Paweł Gut

Chromogranin A – unspecific neuroendocrine marker. Clinical utility and potential diagnostic pitfalls

Chromogranin A, despite a number of limitations, is still the most valuable marker of neuroendocrine tumors (NETs). Granins belong to the family of acidic proteins that constitute a major component of secretory granules of various endocrine and neuroendocrine cells, which are components of both the classical endocrine glands and the diffuse neuroendocrine system. These cells are a potential source of transformation into neuroendocrine tumors. The awareness of potential causes influencing the false results of its concentrations simplifies diagnosis and treatment. One of the disadvantages of this marker is its non-specificity and the existence of a number of pathological processes leading to an increase in its concentration, which often results in confusion and diagnostic difficulties. The molecular structure is characterized by a number of sites susceptible to the proteolytic activity of enzymes, resulting in the formation of a number of biologically active peptides. Presumably they act as precursors of active proteins. Chromogranin expression correlates with the amount of secretory vesicles in neuroendocrine cells. The peptide chain during biochemical changes becomes a precursor of biologically active proteins with a wide range of activities. There are a number of commercially available kits for the determination of chromogranin A, which differ in methodology. We present the evaluation of chromogranin A as a marker of neuroendocrine tumors in clinical practice and the possible factors that may affect the outcome of its concentration.

Polish experience in Peptide receptor radionuclide therapy.

PATIENTS AND METHODS During the period from April 2004 to December 2010, 358 patients underwent peptide receptor radionuclide therapy (PRRT) ((90)Y-DOTATATE, (177)Lu-DOTATATE, and (90)Y/(177)Lu-DOTATATE) in Poland. RESULTS The majority of patients underwent (90)Y-DOTATATE therapy (n = 177) with progression-free survival (PFS)/time to progression (TTP) of 17-44 months and overall survival (OS) of 22-34.2 months. Twelve-month follow-up revealed stable disease (SD) in 46-60%, disease regression (RD) in 16-35%, disease progression (PD) in 7-17%, and complete remission (CR) in 3% of patients. In patients treated with (90)Y/(177)Lu-DOTATATE (n = 44), PFS/TTP was 24.2-28.3 months and OS was 49.8-52.8 months. Twelve-month follow-up showed SD in 62-70%, RD in 15-20%, and PD in 10-12% of patients. The treatment was well tolerated. No severe adverse events occurred. Grade 3 toxicity [in leucocytes (WBC) and thrombocytes (PLT)] was seen in 6-20% of patients treated with (90)Y-DOTATATE. In that group, renal toxicity grade 3 was seen in 5-12% and grade 4 in 3-8%. In patients treated with tandem therapy with (90)Y/(177)Lu-DOTATATE or (177)Lu-DOTATATE alone, hematological and renal toxicity grade 3 or 4 was not observed. CONCLUSIONS The results indicate that PRRT with the procedures and isotopes used is an effective and safe therapy option for patients with metastatic or inoperable neuroendocrine tumors (NETs). Our results suggest that tandem therapy with (90)Y/(177)Lu-DOTATATE provides longer overall survival than single-isotope treatment. Hematological toxicity was rare in all treated patients. Renal toxicity grade 3 and 4 was observed only in the group treated with (90)Y-DOTATATE.

Familial syndromes associated with neuroendocrine tumours.

Neuroendocrine tumours may be associated with familial syndromes. At least eight inherited syndromes predisposing to endocrine neoplasia have been identified. Two of these are considered to be major factors predisposing to benign and malignant endocrine tumours, designated multiple endocrine neoplasia type 1 and type 2 (MEN1 and MEN2). Five other autosomal dominant diseases show more heterogeneous clinical patterns, such as the Carney complex, hyperparathyroidism-jaw tumour syndrome, Von Hippel-Lindau syndrome (VHL), neurofibromatosis type 1 (NF1) and tuberous sclerosis. The molecular and cellular interactions underlying the development of most endocrine cells and related organs represent one of the more complex pathways not yet to be deciphered. Almost all endocrine cells are derived from the endoderm and neuroectoderm. It is suggested that within the first few weeks of human development there are complex interactions between, firstly, the major genes involved in the initiation of progenitor-cell differentiation, secondly, factors secreted by the surrounding mesenchyme, and thirdly, a series of genes controlling cell differentiation, proliferation and migration. Together these represent a formula for the harmonious development of endocrine glands and tissue.

