What We Know about and What Is New in Primary Aldosteronism.

Primary aldosteronism (PA), a significant and curable cause of secondary hypertension, is seen in 5-10% of hypertensive patients, with its prevalence contingent upon the severity of the hypertension. The principal aetiologies of PA include bilateral idiopathic hypertrophy (BIH) and aldosterone-producing adenomas (APAs), while the less frequent causes include unilateral hyperplasia, familial hyperaldosteronism (FH) types I-IV, aldosterone-producing carcinoma, and ectopic aldosterone synthesis. This condition, characterised by excessive aldosterone secretion, leads to augmented sodium and water reabsorption alongside potassium loss, culminating in distinct clinical hallmarks: elevated aldosterone levels, suppressed renin levels, and hypertension. Notably, hypokalaemia is present in only 28% of patients with PA and is not a primary indicator. The association of PA with an escalated cardiovascular risk profile, independent of blood pressure levels, is notable. Patients with PA exhibit a heightened incidence of cardiovascular events compared to counterparts with essential hypertension, matched for age, sex, and blood pressure levels. Despite its prevalence, PA remains frequently undiagnosed, underscoring the imperative for enhanced screening protocols. The diagnostic process for PA entails a tripartite assessment: the aldosterone/renin ratio (ARR) as the initial screening tool, followed by confirmatory and subtyping tests. A positive ARR necessitates confirmatory testing to rule out false positives. Subtyping, achieved through computed tomography and adrenal vein sampling, aims to distinguish between unilateral and bilateral PA forms, guiding targeted therapeutic strategies. New radionuclide imaging may facilitate and accelerate such subtyping and localisation. For unilateral adrenal adenoma or hyperplasia, surgical intervention is optimal, whereas bilateral idiopathic hyperplasia warrants treatment with mineralocorticoid antagonists (MRAs). This review amalgamates established and emerging insights into the management of primary aldosteronism.

COVID-19-related thyroiditis: A novel disease entity?

The literature on COVID-19-related thyroid complications has accumulated over the past year or so as the pandemic has accelerated throughout the world. In particular, several recent case reports have been published describing a possible correlation between COVID-19 disease and subacute thyroiditis (SAT). In this review, we briefly present one of our own patients and review the current published literature in this area up to January 2021, including analyses of major series of thyroid function tests in patients with significant COVID-19 infection. We conclude that while the great majority of patients with severe COVID-19 infection may show manifestations of the sick euthyroid syndrome, clinicians should be aware of the possibility of SAT, especially in the early weeks and months following even mild COVID-19 infection.

Thyroid disease in the time of COVID-19.

The novel coronavirus disease COVID-19 is produced by SARS-CoV-2. WHO has declared COVID-19 as a public health emergency, with the most susceptible populations (requiring ventilation) being the elderly, pregnant women and people with associated co-morbidities including heart failure, uncontrolled diabetes, chronic obstructive pulmonary disease, asthma and cancer. However, such general guidance does not provide information regarding COVID-19 risks in patients with suffering from pre-existing thyroid problems, and furthermore, we do not know whether patients with COVID-19 (symptomatic or without symptoms), who have not previously had thyroid issues develop endocrine thyroid dysfunction after infection. The European Society for Endocrinology recently published a statement on COVID-19 and endocrine diseases (Endocrine, 2020); however, thyroid diseases were not mentioned specifically. We have therefore reviewed the current literature on thyroid diseases (excluding cancer) and COVID-19, including data from the previous coronavirus pandemic caused by the SARS-associated coronavirus (SARS-CoV), a member of the same family Coronaviridae leading to severe acute respiratory syndrome (SARS). At the moment there are no data suggesting that thyroid patients are at higher risk of COVID-19, but this requites further research and data analysis.

Colonic Cancer and Acromegaly.

Acromegaly results in a significantly increased morbidity and mortality due to cardiovascular and respiratory complications, as well as malignancies arising mainly from the colon. Furthermore, an increased lifetime risk of malignant transformation of pre-malignant colonic lesions relates to a worse overall prognosis from colorectal cancer, which is currently considered a major disease-related complication. In this review we provide some insight into colonic changes in this condition, summarize current knowledge and evidence on the use of colonoscopic screening in patients with acromegaly, and suggest a recommended screening protocol.

