Paragangliomas (PGLs) are rare vascular, neuroendocrine tumors of paraganglia, which are associated with either sympathetic tissue in adrenal (pheochromocytomas (PCCs)) and extraadrenal (sympathetic paraganglioma (sPGLs)) locations or parasympathetic tissue of the head and neck paragangliomas (HNPGLs). As HNPGLs are usually benign and most tumors grow slowly, a wait-and-scan policy is often advised. However, their location in the close proximity to cranial nerves and vasculature may result in considerable morbidity due to compression or infiltration of the adjacent structures, necessitating balanced decisions between a wait-and-see policy and active treatment. The main treatment options for HNPGL are surgery and radiotherapy. In contrast to HNPGLs, the majority of sPGL/PCCs produces catecholamines, in advanced cases resulting in typical symptoms and signs such as palpitations, headache, diaphoresis, and hypertension. The state-of-the-art diagnosis and localization of sPGL/PCCs are based on measurement of plasma and/or 24-h urinary excretion of (fractionated) metanephrines and methoxytyramine (MT). sPGL/PCCs can subsequently be localized by anatomical (computed tomography and/or magnetic resonance imaging) and functional imaging studies (123I-metaiodobenzylguanidine-scintigraphy, 111In-pentetreotide scintigraphy, or positron emission tomography with radiolabeled dopamine or dihydroxyphenylalanine). Although most PGL/PCCs are benign, factors such as genetic background, tumor size, tumor location, and high MT levels are associated with higher rates of metastatic disease. Surgery is the only curative treatment. Treatment options for patients with metastatic disease are limited. PGL/PCCs have a strong genetic background, with at least one-third of all cases linked with germline mutations in 11 susceptibility genes. As genetic testing becomes more widely available, the diagnosis of PGL/PCCs will be made earlier due to routine screening of at-risk patients. Early detection of a familial PGL allows early detection of potentially malignant PGLs and early surgical treatment, reducing the complication rates of this operation.
Eleonora P Corssmit and Johannes A Romijn
Marleen Kars, Ferdinand Roelfsema, Johannes A Romijn and Alberto M Pereira
Pituitary carcinomas are extremely rare. In general, the initial clinical, biochemical, and histological characteristics are of minimal utility in distinguishing benign adenomas from pituitary carcinomas. We describe a 63-year-old woman with a macroprolactinoma, who presented with diplopia and blurred vision. This unusual initial presentation and the subsequent aggressive clinical course, with diffuse local and distant intramedulary metastases, prompted us in retrospect to make a detailed analysis of the therapeutic interventions and histology. In addition, we reviewed all available literature on published cases of malignant prolactinoma and detailed their epidemiological, clinical, and histopathological characteristics. In brief, it is postulated that pituitary carcinomas arise from the transformation of initially large, but benign, adenomas. Unusual and/or atypical clinical manifestations appear to occur more frequently. In vivo, the development of dopamine agonist resistance in invasive macroprolactinoma is indicative of malignancy and should prompt the clinician to perform a biopsy of the tumor. For pituitary tumors that exhibit high mitotic activity, increased Ki-67 and/or p53 immunoreactivity, it may be useful to denote these tumors as ‘atypical’ prolactinomas to raise the possibility of future malignant development.
Ria Adriaanse, Johannes A Romijn, Erik Endert and Wilmar M Wiersinga
The nocturnal TSH surge was studied in controls, in 34 patients with hypothalamic/pituitary disease and in 21 patients with primary hypothyroidism. It was absent in 5/12 hypothyroid patients and in 5/22 euthyroid patients with hypothalamic/pituitary disease (42% vs 23%. NS). Central hypothyroidism relative to euthyroidism was associated with a lower absolute (0.3±0.4 vs 0.9±1.0 mU/l, p<0.05) and relative (24±31 vs 63±51%, p<0.05) nocturnal rise in TSH. In primary hypothyroidism, the nocturnal TSH surge was absent in eight often patients with overt, in one of five patients with mild and in none of six patients with subclinical hypothyroidism. The relative nocturnal rise in TSH was normal in mild (54±33%) and subclinical (92±69%), but decreased in overt hypothyroidism (2±10%). Plasma T4 was positively and 09.00 plasma TSH negatively related to the relative nocturnal TSH surge in primary hypothyroidism, but not in central lesions. In both conditions, however, a positive relationship was observed between the relative nocturnal TSH surge and the relative increase of TSH to TRH. In conclusion: (a) The nocturnal TSH surge is usually absent in overt hypothyroidism but present in mild primary hypothyroidism and equivocal in central hypothyroidism. This limits its usefulness as an adjunct in the diagnosis of central hypothyroidism. (b) The magnitude of the nocturnal TSH surge in patients with hypothalamic/pituitary disease or primary hypothyroidism is directly related to the TSH response to TRH, and thus appears to be determined by the directly releasable TSH pool of the pituitary.
