Ilkka Heiskanen

Complementary Roles of 18F-DOPA PET/CT and 18F-FDG PET/CT in Medullary Thyroid Cancer

Serum calcitonin and carcinoembryonic antigen (CEA) are markers of recurrent or persistent disease in medullary thyroid cancer (MTC). However, conventional imaging often fails to localize metastatic disease. Our aim was to compare fluorine-labeled dihydroxyphenylalanine (18F-DOPA) and 18F-FDG PET/CT with multidetector CT (MDCT) and MRI in recurrent or persistent MTC. Methods: Nineteen MTC patients with increased calcitonin or CEA on follow-up (mean ± SD, 93 ± 91 mo; range, 4–300 mo) after primary therapy were prospectively imaged with 4 techniques: 18F-DOPA PET/CT, 18F-FDG PET/CT, MDCT, and MRI. Images were analyzed for pathologic lesions, which were surgically removed when possible. The correlation between the detection rate for each method and the calcitonin and CEA concentrations and histopathologic findings was investigated. Results: On the basis of histology and follow-up, one or more imaging methods accurately localized metastatic disease in 12 (63%) of 19 patients. The corresponding figures for 18F-DOPA PET/CT, 18F-FDG PET/CT, MDCT, and MRI were 11 (58%) of 19, 10 (53%) of 19, 9 (47%) of 19, and 10 (59%) of 17, respectively. Calcitonin and CEA correlated with 18F-DOPA PET/CT (P = 0.0007 and P = 0.0263, respectively) and 18F-FDG PET/CT findings (both P < 0.0001). In patients with an unstable calcitonin doubling time (n = 8), 18F-DOPA and 18F-FDG PET/CT were equally sensitive. In contrast, for patients with an unstable CEA doubling time (n = 4), 18F-FDG PET/CT was more accurate. Conclusion: For most MTC patients with occult disease, 18F-DOPA PET/CT accurately detects metastases. In patients with an unstable calcitonin level, 18F-DOPA PET/CT and 18F-FDG PET/CT are complementary. For patients with an unstable CEA doubling time, 18F-FDG PET/CT may be more feasible. MRI is sensitive but has the highest rate of false-positive results.

Planar Scintigraphy with 123I/99mTc-Sestamibi, 99mTc-Sestamibi SPECT/CT, 11C-Methionine PET/CT, or Selective Venous Sampling Before Reoperation of Primary Hyperparathyroidism?

All patients with primary hyperparathyroidism should undergo localization studies before reoperation, but it is not known which method is most accurate. The purpose of this prospective study was to compare the performance of planar scintigraphy with 123I/99mTc-sestamibi, 99mTc-sestamibi SPECT (SPECT/CT), 11C-methionine PET/CT, and selective venous sampling (SVS) in persistent primary hyperparathyroidism. Methods: Twenty-one patients referred for reoperation of persistent hyperparathyroidism were included and investigated with 123I/99mTc-sestamibi, SPECT/CT (n = 19), 11C-methionine PET/CT, and SVS (n = 18) before reoperation. All patients had been operated on 1–2 times previously because of hyperparathyroidism. The results of the localization studies were compared with operative findings, histology, and biochemical cure. Results: Eighteen (86%) of 21 patients were biochemically cured. Nineteen parathyroid glands (9 adenomas, 1 atypical adenoma, and 9 hyperplastic glands) were removed from 17 patients, and 1 patient who was biochemically cured had an unclear histology result. The accuracy for localizing a pathologic parathyroid gland to the correct side of the neck was 59% (95% confidence interval [CI], 36%–79%) for 123I/99mTc-sestamibi, 19% (95% CI, 5%–42%) for SPECT/CT, 65% (95% CI, 43%–84%) for 11C-methionine PET/CT, and 40% (95% CI, 19%–65%) for SVS (P < 0.01 for 123I/99mTc-sestamibi vs. SPECT/CT). The corresponding accuracy for the correct quadrant or more specific site was 48% (95% CI, 27%–69%) for 123I/99mTc-sestamibi, 14% (95% CI, 3%–36%) for SPECT/CT, 61% (95% CI, 39%–80%) for 11C-methionine PET/CT, and 25% (95% CI, 9%–49%) for SVS (P < 0.02 for 123I/99mTc-sestamibi vs. SPECT/CT). In the 3 patients not cured, preoperative 123I/99mTc-sestamibi and SPECT/CT remained negative, SVS was false predictive in all, and 11C-methionine PET/CT in 1. 11C-methionine PET/CT accurately revealed the pathologic gland in 4 of 8 (50%) patients with a negative 123I/99mTc-sestamibi scan result, all of whom were biochemically cured after reoperation. Conclusion: Planar scintigraphy with 123I/99mTc-sestamibi performs well in complicated primary hyperparathyroidism and is recommended as first-line imaging before reoperation. 11C-methionine PET/CT provides valuable additional information if 123I/99mTc-sestamibi scan results remain negative. 99mTc-sestamibi SPECT/CT and SVS provide no additional information, compared with the combined results of 123I/99mTc-sestamibi and 11C-methionine PET/CT imaging.

