Filamin A and parafibromin expression in parathyroid carcinoma.

OBJECTIVE: Parathyroid carcinoma (PC), atypical parathyroid tumours (APT) and parathyroid adenoma (PA), all present with hypercalcemia. Diminished calcium-sensing receptor (CaSR) expression is reported in PC but is rare in benign tumours. Filamin A (FLNA) binds to the CaSR and activates the mitogen-activated protein kinase (MAPK) signalling pathway. FLNA is related to tumour aggressiveness in several cancers, but its role in parathyroid neoplasia is unknown. DESIGN: We examined FLNA, CaSR and parafibromin expression in PCs (n = 32), APTs (n = 44) and PAs (n = 77) and investigated their potential as diagnostic and/or prognostic markers. METHODS: Tissue microarray slides were immunohistochemically stained with antibodies for FLNA, CaSR and parafibromin. Staining results were correlated with detailed clinical data. RESULTS: All tumours stained positively for CaSR, with two tumours (one PC and one APT) showing diminished expression. Carcinomas were characterized by increased cytoplasmic FLNA expression compared to APTs and PAs (P = 0.004). FLNA expression was not correlated with Ki-67 proliferation index or loss of parafibromin expression. Cytoplasmic FLNA expression was also associated with higher serum calcium, PTH concentrations and male sex (P = 0.014, P = 0.017 and P = 0.049 respectively). Using a combined marker score, we found that parathyroid tumours with low FLNA expression and positive parafibromin staining were extremely likely to be benign (P < 0.001). CONCLUSION: Cytoplasmic and membranous FLNA expression is increased in parathyroid carcinomas compared to benign tumours. A combined FLNA and parafibromin expression score shows potential as a prognostic predictor of indolent behaviour in parathyroid neoplasms.

WNT2 activation through proximal germline deletion predisposes to small intestinal neuroendocrine tumors and intestinal adenocarcinomas.

Many hereditary cancer syndromes are associated with an increased risk of small and large intestinal adenocarcinomas. However, conditions bearing a high risk to both adenocarcinomas and neuroendocrine tumors are yet to be described. We studied a family with 16 individuals in four generations affected by a wide spectrum of intestinal tumors, including hyperplastic polyps, adenomas, small intestinal neuroendocrine tumors, and colorectal and small intestinal adenocarcinomas. To assess the genetic susceptibility and understand the novel phenotype, we utilized multiple molecular methods, including whole genome sequencing, RNA sequencing, single cell sequencing, RNA in situ hybridization and organoid culture. We detected a heterozygous deletion at the cystic fibrosis locus (7q31.2) perfectly segregating with the intestinal tumor predisposition in the family. The deletion removes a topologically associating domain border between CFTR and WNT2, aberrantly activating WNT2 in the intestinal epithelium. These consequences suggest that the deletion predisposes to small intestinal neuroendocrine tumors and small and large intestinal adenocarcinomas, and reveals the broad tumorigenic effects of aberrant WNT activation in the human intestine.

Functional imaging with 11C-metomidate PET for subtype diagnosis in primary aldosteronism.

OBJECTIVE: Endocrine Society guidelines recommend adrenal venous sampling (AVS) in primary aldosteronism (PA) if adrenalectomy is considered. We tested whether functional imaging of adrenal cortex with 11C-metomidate (11C-MTO) could offer a noninvasive alternative to AVS in the subtype classification of PA. DESIGN: We prospectively recruited 58 patients with confirmed PA who were eligible for adrenal surgery. METHODS: Subjects underwent AVS and 11C-MTO-PET without dexamethasone pretreatment in random order. The lateralization of 11C-MTO-PET and adrenal CT were compared with AVS in all subjects and in a prespecified adrenalectomy subgroup in which the diagnosis was confirmed with immunohistochemical staining for CYP11B2. RESULTS: In the whole study population, the concordance of AVS and 11C-MTO-PET was 51% and did not differ from that of AVS and adrenal CT (53%). The concordance of AVS and 11C-MTO-PET was 55% in unilateral and 44% in bilateral PA. In receiver operating characteristics analysis, the maximum standardized uptake value ratio of 1.16 in 11C-MTO-PET had an AUC of 0.507 (P = n.s.) to predict allocation to adrenalectomy or medical therapy with sensitivity of 55% and specificity of 44%. In the prespecified adrenalectomy subgroup, AVS and 11C-MTO-PET were concordant in 10 of 19 subjects with CYP11B2-positive adenoma and in 6 of 10 with CYP11B2-positivity without an adenoma. CONCLUSIONS: The concordance of 11C-MTO-PET with AVS was clinically suboptimal, and did not outperform adrenal CT. In a subgroup with CYP11B2-positive adenoma, 11C-MTO-PET identified 53% of cases. 11C-MTO-PET appeared to be inferior to AVS for subtype classification of PA.