Dysfunction of the thyroid gland during amiodarone therapy: a study of 297 cases

Aim This study aims to explore and compare the efficacy of radioiodine treatment (RIT) in hyperthyroid and euthyroid patients who have been treated with amiodarone (AM) in the past or are currently undergoing AM treatment. Clinical observation of a group of patients with amiodarone-induced hypothyroidism during a 12-month follow-up period was used for comparison. Design This was a observational, two-centered study. Patients were assessed at baseline and at 2 months, 6 months, 8 months, and 12 months after RIT. Patients Group A: At baseline (61 males [M] and 17 females [F], mean age 50±19 years), there were 78 euthyroid patients with cardiac arrhythmias, who were treated with AM and developed amiodarone-induced thyrotoxicosis, and currently require retreatment with AM. Group B: Hyperthyroid patients (92 M and 26 F, mean age 72±11.8 years) after AM therapy in the past. Group C: Hyperthyroid patients (66 M and 13 F, mean age 63.9±13.2 years) currently treated by AM. Group D: Hypothyroid patients (6 M and 16 F, mean age 61.4±10.4 years) after AM therapy. The patients from Groups A, B, and C were retreated with AM after ~3–6 weeks of RIT. Results In Group A, after 12 months of RIT therapy, recurrent thyrotoxicosis was observed in six (7.7%) cases, and persistent hypothyroidism was diagnosed in 42 (53.8%) cases. In Group B, hyperthyroidism occurring during treatment with AM was found in 40 (33.9%) patients, and permanent hypothyroidism was observed in eleven (12.5%) cases. After annual follow-up in Group C, nine (11.4%) patients were diagnosed with hypothyroidism, while 27 (34.1%) patients were diagnosed with hyperthyroidism. In Group D, all patients had permanent hypothyroidism and when the concentration of serum thyroid-stimulating hormone was >10 µIU/mL, l-thyroxine was applied. Conclusion Our study showed that radioiodine administration is advisable in certain circumstances, even in euthyroid patients. It allows for continuation of further long-term AM treatment. Additionally, RIT allows for the reintroduction of AM therapy that was previously terminated. Hence, it can help control life-threatening tachyarrhythmias and decrease episodes of thyrotoxicosis.

Management of the hormonal syndrome of neuroendocrine tumors

Gastroenteropancreatic neuroendocrine tumors (GEP/NET) are unusual and rare neoplasms that present many clinical challenges. They characteristically synthesize store and secrete a variety of peptides and neuroamines which can lead to the development of distinct clinical syndrome, however many are clinically silent until late presentation with mass effects. Management strategies include surgery cure and cytoreduction with the use of somatostatin analogues. Somatostatin have a broad range of biological actions that include inhibition of exocrine and endocrine secretions, gut motility, cell proliferation, cell survival and angiogenesis. Five somatostatin receptors (SSTR1-SSTR5) have been cloned and characterized. Somatostatin analogues include octreotide and lanreotide are effective medical tools in the treatment and present selectivity for SSTR2 and SSTR5. During treatment is seen disapperance of flushing, normalization of bowel movements and reduction of serotonin and 5-hydroxyindole acetic acid (5-HIAA) secretion. Telotristat represents a novel approach by specifically inhibiting serotonin synthesis and as such, is a promising potential new treatment for patients with carcinoid syndrome. To pancreatic functionig neuroendocrine tumors belongs insulinoma, gastrinoma, glucagonoma and VIP-oma. Medical management in patients with insulinoma include diazoxide which suppresses insulin release. Also mTOR inhibitors may inhibit insulin secretion. Treatment of gastrinoma include both proton pump inhibitors (PPIs) and histamine H2 – receptor antagonists. In patients with glucagonomas hyperglycaemia can be controlled using insulin and oral blood glucose lowering drugs. In malignant glucagonomas smatostatin analogues are effective in controlling necrolytic migratory erythemia. Severe cases of the VIP-oma syndrome require supplementation of fluid losses. Octreotide reduce tumoral VIP secretion and control secretory diarrhoea.

