Optimizing efficacy of quick parathyroid hormone determination in the operating theater

The usefulness of intraoperative parathyroid hormone (PTH) monitoring has been extensively documented in primary hyperparathyroidism (HPT), whereas few data have been published on its use in reoperations or in secondary and tertiary HPT. We report our initial experience with a rapid (12 min response) PTH immunochemiluminometric assay performed in the operating room during surgery in 12 patients with primary HPT, 16 end-stage renal disease patients with secondary HPT and five kidney transplanted subjects with tertiary HPT. Blood samples were taken at baseline, within 10 min after resection and subsequently at various intervals whenever needed. The mean PTH levels before and after parathyroidectomy were 230.5 pg/mL (range 69–842) and 47.3 pg/mL (range 5–184), respectively, in primary HPT, 855.0 pg/mL (416–1655) and 202.2 pg/mL (53–440) in secondary HPT, and 205.6 pg/mL (116–301) and 45.4 pg/mL (18–97) in tertiary HPT. All patients but one had a significant percentage decline from pre-excision values (mean 76.9%, 76.0%, and 76.1% in primary, secondary and tertiary HPT, respectively). While a reduction of more than 50% was observed in 30 out of 33 patients after the first intraoperative sampling, additional measurements were performed in 10 cases. On-site PTH monitoring with this user-friendly and reliable system has proved helpful in targeting PTH tests to give the surgeon a rapid and accurate assessment of the intervention. The development of optimal PTH sequence strategies with decision-focused analytical and clinical limits will improve the efficacy of “point-of-care” PTH assay and resource utilization.

Recurrence in Parathyroid Hyperplasias Owing to Secondary Hyperparathyroidism is Predicted by Morphological Patterns and Proliferative Activity Values.

The histological pattern and the cell proliferative activity (as detected by Ki-67 immunostaining) of a series of 50 parathyroid hyperplasias (PTHs) secondary to renal failure were studied to assess their value in predicting recurrence of hyperparathyroidism (HPT). On account of their clinical evolution, these cases were divided into two groups: recurrent HPT (23 cases) and nonrecurrent HPT (27 cases). A nodular growth pattern (as opposed to diffuse) was the prevalent one and was observed in 20 (74%) cases of nonrecurrent HPT and in 22 (95.6%) cases of recurrent HPT, a statistically significant difference (p<0.05). The Ki-67 proliferative fraction was 1.9% in recurrent HPT cases, as compared with 0.81% in nonrecurrent HPT, a difference which was statistically significant (p=0.001). We conclude that a nodular pattern of growth and an elevated Ki-67 proliferative fraction (>1.5%) in PTH are both associated with a higher risk of recurrence (4.30) of HPT.

The diagnostic accuracy of the immunocytochemical markers in the pre-operative evaluation of follicular thyroid lesions

Aim of the study was to consider the diagnostic accuracy of galectine-3 (GAL3) in the pre-operative cytological evaluation of follicular lesions. Materials and methods: We retrospectively evaluated 100 patients suffering from thyroid nodular disease submitted to thyroidectomy from 2006 to 2007 in our Institution. Before surgery all patients underwent fine needle aspiration biopsy. The immunocytochemical analysis was performed on fine needle aspiration specimens using species-specific monoclonal antibodies and a biotin-free detection system. Based on preoperative cytological reports, 40 patients had pre-operative malignant results, and 60 patients (46 females and 14 males) showed follicular lesions. The sensitivity, specificity, positive and negative predictive values, and diagnostic accuracy of GAL3 was evaluated. Statistical analysis: Chisquare test was used to compare frequencies of GAL3 expression between the different hystopathological groups. Results: GAL3 proved to have 55% sensitivity, 100% specificity, 70% negative predictive value, and 78% diagnostic accuracy. The GAL3 expression in neoplastic and benign lesions was significantly different (GAL3+ in 16 out of 29 neoplastic lesions, GAL3+ 0 out of 31 benign lesions, p<0.01). Even comparing the GAL3 positivity between the follicular adenomas (0 GAL3+ out of 20) and the group of follicular carcinomas (5 GAL3+ out of 6), we found a statistically significant difference (p<0.01). Conclusions: Based on the data from our experience, the patients with a cytological diagnosis of GAL3 positive follicular neoformation should be referred for surgery without any further immunocytological testing.