Multidisciplinary Oncovascular Surgery is Safe and Effective in the Treatment of Intra-abdominal and Retroperitoneal Sarcomas: A Retrospective Single Centre Cohort Study and a Comprehensive Literature Review.

OBJECTIVE: Radical excision of retroperitoneal or intra-abdominal soft tissue sarcomas may necessitate vessel resection and reconstruction. The aim of this study was to assess surgical results of retroperitoneal or intra-abdominal sarcomas involving major blood vessels. METHODS: This was a retrospective single centre cohort study and a comprehensive review of literature. Patients with retroperitoneal or intra-abdominal sarcomas treated by the oncovascular team in Helsinki University Hospital from 2010 to 2018 were reviewed for vascular and oncological outcomes. A comprehensive literature review of vascular reconstructions in patients with retroperitoneal sarcoma was performed. RESULTS: Vascular reconstruction was performed in 17 patients, 11 of whom required arterial reconstructions. Sixteen of the operations were sarcoma resections; the post-operative diagnosis for one patient was thrombosis instead of the presumed recurrent leiomyosarcoma. Early graft thrombosis occurred in two venous and one arterial reconstruction. Late thrombosis was detected in three (18%). The median follow up was 27 (range 0-82) months. Of the patients with sarcoma resections 5 (31%) died of sarcoma and further 4 (25%) developed local recurrence or new distant metastases. The comprehensive review of literature identified 37 articles with 110 patients, 89 of whom had inferior vena cava reconstruction only. Eight arterial reconstructions were described. Late graft thrombosis occurred in 14%. The follow up was 0-181 months, during which 57% remained disease free and 7% died of sarcoma. CONCLUSION: Vascular reconstructions enable radical resection of retroperitoneal and intra-abdominal sarcomas in patients with advanced disease. The complex operations are associated with an acceptable rate of serious peri-operative complications and symptomatic thrombosis of the repaired vessel is rare. However, further studies are needed to assess the performance of the vascular reconstructions in the long term.

Single centre 30-year experience in treating retroperitoneal liposarcomas.

BACKGROUND AND OBJECTIVES: Liposarcomas form a diverse group of tumors that represent the majority of retroperitoneal soft tissue sarcomas. Radical excision of these retroperitoneal liposarcomas is often challenging due to their large size and proximity to visceral organs and major vessels. Here we present the 30-year experience of our multidisciplinary sarcoma team in the treatment of these tumors and analysis of factors influencing survival. METHODS: Patients with retroperitoneal liposarcomas treated in Helsinki University Hospital from 1987 to 2017 were reviewed. Local recurrence-free survival, metastases-free survival, and disease-specific survival were assessed with Kaplan-Meier analysis, and factors influencing survival were evaluated with Cox regression. RESULTS: A total of 107 patients were identified. The median follow-up time was 5.4 years (interquartile range: 2.2-8.8 years). Local recurrence developed in 72% and metastases in 15% during follow-up. The 5-year disease-free survival was 31% and disease-specific survival was 66%. The multifactorial analysis revealed histological type and grade as predictors of disease-specific survival (P < .01) while multifocality carried a poor prognosis for local recurrence (P = .02) and higher histological grade for metastases (P < .01). CONCLUSIONS: Retroperitoneal liposarcomas rarely metastasize but tend to recur locally. For tumors that have been resected with macroscopically clear margins, histological, type, and grade are significant predictors of survival.