Ying Y Liu, Hans Morreau, Job Kievit, Johannes A Romijn, Nancy Carrasco and Johannes W Smit
The microscopic distinction between benign and malignant thyroid lesions in clinical practice is still largely based on conventional histology. This study was performed to evaluate the diagnostic value of galectin-3 (Gal-3), Hector Battifora mesothelial-1 (HBME-1), cytokeratin (CK)-19, CBP P300-interacting transactivator with glutamic acid E- and aspartic acid D-rich C-terminal domain (CITED-1), fibronectin (FN)-1, peroxisome proliferator-activated receptor (PPAR)-γ, and intracellular sodium/iodide symporter (iNIS) immunostaining in a large panel of thyroid neoplasms. Our study differed from earlier ones with regard to the identification of optimal semiquantitative cut-off levels using receiver operator curve (ROC) analysis and hierarchical cluster analysis.
We used tissue arrays containing 177 thyroid tissues: 100 benign tissues (including normal thyroid, Graves disease, multinodular goiter, and follicular adenoma (FA)) and 77 thyroid carcinomas (including papillary thyroid carcinoma (PTC), follicular thyroid carcinoma, and follicular variant of PTC (FVPTC)). Antibody staining was scored semiquantitatively based on the ROC analyses and with hierarchical cluster analysis.
In general, we found overexpression of FN-1, CITED-1, Gal-3, CK-19, HBME-1, and iNIS in malignant thyroid lesions. Gal-3, FN-1, and iNIS had the highest accuracy in the differential diagnosis of follicular lesions. A panel of Gal-3, FN-1, and iNIS, identified by hierarchical cluster analysis, had a 98% accuracy to differentiate between FA and malignant thyroid lesions. In addition, HBME-1 was found to be useful in the differentiation between FA and FVPTC (accuracy 88%).
We conclude that identifying optimal antibody panels with cluster analysis increases the diagnostic value in the differential diagnosis of thyroid neoplasms, the combination of FN-1, Gal-3, and iNIS having the best accuracy (98%).
Jitske Tiemensma, Adrian A Kaptein, Alberto M Pereira, Johannes W A Smit, Johannes A Romijn and Nienke R Biermasz
Illness perceptions pertain to the pattern of beliefs patients develop about their illness. Illness perceptions are determinants of quality of life (QoL). Factors contributing to persisting impaired QoL after Cushing's syndrome (CS) remain largely unknown. Therefore, the objective of this study was to explore illness perceptions, as potentially modifiable psychological factors, in relation to QoL in patients with long-term remission of CS.
We included patients with long-term remission of CS (n=52). Illness perceptions were evaluated using the Illness Perception Questionnaire (IPQ)-Revised, and QoL was measured using the physical symptom checklist, EuroQoL-5D (EQ-5D), and the CushingQoL. Reference data were derived from recent studies and included patients with vestibular schwannoma (n=80), acute (n=35) or chronic (n=63) pain, and chronic obstructive pulmonary disease (COPD; n=171).
Illness perceptions showed a strong correlation with QoL. Patients with CS scored distinctively more negative on the IPQ compared with patients with vestibular schwannoma and patients with acute pain, and also reported more illness-related complaints (all P<0.01). There were also some differences in illness perceptions between patients with CS and patients with chronic pain and patients with COPD, but there was no distinct pattern.
Patients after long-term remission of CS report more negative illness perceptions compared with patients with other acute or chronic conditions. Further research is needed to assess whether QoL in CS can be improved by addressing these illness perceptions, for example, by a self-management intervention program.