Aggressive and malignant pituitary tumours: state-of-the-art

Pituitary adenomas are unique in multiple ways. They are rarely malignant in terms of metastases; yet, they may be aggressive. Their cancerous potential is defined in a classic oncological way by the ability to metastasise, and therefore, it has been crucial to differentiate this process from aggressive behaviour, characterised as a particularly invasive and/or recurrent behaviour and resistance to common modalities of therapy. Recently, however, important changes have been introduced to the diagnosis and management of aggressive and malignant pituitary tumours including the 4th edition of the World Health Organization (WHO) classification for endocrine tumours (2017) as well as ESE Clinical Guidelines (2018), although an attempt to establish predictive and/or prognostic markers of clinical aggressiveness remains difficult. In this review, we focus on a group of pituitary tumours causing significant problems in clinical practice and requiring multidisciplinary input. We summarise updates in definitions of tumour invasiveness, aggressiveness and malignant transformation, as well as histological classification, and emphasise the new considerations regarding aggressive and malignant potential and its relationship to therapeutic strategies.

Molecular pathways of human adrenocortical carcinoma - translating cell signalling knowledge into diagnostic and treatment options.

Adrenocortical carcinoma is associated with a low cure rate and a high recurrence rate. The prognosis is poor, and at diagnosis 30-40% of cases are already metastatic. The current therapeutic options (surgical resection, followed by adjuvant mitotane treatment +/- chemotherapy) are limited, and the results remain unsatisfactory. Key molecular events that contribute to formation of adrenocortical cancer are IGF2 overexpression, TP53-inactivating mutations, and constitutive activation of the Wnt/b-catenin signalling pathway via activating mutations of the b-catenin gene. The underlying genetic causes of inherited tumour syndromes have provided insights into molecular pathogenesis. The increased occurrence of adrenocortical tumours in Li-Fraumeni and Beckwith-Wiedemann syndromes, and Carney complex, has highlighted the roles of specific susceptibility genes: TP53, IGF2, and PRKAR1A, respectively. Further studies have confirmed that these genes are also involved in sporadic tumour cases. Crucially, transcriptome-wide studies have determined the differences between malignant and benign adrenocortical tumours, providing potential diagnostic tools. In conclusion, enhancing our understanding of the molecular events of adrenocortical tumourigenesis, especially with regard to the signalling pathways that may be disrupted, will greatly contribute to improving a range of available diagnostic, prognostic, and treatment approaches. (Endokrynol Pol 2016; 67 (4): 427-440).

Adrenocortical adenomas with regression and myelolipomatous changes: urinary steroid profiling supports a distinctive benign neoplasm.

BACKGROUND: Adrenocortical neoplasms are classically divided into adenomas (ACA) and carcinomas (ACC). Heterogeneous appearance and greater size are criteria to suggest malignancy, along with the urinary steroid profile (USP). The presence of regression and myelolipomatous changes in adenomas (ACA-RML) can contribute to confusion with ACC and its USP remains unknown. OBJECTIVE: To evaluate the features of ACA-RML in comparison with other adrenocortical neoplasms. METHODS: We selected consecutive ACA (11), ACA-RML (7) and ACC (13) cases for which USP analysis was performed before surgery and tissue was available for histological evaluation (King's College Hospital, 2005-2012). Cases were classified according to WHO and Armed Forces Institute of Pathology criteria. USPs were obtained by gas chromatography/mass spectrometry. Total excretion of individual steroids and indices (sums and ratios chosen to reflect steroid metabolic activity) were compared between ACA-RML, ACA and ACC. RESULTS: In comparison with ACA, tumours in ACA-RML were significantly larger (8·5 ± 2·4 vs 3·5 ± 1·0, P = 0·002), presented in older patients and showed relatively higher incidence in males. Mitotic figure counts were significantly lower (0·39 ± 0·04 vs 0·93 ± 0·11 in ACA, P = 0·001) and revealed higher frequency of apoptotic cells (100% vs 9% in ACA, P = 0·001). The USP of ACA-RML showed no diagnostic features of ACC. No differences from ACA were significant, but there was a tendency towards lower dehydroepiandrosterone DHA and DHA metabolites. CONCLUSIONS: ACA-RML reveals distinctive histological features and lack of USP markers of malignancy. More cases of this rare tumour may confirm differences from ACA in steroid excretion. It is important to recognize ACA-RML because its size and heterogeneous appearance raise the possibility of ACC.

Adrenocortical cancer (ACC) - literature overview and own experience.