IDH1 Expression via the R132H Mutation-Specific Antibody in Adrenocortical Neoplasias-Prognostic Impact in Carcinomas.

CONTEXT: Mutations to isocitrate dehydrogenase (IDH) appear to play a prognostic or predictive role in several neoplasias. Immunohistochemical staining designed to detect a specific R132H mutation to IDH1 showed expression in the normal adrenal cortex, raising interest to study the potential role of IDH1 in the pathogenesis of adrenocortical tumors. OBJECTIVE: The objective of this work is to study the role of IDH1 and its mutations in adrenocortical tumors. DESIGN AND PATIENTS: IDH1 R132H immunohistological staining was performed on a cohort of 197 adrenocortical tumors. The exon of the IDH1 gene was sequenced in 16 tumors. RESULTS: Positive IDH1 R132H immunohistochemical staining correlated with a better prognosis among patients with a malignant adrenocortical tumor. However, IDH1 R132H immunohistochemistry did not distinguish between local and metastasized tumors. We were unable to identify IDH1 mutations among our adrenocortical tumors using a targeted next-generation sequencing panel or via exon sequencing. CONCLUSIONS: Among adrenocortical carcinomas, IDH1 R132H immunopositivity correlated with a better prognosis. Thus, IDH1 R132H immunohistochemical staining could serve as a prognostic or as a potential predictive marker in adrenocortical carcinomas. Further research is needed to identify the possible alterations in IDH1 that could explain our findings, because we identified no known mutations to the IDH1 gene.

MGMT Promoter Methylation and Parathyroid Carcinoma.

CONTEXT: Parathyroid carcinoma (PC) is extremely rare. Prognosis is poor, with no known evidence-based systemic therapies. We previously reported complete remission in a patient with metastasized parathyroid carcinoma and high tumor MGMT promoter methylation status who was treated with temozolomide. OBJECTIVE: To study MGMT promoter methylation status in an additional set of aggressive parathyroid tumors. DESIGN/SETTING: The study included 12 patients: 7 with sporadic and 5 with familial primary hyperparathyroidism (two of the latter carried a CDC73 gross deletion). Patient 9 is the previously described patient with PC and high MGMT methylation status. Her daughter (patient 12) had surgery for severe primary hyperparathyroidism due to atypical parathyroid adenoma during pregnancy. Eleven patients thus had PC and one had atypical parathyroid adenoma. MGMT promoter methylation status was determined from DNA extracted from primary (n = 10) or metastatic (n = 2) tumors. A mean methylation level >20% was considered high. Patient 11 had metastatic PC and received temozolomide cycles. RESULTS: Only the previously published patient (patient 9) had high tumor MGMT promoter methylation status. This was not a characteristic of the atypical parathyroid adenoma of the daughter (patient 12). Patient 11 (CDC73 intragenic deletion) has disseminated PC, low MGMT promoter methylation, and stable disease on follow-up after temozolomide treatment. CONCLUSION: High MGMT promoter methylation status seems rare in PC. However, as demonstrated in other neuroendocrine tumors, some patients with disseminated PC might benefit from temozolomide. Demonstration of high methylation status could be a predictor of positive response to temozolomide treatment.

Recurrent Metastasized Parathyroid Carcinoma-Long-Term Remission After Combined Treatments With Surgery, Radiotherapy, Cinacalcet, Zoledronic Acid, and Temozolomide.