Alberto M Pereira, Victoria Delgado, Johannes A Romijn, Johannes W A Smit, Jeroen J Bax and Richard A Feelders
In patients with active Cushing's syndrome (CS), cardiac structural and functional changes have been described in a limited number of patients. It is unknown whether these changes reverse after successful treatment. We therefore evaluated the changes in cardiac structure and dysfunction after successful treatment of CS, using more sensitive echocardiographic parameters (based on two-dimensional strain imaging) to detect subtle changes in cardiac structure and function.
In a prospective study design, we studied 15 consecutive CS patients and 30 controls (matched for age, sex, body surface area, hypertension, and left ventricular (LV) systolic function). Multidirectional LV strain was evaluated by two-dimensional speckle tracking strain imaging. Systolic (radial thickening, and circumferential and longitudinal shortening) and diastolic (longitudinal strain rate at the isovolumetric relaxation time (SRIVRT)) parameters were measured.
At baseline, CS patients had similar LV diameters but had significantly more LV hypertrophy and impaired LV diastolic function, compared to controls. In addition, CS patients showed impaired LV shortening in the circumferential (−16.5±3.5 vs −19.7±3.4%, P=0.013) and longitudinal (−15.9±1.9 vs −20.1±2.3%, P<0.001) directions and decreased SRIVRT (0.3±0.15 vs 0.4±0.2/ s, P=0.012) compared to controls. After normalization of corticosteroid excess, LV structural abnormalities reversed, LV circumferential and longitudinal shortening occurred, and SRIVRT normalized.
CS induces not only LV hypertrophy and diastolic dysfunction but also subclinical LV systolic dysfunction, which reverses upon normalization of corticosteroid excess.
Nieke E Kokshoorn, Nienke R Biermasz, Ferdinand Roelfsema, Johannes W A Smit, Alberto M Pereira and Johannes A Romijn
Recombinant human GH (rhGH) is prescribed for the treatment of adults with GH deficiency (GHD). However, conflicting data are available on the efficacy of rhGH treatment in elderly GHD patients.
To assess the efficacy of rhGH treatment in elderly GHD subjects.
We searched the available literature in PubMed, Cochrane Library, Web of Science and EMBASE.
Studies on GHD patients, aged >60 years, treated with rhGH were eligible for inclusion. Data extraction was performed by two reviewers independently.
We found 11 eligible studies with a total of 534 patients. Only two studies had prospective, randomized, placebo-controlled study designs of rhGH treatment with a duration of 6 (n=15) and 12 months (n=62), respectively. Treatment with rhGH decreased total and low density lipoprotein (LDL) cholesterol levels by 4–8 and 11–16%, respectively, but did not alter high density lipoprotein or triglyceride levels. RhGH did not affect body mass index, but decreased waist circumference (by ∼3 cm) and waist/hip ratio. RhGh did not consistently affect blood pressure or bone mineral density. RhGH increased lean body mass by 2–5% and decreased total fat mass by 7–10% in four studies, but did not affect body composition in two other studies. RhGH consistently improved quality of life (QoL) parameters reflected in AGHDA-scores. There were no explicit data on elderly GHD patients aged >80 years.
RhGH replacement in elderly subjects with GHD decreases LDL cholesterol levels and improves QoL, but the effects on other parameters are not unequivocal. There were no data on the efficacy and safety of rhGH treatment in octogenarians with GHD.
Jitske Tiemensma, Alberto M Pereira, Johannes A Romijn, Elizabeth Broadbent, Nienke R Biermasz and Adrian A Kaptein
Context and objective
Patients with acromegaly have persistent complaints despite long-term biochemical control. Drawings can be used to assess patients' perceptions about their disease. We aimed to explore the utility of the drawing test and its relation to illness perceptions and quality of life (QoL) in patients after long-term remission of acromegaly.
A cross-sectional study was conducted to evaluate the utility of the drawing test.
A total of 50 patients after long-term remission (mean±s.e.m., 16±1.2 years) of acromegaly were included in this study. Patients completed the drawing test (two retrospective drawings of their body perception before acromegaly and during the active phase of acromegaly, and one drawing on the current condition after long-term remission), Illness Perception Questionnaire-Revised, Physical Symptom Checklist, EuroQoL-5D, and AcroQoL.
