Parathyroid Retrospective Analysis of Neoplasms Incidence (pTRANI Study): An Italian Multicenter Study on Parathyroid Carcinoma and Atypical Parathyroid Tumour.

BACKGROUND: Parathyroid cancer (PC) is a rare sporadic or hereditary malignancy whose histologic features were redefined with the 2022 WHO classification. A total of 24 Italian institutions designed this multicenter study to specify PC incidence, describe its clinical, functional, and imaging characteristics and improve its differentiation from the atypical parathyroid tumour (APT). METHODS: All relevant information was collected about PC and APT patients treated between 2009 and 2021. RESULTS: Among 8361 parathyroidectomies, 351 patients (mean age 59.0 ± 14.5; F = 210, 59.8%) were divided into the APT (n = 226, 2.8%) and PC group (n = 125, 1.5%). PC showed significantly higher rates (p < 0.05) of bone involvement, abdominal, and neurological symptoms than APT (48.8% vs. 35.0%, 17.6% vs. 7.1%, 13.6% vs. 5.3%, respectively). Ultrasound (US) diameter >3 cm (30.9% vs. 19.3%, p = 0.049) was significantly more common in the PC. A significantly higher frequency of local recurrences was observed in the PC (8.0% vs. 2.7%, p = 0.022). Mortality due to consequences of cancer or uncontrolled hyperparathyroidism was 3.3%. CONCLUSIONS: Symptomatic hyperparathyroidism, high PTH and albumin-corrected serum calcium values, and a US diameter >3 cm may be considered features differentiating PC from APT. 2022 WHO criteria did not impact the diagnosis.

Updates in primary hyperparathyroidism.

This is a review of the latest papers on PHPT with the purpose of assessing the most recent evidence in the management of PHPT and to give updated recommendations for its evaluation, diagnosis, and treatment. I used my personal experience to collect papers that reinforce my ideas for the diagnosis and treatment of PHPT. Perhaps, in the near future, we will have more information about genetics, localization studies, surgical techniques, medical treatments, and statements that we have presented today will be obsolete.

Diagnostic performance of elastography in cytologically indeterminate thyroid nodules.

Cytological examination of material from fine-needle aspiration biopsy is the mainstay of diagnosis of thyroid nodules, thanks to its remarkable accuracy and scarcity of complications. However, follicular lesions (also called indeterminate lesions or Thy3 in the current classification), a heterogeneous group of lesions in which cytology is unable to give a definitive diagnosis to, represent its main limit. Elastography has been proposed as a potential diagnostic tool to define the risk of malignancy in the aforementioned nodules, but at present there is no conclusive data due to the small number of specifically addressed studies and the lack of concordance among them. The objective of our study was to evaluate the role of real-time elastography (RTE) for refining diagnosis of Thy3 nodules, by integrating diagnostic information provided by traditional ultrasound (US). The study included 108 patients with Thy3 nodules awaiting for surgery, which were evaluated by US (considering hypoecogenicity, irregular margins, microcalcifications, halo sign, and intranodular vascularization) and RTE. Nodules were classified at RTE using a four-class color scale. At histologic examination, 75 nodules were benign and 33 malignant. As expected, none of the ultrasound parameters alone was adequate in predicting malignancy or benignity of the nodules; in the presence of at least two US risk factors, we obtained 61 % sensitivity, 83 % specificity, and 77 % accuracy with 6.8 OR (95 % CI 2.4-20.4). RTE scores 3 and 4 showed 76 % sensitivity, 88 % specificity, 74 % PPV, and 89 % NPV with diagnostic accuracy of 84 %; the data are statistically significant (p < 0.0001) with a OR of 21.9 (95 % CI 7.1-76). By combining RTE with US parameters, the presence of at least 2 characters of suspicion had 88 % sensitivity and 94 % NPV with 23.8 OR (95 % CI 7-106.3). The use of combined RTE and US leads to the identification of two patients subpopulations which have a significantly different malignancy risk (6 vs. 63 %); further studies are needed to verify if it is possible to send only the first group to thyroidectomy and the other to follow-up.