Parathyroid carcinoma is a rare cause of primary hyperparathyroidism with rather poor prognosis. Apart from surgery, no evidence-based treatments exist. A 48-year-old woman presented with weight loss, nausea, constipation, hypercalcemic crisis, and a recurrent neck tumor 5 years after primary surgery of a parathyroid tumor that primarily was classified as an adenoma. Histopathological reevaluation of the original tumor revealed the correct diagnosis to be parathyroid carcinoma (PC). The patient underwent surgery of the recurrent tumor, which was locally invasive with metastatic spread to the mediastinum and neck lymph nodes. Computed tomography demonstrated large lytic bone lesions in both iliac bones including, on the right, a soft tissue mass compatible with bone metastasis. The patient was treated with cinacalcet, repeated zoledronic acid infusions, and temozolomide cycles for 1 year. She underwent two additional neck surgeries for PC and sternotomy for resection of mediastinal metastases. Massive osteolytic lesions in both femoral necks caused imminent fracture risk and therefore both femurs were prophylactically stabilized by intramedullary nail. Serum calcium normalized after the third neck surgery, cinacalcet was discontinued, and parathyroid hormone gradually normalized during continued treatments with temozolomide, adjuvant radiotherapy, and zoledronic acid, with no signs of active disease on imaging and normal biochemistry. The patient remains in remission 17 years after successful combined treatments for recurrent, metastasized PC. The parathyroid tumor tissue demonstrated high O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status, a known predictor of positive temozolomide treatment response in other tumors. In addition, synergistic effects of multiple treatments may have accounted for the favorable response. © 2018 The Authors. JBMR Plus is published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.

Adrenocortical carcinoma: presentation and outcome of a contemporary patient series.

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare endocrine carcinoma with poor 5-year survival rates of < 40%. According to the literature, ACC is rarely an incidental imaging finding. However, presentation, treatment and outcome may differ in modern series. DESIGN AND METHODS: We studied all patients (n = 47, four children) from a single centre during years 2002-2018. We re-evaluated radiologic and histopathological findings and assessed treatments and outcome. We searched for possible TP53 gene defects and assessed nationwide incidence of ACC. RESULTS: In adults, incidental radiologic finding led to diagnosis in 79% at median age of 61 years. ENSAT stage I, II, III and IV was 19%, 40%, 19% and 21%, respectively. Nonenhanced CT demonstrated > 20 Hounsfield Units (HU) for all tumours (median 34 (21-45)), median size 92 mm (20-196), Ki67 17% (1-40%), Weiss score 7 (4-9) and Helsinki score 24 (4-48). ACC was more often found in the left than the right adrenal (p < 0.05). One child had Beckwith-Wiedemann and one a TP53 mutation. In adults, the primary tumour was resected in 88 and 79% received adjuvant mitotane therapy. Median hospital stay was significantly shorter in the laparoscopic vs. open surgery group (4 (3-7) vs. 8 (5-38) days, respectively; p < 0.001). In 3/4 patients, prolonged remission of > 5 to > 10 years was achieved after repeated surgery of metastases. Overall 5-year survival was 67%, and 96% vs. 26% for ENSAT stage I-II vs. III-IV (p < 0.0001). ENSAT stage and Ki67 predicted survival, type of surgery did not. Mitotane associated with better survival. CONCLUSIONS: Contemporary ACC predominantly presents as an incidental imaging finding, characterised by HU > 20 on nonenhanced CT but variable tumour size (20-196 mm). Malignancy cannot be ruled out by small tumour size only. The 5-year survival of 96% in ENSAT stage I-III compares favourably to previous studies.

Health-Related Quality of Life in Patients with Small Intestine Neuroendocrine Tumors.