TLR-4 expression and decrease in chronic inflammation: indicators of aggressive follicular thyroid carcinoma.

Background Well-differentiated follicular thyroid carcinoma usually has a favourable prognosis and metastases are rare. Toll-like receptors (TLRs) that take part in adaptive and innate immunity have, in many tumours, both apoptotic and antiapoptotic effects, making their role in tumourigenesis controversial. Chronic inflammation is involved in many cancers. Aims To examine the clinical relevance of TLR-2, TLR-4, and CD45 in follicular thyroid neoplasias. Methods The authors studied the immunohistochemical expression of TLR-2 and TLR-4 in 127 follicular thyroid neoplasms, both in adenomas and in carcinomas including oxyphilic tumours. Their degree of chronic inflammation was evaluated by a count of CD45-positive lymphocytes within and adjacent to the tumourous tissue. Results Both high TLR-4 expression and lack of TLR-4 expression in carcinomas were associated with metastatic and aggressive disease. In oxyphilic tumours, both in adenomas and in carcinomas, TLR-4 expression was significantly stronger. TLR-2 expression was stronger in adenomas than in carcinomas but without any correlation with clinical variables. Degree of chronic inflammation outside the primary tumour was lower for metastasized carcinomas than for non-metastasised carcinomas. Conclusions Varying expression of TLR-4 and lack of inflammation are indicators of aggressive disease among follicular thyroid cancer.

Loss of estrogen receptor Beta expression in follicular thyroid carcinoma predicts poor outcome.

BACKGROUND Well-differentiated follicular thyroid carcinomas (FTCs) usually act indolently, while aggressively acting tumors are difficult to detect early enough. Estrogen receptors (ERs) have prognostic significance in many cancers. Thyroid diseases, including neoplasms, are associated with the female sex. The prognostic significance of ERs in FTCs has not been reported previously. METHODS We studied the role of ERα and ERβ in 83 cases of follicular thyroid adenoma (FTA) and 43 FTC cases, including seven cases of poorly differentiated FTC, obtained from the Department of Surgery, Helsinki University Central Hospital between 1990 and 2009. Patient follow-up was conducted until March 2011. Expression of ERα, ERβ, and MIB-1/Ki-67 was investigated by immunohistochemistry and correlated with clinicopathological characteristics, including survival. RESULTS Two major observations were apparent. First, ERβ expression was significantly higher in FTA than in FTC, and it was a stronger differential diagnostic marker than MIB-1/Ki-67. Second, low ERβ expression correlated with poor survival in FTC. All cancer-specific deaths due to FTC were among low ERβ-score patients. CONCLUSION ERβ is a differential marker for malignancy and could thus be used as a preoperative tool. FTC patients with a low ERβ score need more thorough follow-up and may benefit from more aggressive treatment.

A nationwide study on parathyroid carcinoma

Abstract 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.

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.

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 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.

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 in Patients with Small Intestine Neuroendocrine Tumours

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.