Early surgery and survival of patients with anaplastic thyroid carcinoma: analysis of a case series referred to a single institution between 1999 and 2012.

BACKGROUND: Extensive resection of the tumor has been associated with better survival of anaplastic thyroid carcinoma (ATC) patients. However, surgery is not the rule for ATC patients with distant metastases at the time of diagnosis (stage IV-C), regardless of tumor resectability. The aim of this work was to explore the potential role of surgery in ATC patients, including those in stage IV-C. METHODS: We considered all the consecutive ATC patients referred to our institution from June 1999 to July 2012. Patients with stage IV-A incidentally discovered ATC were excluded because of their better prognosis. All patients eligible for surgery at the time of diagnosis were first operated with the intent to obtain a macroscopically complete resection (R0, R1), or a R2 resection with minimal macroscopical residual tumor. These operations were defined as "maximal debulking," whereas operations that did not achieve this goal were defined as "partial debulking." After surgery, almost all patients received adjuvant chemotherapy, associated to radiotherapy in more than 50% of patients. RESULTS: There were 55 eligible patients (34 women; median age 73.15 years). Thirty-one patients had distant metastases (stage IV-C). The median overall survival was 5.55 months [CI 4.94-6.60], with no difference according to stage. "Maximal debulking" was obtained in 70.73% of operated patients as a first modality and resulted associated with better survival than "partial debulking" (6.57 months [CI 5.52-12.09] vs. 3.25 months [CI 0.66-4.80]), without any difference between stage IV-B and IV-C patients. Furthermore, 21% of patients submitted to "maximal debulking" died secondary to local progression of the tumor, whereas this was the case for 69% of patients treated with "partial debulking" or not operated at all. CONCLUSIONS: Early "maximal debulking," followed by adjuvant therapy, can improve the survival and ameliorate the quality of residual life preventing the risk of suffocation. This effect is also observed in patients with distant metastasis at diagnosis and treated with this approach: they have an outcome similar to that observed in stage IV-B patients. We thus suggest that surgery may be considered in the management of all ATC patients, and should not be restricted a priori to stages IV-A and IV-B.

Segmental tracheal resection for invasive differentiated thyroid carcinoma. Our experience in eight cases.

PURPOSE: In differentiated thyroid carcinoma (DTC), complete resection of local disease provides the longest survival and the best palliation. In pursuit of this goal, segmental tracheal or laryngotracheal resection can be performed on patients with DTC invading the airway. The study summarizes the technical aspects of the intervention and analyzes its results in eight patients. METHODS: The results of eight tracheal or laryngotracheal resections for DTC invading the airway were analyzed. Three patients presented with local recurrent disease, whereas five underwent airway resection at the time of thyroidectomy or shortly after. All received a circumferential sleeve resection of the trachea (2­4 tracheal rings) that in three cases extended to the cricoid, followed by end-to-end anastomosis. RESULTS: Pathologic evaluation identified seven papillary and one poorly differentiated carcinomas. No postoperative deaths occurred; one patient required surgical reexploration because of postoperative bleeding, and two air leaks resolved with conservative treatment. Functional results were excellent. During follow-up, one patient died of lung and bone metastases, while in two cases locally persistent/recurrent disease has been detected; two patients are currently free of disease, and in the last three cases only persistent thyroglobulin levels are indicative of residual disease. CONCLUSIONS: In our experience, segmental airway resection is safe, provides excellent functional results, and can warrant adequate control of local disease.

CDC73 mutational status and loss of parafibromin in the outcome of parathyroid cancer.