BACKGROUND: The prevalence of small intestine neuroendocrine tumors (SI-NETs) is increasing. Disease progression is often slow and treatment options and long-term survival rates have improved, but little is known about health-related quality of life (HRQoL) in these patients. OBJECTIVE: To assess HRQoL and its predictors in SI-NET patients receiving contemporary treatments. METHODS: We measured HRQoL with 15D and SF-36 questionnaires in 134 SI-NET patients and compared the 15D results to those of an age- and gender-standardized sample of the general population (n = 1,153). In the patients, we studied the impact of treatments, Ki-67, liver metastases, circulating tumor markers, comorbidities, and/or socioeconomic factors on HRQoL with linear regression analysis. RESULTS: The mean disease duration of the patients was 81 (4-468) months, 91% had metastatic disease, and 79% received somatostatin analog treatment. Hepatic tumor load was 0% in 44.8%, < 10-25% in 44.0%, and > 25% in 11.2%, respectively. Mean fP-CgA and S-5HIAA concentrations were 15 (1.3-250) and 344 (24-7,470) nmol/L, respectively. Overall, HRQoL was significantly impaired in patients compared to controls (15D score 0.864 ± 0.105 vs. 0.905 ± 0.028, p < 0.001). SI-NET patients scored worse on 9 of 15 dimensions: sleep, excretion (i.e., bladder and bowel function), depression, distress, vitality, sexual activity (p < 0.001), breathing, usual activities, and discomfort and symptoms (p < 0.01-0.05). SF-36 scores were impaired and highly correlated with 15D scores (p < 0.001). HRQoL was impaired in patients with (n = 85) compared to patients without (n = 49) impaired excretion (0.828 vs. 0.933, p < 0.001). In the patient group, number of medications predicted impaired HRQoL. CONCLUSIONS: Despite contemporary treatments, SI-NET patients have severely impaired HRQoL, including diarrhea, sleep, depression, vitality, and sexual activity.

C-myc expression in adrenocortical tumours.

AIMS: Widespread use of high-resolution imaging techniques and thus increased prevalence of adrenal lesions has made diagnostics of adrenocortical tumours an increasingly important clinical issue. In non-metastatic tumours, diagnosis is based on histology. New or enhanced information for clinicopathological diagnosis, revealing the malignant potential of the tumour, could emerge by means of biomarkers. The connection of proto-oncogene c-myc to adrenocortical neoplasias is poorly known, although the Wnt/beta-catenin pathway, one of the signalling pathways leading to induction of c-myc expression, has been connected to development of adrenocortical neoplasias. We studied c-myc expression in adrenocortical tumours and investigated molecules associated with the signalling pathway of c-myc, including cell cycle-related proteins p27, cyclin E and cyclin D1. METHODS: We studied 195 consecutive adult patients with 197 primary adrenocortical tumours. Histopathological diagnosis was determined by Weiss score and the novel Helsinki score. C-myc, cyclin D1, cyclin E and p27 expressions were determined by immunohistochemistry. RESULTS: Benign adenomas showed prominent nuclear c-myc expression comparable to that of normal adrenocortical cells, whereas carcinomas showed increased cytoplasmic expression. Strong cytoplasmic and weak nuclear c-myc expressions associated with malignancy and adverse outcome. C-myc staining did not correlate with cyclin E. Cyclin D1 correlated with cytoplasmic c-myc expression and to a lesser extent with nuclear c-myc. P27 correlated with cytoplasmic c-myc, but not with nuclear c-myc. P27 correlated with cyclin E. CONCLUSIONS: Strong cytoplasmic c-myc expression and weak nuclear expression in adrenocortical tumours associated with malignancy and shorter survival.

Surgery Significantly Improves Neurocognition, Sleep, and Blood Pressure in Primary Hyperparathyroidism: A 3-Year Prospective Follow-Up Study.

Surgery for primary hyperparathyroidism (PHPT) improves health-related quality of life (HRQoL), but it is unclear whether the effects are sustained after medium-term (>2 years) follow-up, and whether the results on some or all dimensions of HRQoL will reach that of the general population. We performed a follow-up of HRQoL on average 3.3 years after surgery for PHPT using the 15D in our patient cohort (n=124) and compared the results to those of an age- and gender-standardized general population (n=1099). We studied self-reported blood pressure and current medications; new comorbidities were retrieved from electronic patient records. A total of 104 (83%) patients [eight with serum calcium (1.34-1.46 mmol/l)] returned the questionnaires. After a follow-up of 3.3 years (range 23 to 55 months), systolic and diastolic blood pressure had decreased significantly compared to baseline (the situation before surgery, p<0.001). Thirty-four (33%) had acquired a new diagnosis (range 1-7), the most common being cardiovascular disease and cancer. Mean 15D score was significantly better compared to baseline (p<0.001), the dimensions of sleeping, mental function, discomfort and symptoms, and depression had further improved (p<0.01), and no longer differed from that of the general population. In PHPT, after >2 years follow-up, surgery improves blood pressure and restores neurocognitive function and sleep to the level of the general population. The improvements observed in overall HRQoL at one year after surgery are sustained, but overall HRQoL does not reach that of the general population.