Growth hormone-secreting macroadenoma of the pituitary gland successfully treated with the radiolabeled somatostatin analog (90)Y-DOTATATE: case report.

Pituitary tumors causing acromegaly are usually macroadenomas at the time of diagnosis, and they can grow aggressively, infiltrating surrounding tissues. Difficulty in achieving complete tumor removal at surgery can lead toward a strong tendency for recurrence, making it necessary to consider a means of treatment other than those currently used such as somatostatin analogs (SSAs), growth hormone (GH) receptor antagonist, surgical removal, and radiotherapy. The purpose of this paper is to describe a patient diagnosed with an aggressive, giant GH-secreting tumor refractory to medical therapy but ultimately treated with the radiolabeled somatostatin analog (90)Y-DOTATATE. A 26-year-old male with an invasive macroadenoma of the pituitary gland (5.6 × 2.5 × 3.6 cm) and biochemically confirmed acromegaly underwent 2 partial tumor resections: the first used the transsphenoidal approach and the second used the transcranial method. The patient received SSAs pre- and postoperatively. Because of the progression in pituitary tumor size, he underwent classic irradiation of the tumor (50 Gy). One and a half years later, the patient presented with clinically and biochemically active disease, and the tumor size was still 52 mm in diameter (height). Two neurosurgeons disqualified him from further surgical procedures. After confirming the presence of somatostatin receptors in the pituitary tumor by using (68)Ga-DOTATATE PET/CT, we treated the patient 4 times with an SSA bound with (90)Y-DOTATATE. After this treatment, the patient attained partial biochemical remission and a reduction in the tumor mass for the first time. Treatment with an SSA bound with (90)Y-DOTATATE may be a promising option for some aggressive GH-secreting pituitary adenomas when other methods have failed.

Contemporary methods of therapy and follow-up of neuroendocrine tumours of the gastrointestinal tract and the pancreas.

The growing interest in neuroendocrine tumours is due to the dynamic growth of detection of this type of cancer. Neuroendocrine tumours (neuroendocrine neoplasms – NENs / neuroendocrine tumours – NETs) derive from glands, groups of endocrine cells and diffuse neuroendocrine system cells. Mainly they derive from the gastrointestinal tract (gastroenteropancreatic-neuroendocrine tumours – GEP-NETs). Currently the modified WHO classification from 2010 is widely used. An important element in the choice of treatment is histological maturity based on mitotic activity and on assessment of proliferation activity (Ki-67). The treatment of choice is surgery. In most cases, complete surgical removal is impossible because of the advanced staging at the time of diagnosis. In well-differentiated neoplasms where the expression of somatostatin receptors is expected, patients are qualified for somatostatin analogues therapy. Poorly differentiated lesions are qualified for chemotherapy. In the guidelines of ENETS (European Neuroendocrine Tumor Society) from 2007 the rules concerning monitoring depending on the WHO classification were specified.

Delayed diagnosis of primary hyperparathyroidism in a patient with osteoclastoma.

Primary hyperparathyroidism (HPTo) nowadays is most often recognized incidentally in the asymptomatic period as a result of biochemical screening or evaluation of low bone mass. Classical manifestations of the disease are present in about 15-20% of patients. We present the case of a 28-year-old male patient who had been treated for two years for osteoclastoma of the proximal tibia, first by intralesional curettage with cement filling followed by bone grafting, and finally with a reconstructive arthroplasty of the knee joint. The patient had been consulted in different medical centers by at least 14 doctors representing 9 different specialties, but the correct diagnosis of HPTo had not been made, although classic manifestations of the disease had been present for 5-6 years. This suggests that a diagnosis of HPTo is difficult nowadays. Therefore, determination of serum calcium concentration and other markers of calcium and phosphate metabolism should be obligatory in patients with bone lesions.