Inactivating mutations of the CDC73 tumor suppressor gene have been reported in parathyroid carcinomas (PC), in association with the loss of nuclear expression of the encoded protein, parafibromin. The aim of this study was to further investigate the role of the CDC73 gene in PC and evaluate whether gene carrier status and/or the loss of parafibromin staining might have an effect on the outcome of the disease. We performed genetic and immunohistochemical studies in parathyroid tumor samples from 35 patients with sporadic PC. Nonsense or frameshift CDC73 mutations were detected in 13 samples suitable for DNA sequencing. Six of these mutations were germline. Loss of parafibromin expression was found in 17 samples. The presence of the CDC73 mutation as well as the loss of parafibromin predicted a high likelihood of subsequent recurrence and/or metastasis (92.3%, P=0.049 and 94.1%, P=0.0017 respectively), but only the latter was associated with a decreased overall 5- and 10-year survival rates (59%, P=0.107, and 23%, P=0.0026 respectively). The presence of both the CDC73 mutation and loss of parafibromin staining compared with their absence predicted a lower overall survival at 10- (18 vs 84%, P=0.016) but not at 5-year follow-up. In conclusion, loss of parafibromin staining, better than CDC73 mutation, predicts the clinical outcome and mortality rate. The added value of CDC73 mutational analysis is the possibility of identifying germline mutations, which will prompt the screening of other family members.

Neoadjuvant chemo-radiotherapy for locally advanced esophageal cancer: a monocentric study.

AIMS AND BACKGROUND: Multimodal therapy is a keystone of care in advanced esophageal cancer. Although neoadjuvant chemoradiotherapy is known to provide a survival advantage in selected cases, reliable prognostic and response predictive factors remain elusive. We report the outcome in a series of esophageal cancer patients treated at our center and the results of a retrospective analysis of epidermal growth factor receptor (EGFR) expression and EGFR/HER2 gene copy numbers taken as possible prognostic and predictive factors. METHODS AND STUDY DESIGN: Between 2001 and 2009, a total of 40 consecutive patients (34 men and 6 women; median age, 59 years) were treated for esophageal cancer. TREATMENT: cisplatin, 80 mg/m² day 1, and 5-fluorouracil, 800 mg/m²/24 h on days 1-5, every 21 days, concomitant with 3D-conformal radiotherapy (54-59.4 in 30-33 fractions) for three up to four cycles. Surgery was performed in eligible patients 6-8 weeks after chemoradiation. EGFR expression and EGFR/HER2 amplification and gene copy number were studied by immunohistochemical analysis and fluorescence in situ hybridization, respectively. RESULTS: Acceptable toxicity following chemoradiation was recorded, with G3-G4 hematological toxicity in 20% of patients and G3-G4 dysphagia in less than 10%; 14 (35%) patients achieved complete response and 19 (48%) partial response; 18 underwent surgery after chemoradiation, of which 8 (20%) achieved pathologic complete response. The median survival was 29 months (95% CI, 25.7-32.1): 42 months for the resected and 20 for the unresected patients. EGFR and HER2 analysis in 28 patients showed that 89% had immunohistochemical EGFR expression, with 5 cases of EGFR and 10 of HER2 gene gain without a significant difference in response rate and survival in these patient subgroups. CONCLUSIONS: Our results suggest a better outcome in patients who underwent surgery after chemoradiation. A larger sample size is necessary to clarify the role of EGFR and HER2 gene gain in predict response and survival.

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.

Hyperparathyroidism, an emerging disease.

A retrospective study based on 35 years of personal experience was done. Up to today 2,175 patients were operated, 1,318 for primary hyperparathyroidism (HPT) and 857 for secondary and tertiary HPT. Considering recent years (1999 to July 2010), 918 patients were operated for primary HPT. Preoperatively all the patients performed a cervical ultrasound and/or a sestamibi scan. Open mininvasive procedure was preferred: it is an easily reproducible and costless technique. Using magnifying glasses up to 2.5, an excellent three-dimensional vision was obtained. The operating time is short and if there are any doubts it is possible to extend the exploration to the other side of the neck. Immediate and long-term results were excellent, with a cure rate greater than 99%. Complications in the treatment of a single adenoma are around 0.3%. Patients can be discharged 24-48 h after the operation. Regarding reoperations, a correct diagnostic and therapeutic approach is essential. CT, MRI and SPECT must correlate with the information given by ultrasound and scintigraphy. The intraoperative PTH assay (io-PTH) is required and the approach should be limited to the area where the missed gland probably is. The functionality of the autotransplantation (AT) performed immediately was good. The functionality of the cryopreserved tissue is better for the HPT I in comparison with HPT II. Considering HPT I or HPT II the use of io-PTH is helpful. MIBI scanning is helpful but not essential, except in reoperations. Surgeon experience is another very important factor for good results.