A nationwide study on parathyroid carcinoma.

BACKGROUND: Parathyroid carcinoma (PC) is rare and diagnostically challenging. Reported outcomes are rather poor and the incidence might be increasing. MATERIAL AND METHODS: We performed a nationwide study on all cases (n= 32) diagnosed in 2000-2011 in Finland, and compared clinical and histopathological characteristics and outcome to atypical parathyroid (APA; n= 28) and parathyroid adenomas (PA; n= 72). The incidence in years 1955-1999 was compared to that in 2000-2013. RESULTS: Preoperatively, calcium and parathyroid hormone concentrations were higher in PC compared to APA and PA (1.76, 1.56 and 1.44 mmol/l, p < .001; and 989, 355 and 160 µmol/l, p < .001, respectively). Calcium was ≤1.77 mmol/l for all PAs. Hospitalization (44% vs. 22% and 3%, respectively, p = .01), renal (50% vs. 48% vs. 22%, respectively, p = .01) and bone (47% vs. 15% vs. 38%, respectively p = .002) manifestations were more common. PC and APA tumors were larger than PA (p < .001). Histopathological characteristics of PC compared to PA are increased mitotic activity (p= .001), chief cells (p = .003), diffuse growth pattern (p < .001), higher Ki67 (p< .001) and negative parafibromin (p < .001). One PC (1/18) and one APA (1/16) patient had a CDC73 mutation. After 6.7 (2-13.9) years of follow-up, 9.4% of PC had residual, 21% recurrent disease and 12.5% died of disease. Overall mortality did not differ between subgroups (p = .094). Recurrent PC was characterized by vascular invasion, lymph node metastases, high mitotic activity, necrosis and negative parafibromin. Incidence increased from 1.42 (range 0.52-2.14) to 7.14 (range 3.42-10.38)/10.000.000/years; (p < .001). CONCLUSIONS: PC associates with severe primary hyperparathyroidism and must be suspected if calcium ≥1.77 mmol/l. The prevalence of CDC73 germline mutations in PC and APA in Finland is 6%. PC has distinct histopathological characteristics and its incidence has increased over the past decades.

HuR in pheochromocytomas and paragangliomas - overexpression in verified malignant tumors.

Pheochromocytomas and paragangliomas are rare, neural crest-originating, neuroendocrine tumors. HuR is an mRNA-binding protein of the ELAV/Hu-protein family, which participates in posttranscriptional regulation of many cancer-associated genes. HuR expression has been connected with aggressive behavior of several malignancies. Cyclooxygenase-2 (COX-2) is also expressed in several malignant tumors, and its expression is regulated by HuR. Tissue microarray of 153 primary pheochromocytomas and paragangliomas was investigated for the expression of HuR and COX-2 proteins by immunohistochemistry using two different HuR antibodies (HuR19F12 and HuR3A). In these tumors, the expression of both intranuclear and cytoplasmic HuR was detectable. Increased cytoplasmic HuR expression was significantly associated with metastatic tumors. Increased COX-2 and MIB-1 expression also was associated with metastatic potential, and moreover, HuR and COX-2 expression correlated with each other. Our data suggest that increased expression of HuR protein is associated with metastatic potential of paragangliomas and pheochromocytomas, and COX-2 seems to be a target of HuR.

Health-related quality of life is impaired in primary hyperparathyroidism and significantly improves after surgery: a prospective study using the 15D instrument.