Patients perceived a dramatic change in body size during the active state of the disease compared with the healthy state before the awareness of acromegaly. Patients reported that their body did not completely return to the original proportions after long-term remission. In addition, larger drawings indicated more negative consequences (P<0.05), a higher score on emotional representations (P<0.05), and more perceived symptoms that were attributed to acromegaly (P<0.01). Larger drawings also indicated more impaired QoL, especially disease-specific QoL (all P<0.05).
There are strong correlations among the drawing test, illness perceptions, and QoL. The drawing test appears to be a novel and relatively easy tool to assess the perception of patients after long-term remission of acromegaly. The assessment of drawings may enable health care providers to appreciate the perceptions of patients with long-term remission of acromegaly, and enable discussion of symptoms and remission.
Janneke E Witteveen, Job Kievit, Hans Morreau, Johannes A Romijn and Neveen A T Hamdy
Cure rate for primary hyperparathyroidism (PHPT) is reported to be 94–100% 1 year after surgery, but recent data suggest recurrence in 4% of the patients 1–5 years post-operatively. The aim of our study was to establish the cure rate and its maintenance in the long-term after parathyroidectomy (PTx) in patients with sporadic PHPT.
Evaluation of recurrence in patients with sporadic hyperparathyroidism who underwent PTx 1–24 years prior to the study.
Patients and methods
We identified 111 patients who underwent initial PTx between 1984 and 2008, and had no MEN-1, MEN-2, or CaR mutation; parathyroid carcinoma; a history of lithium use; or renal failure. Thirty-eight patients were lost to follow-up or were unwilling or unable to participate in the study. Cure was defined as maintenance of normal serum calcium and parathyroid hormone concentrations 6 months after PTx.
Cure was achieved in 68 of 73 patients studied (93%) and was sustained in all for 6±5 years.
The cure rate of sporadic PHPT after initial surgery is 93%. When cure is achieved, this is sustained in 100% of the patients for up to 24 years post-operatively. Our data suggest that closer early follow-up is advocated in all patients undergoing PTx to definitively establish cure and to provide a safety net for those with residual gland pathology. The data do not support the need for long-term follow-up when cure is established 6 months after PTx.
Nienke R Biermasz, Neveen A T Hamdy, Alberto M Pereira, Johannes A Romijn and Ferdinand Roelfsema
Introduction: The anabolic actions of growth hormone (GH) are well documented. In acromegaly, the skeletal effects of chronic GH excess have been mainly addressed by evaluating bone mineral density (BMD). Most data were obtained in patients with active acromegaly, and apparently high or normal BMD was observed in the absence of hypogonadism. Data on BMD are not available after successful treatment of acromegaly. Whether the positive effect of GH excess on bone mass is maintained in the long term after clinical and biochemical cure of acromegaly remains to be established.
Patients and methods: In a cross-sectional study design, lumbar spine and femoral neck BMD was measured in 79 acromegalic patients cured or well controlled on octreotide treatment (45 male and 34 female patients; mean age 57±1 years). Successful treatment (by surgery, radiotherapy and/or use of octreotide) was defined as normal age-adjusted IGF-I. Mean time after biochemical remission was 10.2±7 years.
Results: Normal or increased BMD was observed at the femoral neck and lumbar spine in both men and women in remission after treatment for acromegaly. Similar results were obtained in patients in remission for 5 years or longer. Osteoporosis was present in 15% of the patients, with similar prevalence in men and women. There was no relationship between BMD and duration or severity of GH excess before treatment, gonadal status and presence of pituitary hormone deficiencies. Pituitary irradiation was a strong negative predictor of bone mass at the femoral neck. Long-term bone loss was observed only at the femoral neck.
Conclusion: Our data suggest that the anabolic effect of GH on trabecular and cortical bone remains demonstrable after remission of acromegaly, although it may not be maintained at cortical sites in the long term. In the present study, the lack of effect of gonadal status on BMD may be explained by the presence of only mild hypogonadism and by our policy of prompt hormonal replacement therapy for severe hypogonadism. The negative effect of pituitary irradiation on femoral neck BMD remains intriguing, although it is probably related to some degree of the diminished GH secretion frequently observed after this form of treatment.