Abnormal expression of Endoglin and its receptor complex (TGF-ß1 and TGF-ß receptor II) as early angiogenic switch indicator in premalignant lesions of the colon mucosa.

The precise timing of the angiogenic switch in colorectal cancer development is still unclear. The simultaneous expression of Endoglin (CD105), transforming growth factor (TGF)-ß1 and TGF-ß receptor (R) II were quantified in surgical specimens comprising normal human colon, pre-malignant dysplastic tissue, in situ, and invasive colon cancer specimens, at mRNA and protein levels, respectively by real-time PCR and immunohistochemistry. Serum concentrations of soluble Endoglin and TGF-ß1 were evaluated. mRNA and CD105+-microvessel density (MVD) increased significantly in dysplastic colon and carcinoma versus normal tissues; values correlated respectively with dysplasia degree and Dukes' stages. TGF-ß1 expression was significantly upregulated in most severe dysplastic adenoma specimens, while TGF-ß1 transcript and protein signals were intense in carcinoma, positively-correlated with tumor progression. TGF-ß1 RII was overexpressed in adenoma and carcinoma versus normal samples, but unrelated with dysplasia or Dukes' stage. Soluble Endoglin serum levels were equivalent in adenoma and normal tissues; in carcinoma the highest levels were in invasive tumor. Circulating TGF-ß1 levels were increased in severe dysplasia and progressed with tumor progression. Correlations between adenoma dysplasia degree and TGF-ß RII and CD105+-MVD, and between tumor Dukes' staging and TGF-ß1 and CD105+-MVD, were significant. TGF-ß1 and Endoglin and TGF-ß1 serum levels, TGF-ß1 staining and CD105+-MVD were significantly and inversely associated with disease-free survival. TGF-ß1 levels were an independent and significant prognostic factor of disease-free survival. These findings suggest active angiogenesis occurs in many pre-malignant colon cases and supports more careful evaluation of different chemopreventive agents.

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.

Gastric vascular lesion: a case report.

Arteriovenous malformations of the gastrointestinal tract are a known but rare cause of bleeding. Those of the stomach are the rarest if compared with other causes of gastric bleeding. The aetiology is still unknown, but senile age is considered an important cause, as are the degenerative processes connected with old age. These lesions are diagnosed by endoscopy which, with a haematostatic intent, often is not sufficient to stop the bleeding. Angiography is necessary for patients with massive bleeding whose endoscopy results are negative. The surgical treatment of gastric arteriovenous malformations requires excision of the lesion and part or all of the stomach. We report the case of a 57-year-old patient admitted to the Casualty Department with haematemesis and anaemia caused by acute gastric bleeding.

Preoperative localization of parathyroid adenoma with sonography and 99mTc-sestamibi scintigraphy in primary hyperparathyroidism.

PURPOSE: To evaluate the sensitivity, specificity, and usefulness of dual-phase 99mTc-Sestamibi scintigraphy (SS) and sonography (US) of the neck, alone and in combination, as noninvasive adenoma localizing procedures in patients with primary hyperparathyroidism prior to parathyroidectomy. METHODS: We retrospectively analyzed the charts of 79 patients with parathyroid (PT) adenomas and confirmed diagnosis of hyperparathyroidism who were evaluated with SS and US prior to successful parathyroidectomy. RESULTS: Ninety-three adenomas were removed during bilateral neck exploration. SS alone showed a sensitivity of 76% and a specificity of 79% compared with 89% and 75%, respectively, for US performed after SS on the same day. Combination of the 2 procedures yielded a sensitivity of 89% and a specificity of 90%, with 22% discordant results. The differences in sensitivity and specificity between the 2 techniques alone or in combination were not statistically significant. CONCLUSIONS: No benefit was gained from using both SS and US for the preoperative localization of PT adenomas in patients with primary hyperparathyroidism. Each technique can be negatively affected by thyroid enlargement and nodularity. US, when performed by a skilled operator, is a reliable tool for PT adenoma localization. If the US findings are inconclusive, SS should be used.