Health-related quality of life (HRQoL) is frequently impaired in primary hyperparathyroidism (PHPT) but it is unclear if surgery is beneficial. The objective was to prospectively assess HRQoL in PHPT (n=124) with the 15D instrument before and after surgery, to compare it with that of a comparable sample of the general population (n=4295), and search for predictors of HRQoL and its change. HRQoL, and clinical and laboratory parameters were measured before and at 6 and 12 months after surgery. Regression techniques were used to search for predictors of HRQoL and gains from treatment. Before surgery, PHPT patients had significantly lower mean 15D score compared to controls (0.813 vs 0.904, P<0.001). Excretion, mental function, discomfort and symptoms, distress, depression, vitality, and sexual activity were most impaired (all P<0.001). Number of medications (P=0.001) and subjective symptoms (P<0.05) but not calcium or parathyroid hormone (PTH) predicted impaired HRQoL. Serum 25-hydroxyvitamin D (25OHD) was of borderline significance (P=0.051). Compared to baseline, mean 15D score improved significantly 6 months after surgery (0.813 vs 0.865, P<0.001) and the effect sustained at 1 year (0.878, P<0.001). The improvement was clinically important in 77.4% of patients (P<0.001). Educational level independently predicted improvement (P<0.005). HRQoL is severely impaired in PHPT but improves significantly after surgery. The 15D is a sensitive tool for assessing HRQoL and recognizing patients likely to benefit from surgery.

A novel stem cell associated marker identified by monoclonal antibody HESC5:3 differentiates between neoplastic lesions in follicular thyroid neoplasms.

Follicular thyroid lesions are the bane of cytopathology. Differentiation between adenoma and carcinoma is impossible, and often these neoplasms are indistinguishable even from uninodular goitre. In other cancers as well, a theory of stem cells as the origin of cancer has been discussed in thyroid carcinogenesis. We aimed to examine a novel stem cell associated marker identified by monoclonal antibody HESC5:3 in follicular lesions in an attempt to find a marker for differential diagnosis in thyroid cytopathology. HESC5:3 was raised against and is specific for undifferentiated human embryonic stem cells. The epitope of this novel antibody is to be defined. Immunohistochemical expression of HESC5:3 was examined in clinical material comprised of follicular neoplasms (83 adenomas, 43 carcinomas) and non-neoplastic lesions (41 goitrous, 22 hyperplastic, 23 normal tissue specimens). Staining differed significantly between neoplastic and non-neoplastic lesions. Nuclear staining was increased in non-neoplastic cells, whereas in neoplastic cells expression was mainly cytoplasmic. There was no difference between benign and malignant lesions, suggesting a role in early tumourigenesis. In conclusion, the HESC5:3 epitope may be of benefit as a neoplasia marker in distinguishing between uninodular goitre and neoplasia. Characterization of the epitope would increase the interest in this promising new stem cell associated marker.

(99m)Technetium Sestamibi-(123)Iodine Scintigraphy Is More Accurate Than (99m)Technetium Sestamibi Alone before Surgery for Primary Hyperparathyroidism.

Objectives. Studies comparing outcome of single-(99m)Tc-methoxyisobutylisonitrile ((99m)Tc-sestamibi) and dual-tracer (99m)Tc-sestamibi scintigraphy in combination with (123)I before primary surgery of primary hyperparathyroidism (PHPT) are scarce. Methods. We compared (99m)Tc-sestamibi/(123)I and (99m)Tc-sestamibi in a single-centre retrospective series of 269 PHPT patients. The results were related to laboratory, surgical and histological findings. Results. (99m)Tc-sestamibi/(123)I and (99m)Tc-sestamibi were positive in 206 (76.6%) and 111 (41.3%) of 269 patients, respectively (P < 0.001). Accuracies for (99m)Tc-sestamibi/(123)I and (99m)Tc-sestamibi were 63.4% and 34.9%, respectively (96% CI, P < 0.001). Prevalence of multiglandular disease was 15.2%. In multiglandular disease, (99m)Tc-sestamibi/(123)I and (99m)Tc-sestamibi revealed 43.8 and 22.1% of pathological glands, respectively (P < 0.001). Cure rate was similar for patients with (191/206; 92.7%) and without (59 of 63; 93.7%) a positive (99m)Tc-sestamibi/(123)I finding. Duration of targeted surgery (one or two quadrants) was 21 and 15 minutes shorter than bilateral neck exploration, respectively (both P < 0.001). Higher serum calcium (P = 0.014) and PTH (P = 0.055) concentrations and larger tumours (P < 0.001) characterized the 206 patients with a positive preoperative scan who were cured by removal of a single adenoma. Conclusions. (99m)Tc-sestamibi/(123)I scintigraphy is more accurate than (99m)Tc-sestamibi before surgery of PHPT. However, outcome of surgery is not determined by scintigraphy alone.