Adrenal hypoplasia congenita – an uncommon reason of primary adrenal insufficiency

Adrenal hypoplasia congenita (AHC) is a rare inherited condition characterised by primary adrenal failure and hypogonadotropic hypogonadism. Most cases arise from mutations in the NR0B1 gene (Xp21.3), which encodes an orphan nuclear receptor DAX-1. A 20-year-old patient was recently diagnosed with AHC. Adrenal failure had been recognized and treated since his infancy. During adolescence, gradual decrease in growth velocity and low body mass were noted. Lack of puberty and skeletal immaturity were observed. Serum DHEA-S and testosterone were undetectable. Low gonadotropin levels failed to rise after stimulation. Neither dysfunction of the somatotropic nor pituitary-thyroid axis was found and no hypothalamo-pituitary pathology was visible on MRI. Androgen replacement therapy induced the development of secondary sexual characteristics, remarkably improved patients growth and advanced his bone age. NR0B1 mutation screening revealed nucleotide transversion C>A, resulting in premature stop codon (Y399X). Same mutation was previously identified in a Scottish family, however, phenotypic differences suggest the role of additional factors modifying the disease course. Although it does not change therapeutic strategy, accurate molecular diagnosis allows genetic counselling in family members. Autoimmunity remains the major cause of adrenal failure; however, other rare conditions should always be considered.

Diagnostic value of selected biochemical markers in the detection of recurrence of medullary thyroid cancer — comparison of calcitonin, procalcitonin, chromogranin A, and carcinoembryonic antigen

INTRODUCTION Medullary thyroid cancer (MTC) is a malignancy of the thyroid gland, which derives from parafollicular C cells. Periodic measurement of biochemical markers of MTC remains a crucial part of patient follow-up and disease monitoring. The aim of the study was to compare the diagnostic value of four selected markers - calcitonin (Ct), procalcitonin (PCT), chromogranin A (CgA), and carcinoembryonic antigen (CEA). MATERIAL AND METHODS Patients with histopathologically confirmed MTC hospitalised in a single department between January 2015 and December 2015 were included in the study. Patients were subdivided into two groups: a remission group and an active disease group, based upon serum markers of MTC and imaging. Levels of Ct, PCT, CgA, and CEA were compared between the groups. RESULTS Forty-four patients were included; 20 patients presented active disease and 24 were in remission. All patients with active disease had Ct exceeding the upper limit of normal range (10 pg/mL) - for that threshold the sensitivity was 100.0% and the specificity was 73.9%; for the best-fit threshold of 121.0 pg/mL the specificity was 95.8% with sensitivity 100.0%. There was significant correlation between Ct and PCT - p < 0.000001, r = 0.93. All patients with active disease exceeded the upper limit of the normal range (0.5 ng/mL) - for that threshold the sensitivity was 100.0% and the specificity was 83.3%; for the best-fit threshold of 0.95 ng/mL the specificity was 95.8% with sensitivity 100.0%. In case of CEA for the best-fit threshold of 12.66 ng/mL the specificity was 100.0% with sensitivity 57.9%; for CgA the best-fit threshold was 75.66 ng/mL with specificity 83.3% and sensitivity 75.0%. CONCLUSIONS Our study confirms that PCT can be considered as an equivalent alternative for measurement of calcitonin. On the other hand, it is also worth noting that MTC can be a rare cause of very high levels of PTC not resulting from infectious diseases. The diagnostic value of CEA and chromogranin A is much lower and can be within the normal range even in patients with advanced, metastatic MTC. They should be used only as accessory markers.