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.

Galectin-3 expression in parathyroid carcinoma: immunohistochemical study of 26 cases.

The diagnosis of parathyroid carcinoma (PC) is difficult and based on morphological features that are not totally reliable. Several molecular markers proved useful in the evaluation of PC, but their sensitivity, specificity, or both are rather low. With the aim of identifying a marker of malignancy in parathyroid tumors, we tested the expression of galectin-3 (Gal-3), a lectin expressed in several malignant tumors, including follicular carcinomas (but not adenomas) of the thyroid. Twenty-six PCs and 30 control parathyroid adenomas (PAs) were collected. The PCs had been diagnosed based on capsular/vascular invasion (26/26 cases), extraparathyroid infiltration (16), local recurrence (9), and distant metastases (6). All cases were immunohistochemically tested for Gal-3 and for other markers claimed to be useful in the differential diagnosis of parathyroid neoplasms, namely, Ki67, p27, and bcl2. Gal-3 was expressed by 24 of the PC (92.3%), but only 1 PA (3.3%) (P < .001). All metastasizing PCs were Gal-3-positive. As expected, the Ki67 proliferative index was higher in PCs (mean, 6.7%) than in PAs (1.9%); p27 was down-regulated in 61.5% of PCs and only 33.3% of PAs, whereas bcl2 was strongly positive in most PAs and in 38.5% of PCs. In a suspected PC, the association of Gal-3 with Ki67 (using a cutoff of 6% for the proliferative activity) appeared the best marker combination (sensitivity 96.2%, specificity 90%), and the profile Gal-3-positive/Ki67 >6% was unique to PCs. We conclude that Gal-3 immunostaining is a valuable tool to support a diagnosis of PC in highly proliferating (Ki67 >6%) tumors affecting a single parathyroid gland.

Decreased expression of stem cell factor in esophageal and gastric mucosa after esophagogastric anastomosis for cancer: potential relevance to motility.

BACKGROUND: Esophageal replacement with gastric tube is a well-established reconstruction of the alimentary tract after esophagectomy in cancer patients. The resulting molecular events in the transposed gastric tube and residual esophagus have yet to be investigated. Stem cell factor (SCF) was recently shown to be critical for signaling in gastrointestinal motility. SCF expression is here correlated with changes in mucosal morphology, acid and biliary reflux, and motility in the residual esophagus and gastric tube. METHODS: Thirteen patients surgically resected for squamous esophageal carcinoma with gastric tube replaced by esophagogastric anastomosis underwent upper endoscopy, esophageal manometry, 24-hour pH monitoring, and bile reflux detection. Esophageal and gastric mucosa samples were examined for SCF expression by immunohistochemical and semiquantitative reverse transcriptase-polymerase chain reaction analysis and for SCF serum levels by enzyme-linked immunosorbent assay. RESULTS: All patients showed severe residual esophagus hypoperistalsis and no gastric tube motor activity. The 24-hour pH monitoring was positive in most; 24-hour bile detection was mostly negative. SCF levels in the residual esophageal and gastric tube mucosa were dramatically decreased compared with those of normal subjects. The correlation between SCF and slow-wave activity was positive. CONCLUSIONS: Hypomotility of the residual esophagus and gastric tube seems closely associated with disruption of the SCF/c-kit signaling pathway. However, the absence of notable relations between mucosal changes after chronic exposure to acid, biliary gastric content, and SCF expression indicates that this analysis cannot be considered part of endoscopic follow-up.

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 hyperparathyrodism (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 now recurrent 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.