Helsinki score-a novel model for prediction of metastases in adrenocortical carcinomas.

Histopathologic diagnosis of adrenocortical tumors is based on adverse features that indicate malignant potential. Proliferation index has served as a supplemental tool in assessing the malignant potential of adrenocortical tumors. None of the current histologic classification systems can sufficiently accurately predict tumors' metastatic potential. We studied 177 consecutive adult patients with primary adrenocortical tumors operated on at Helsinki University Central Hospital between 1990 and 2003, all patients with a minimum follow-up of 5 years. We determined for each tumor the Weiss score and the Weiss revisited score by Aubert. Proliferation index was measured by computer-assisted image analysis. Each of the 9 Weiss criteria and the proliferation index were then used to establish a scoring system to predict the metastatic potential of adrenocortical tumors. Use of stepwise regression analysis led us to propose a calculation: 3 × mitotic rate (>5/50 high-power fields) + 5 × presence of necrosis + proliferation index in the most proliferative area of the tumor. Using a cutoff value of 8.5, the new scoring system was able to diagnose metastatic adrenocortical carcinoma with 100% sensitivity (confidence interval [CI], 76.8%-100%) and 99.4% specificity (CI, 96.6%-100%). The corresponding sensitivity of the Weiss system was 100% (CI, 76.8%-100%), and specificity, 90.2% (CI, 84.6%-94.3%), with sensitivity of the Weiss revisited system at 100% (CI, 76.8%-100%) and specificity at 96.9% (CI, 93.0%-99.0%). The new Helsinki score thus was accurate in predicting the metastatic potential of adrenocortical tumors.

Adrenocortical tumours: high CT attenuation value correlates with eosinophilia but does not discriminate lipid-poor adenomas from malignancy.

BACKGROUND: Characterisation of adrenal tumours is an important clinical problem. Unenhanced CT is the primary imaging modality to assess the nature of these lesions. AIMS: To study the correlation between unenhanced CT attenuation value and the specific histopathology, as well as the proportion of lipid-poor eosinophilic cells in adrenocortical tumours. METHODS: We studied retrospectively primary adrenocortical tumours that had been operated on at Helsinki University Central Hospital between 2002 and 2008. Of 171 tumours, 79 had appropriate preoperative CT scans and were included in the study. We evaluated the unenhanced CT attenuation values (Hounsfield units, HU) of these tumours and determined their histopathological diagnosis by the Weiss scoring system. We also assessed the proportion of lipid-poor eosinophilic cells for each tumour. RESULTS: Unenhanced CT attenuation value (HU) in adrenocortical tumours correlated well with the proportion of lipid-poor eosinophilic cells (rs=0.750, p<0.001). HU and Weiss score also had a correlation (rs=0.582, p<0.001). CONCLUSIONS: Unenhanced CT attenuation value correlates well with the percentage of lipid-poor eosinophilic cells, but unenhanced CT attenuation value fails to differentiate between benign lipid-poor adenomas and malignant adrenocortical tumours. All adrenocortical tumours with unenhanced CT attenuation value ≤10 HU are histologically benign lipid-rich tumours.