Adrenocortical carcinoma (ACC) is a malignant endocrine tumour. The rarity of the disease has stymied therapeutic development. Age distribution shows two peaks: the first and fifth decades of life, with children and women more frequently affected. Although 60-70% of ACCs are biochemically found to overproduce hormones, it is not clinically apparent in many cases. If present, endocrine symptoms include signs of hypercortisolaemia, virilisation or gynaecomastia. ACC carries a poor prognosis, and a cure can be achieved only by complete surgical resection. Mitotane is used both as an adjuvant treatment and also in non-operative patients. The role of radio- and chemotherapy is still controversial. The post-operative disease free survival is low and oscillates around 30% due to high tumour recurrence rate. The diagnosis is based on tumour histological assessment with the use of the Weiss score, however urinary steroid profiling (if available) can serve to differentiate between ACC and other adrenal tumours. Conventional prognostic markers in ACC include stage and grade of disease, and, as currently reported, the presence of hypercortisolaemia. Molecular analysis has had a significant impact on the understanding of the pathogenetic mechanism of ACC development and the evaluation of prognostic and predictive markers, among which alterations of the IGF system, the Wnt pathway, p53 and molecules involved in cancer cell invasion properties and angiogenesis seem to be very promising. We here summarise our own experience related to the management of ACC and present a literature overview. We have not aimed to include a detailed summary of the molecular alterations biology described in ACC, as this has already been addressed in other papers.

The molecular pathogenesis of corticotroph tumours.

BACKGROUND: The pathogenesis of tumour formation in the anterior pituitary including adrenocorticotropic hormone (ACTH)-secreting tumours has been intensively studied, but the causative mechanisms involved in pituitary cell transformation and tumourigenesis remain unclear. MATERIALS AND METHODS: We searched PubMed on any paper related with molecular pathology of pituitary corticotroph adenomas and have included to this review all relevant references published up to June 2011. RESULTS: Current studies increased our knowledge on the genetic basis of McCune-Albright syndrome (MAS), multiple endocrine neoplasia type 1 (MEN1), Carney complex (CNC), pituitary adenoma predisposition syndromes and tuberous sclerosis, but they have performed little to elucidate the causes of sporadic pituitary tumours including Cushing disease. DISCUSSION: The aim of this review was to focus on the most recently published advances in the molecular pathology of corticotroph adenomas, which are presented in the context of changes seen in all types of pituitary adenomas, as well as in terms of corticotrophin-releasing hormone/ACTH/cortisol-specific pathways. CONCLUSIONS: We would expect that over the next 5 years, more detailed analysis of inter-cellular communication pathways between pituitary cells, including the cadherins and integrins, and their interactions with other signalling pathways such as the ß-catenin cascade will help elucidate what exactly goes awry in the formation of a benign corticotroph adenoma. This should in turn predict novel forms of pharmacological tumour control.

Maximizing the accuracy of Inferior petrosal sinus sampling: validation of the use of Prolactin as a marker of pituitary venous effluent in the diagnosis of Cushing's disease.

OBJECTIVE: This study aimed to increase the accuracy of the inferior petrosal sinus sampling (IPSS) procedure and reduce the false-negative rate through the addition of prolactin as a marker of pituitary venous outflow as well as validate this adjunct to the test process. CONTEXT: Inferior petrosal sinus sampling (IPSS) for ACTH is the current gold standard test for the differentiation of pituitary Cushing's disease from the ectopic ACTH syndrome. Although early studies with IPSS reported a diagnostic sensitivity and specificity approaching 100%, additional experience has revealed a false-negative rate of 1-10%. This has been attributed to either technical problems with unsuccessful petrosal sinus catheterization or anomalous venous drainage of the pituitary. Previous studies have suggested that the measurement of other anterior pituitary hormones may be useful during IPSS as a guide to the effectiveness of cannulation and to improve the diagnostic accuracy of the procedure. DESIGN: We reviewed the data, in this retrospective cohort study, for all patients who had undergone IPSS for the investigation of ACTH-dependent hypercortisolism. PATIENTS: The study included 83 patients who underwent IPSS at St. Thomas's hospital between 2005 and 2010. MEASUREMENTS: Plasma ACTH and prolactin levels were measured both centrally and peripherally. The normalized ACTH/Prolactin inferior petrosal sinus/peripheral ratio was then calculated to assess the accuracy of the sampling procedure. RESULTS: A total of 83 patients with confirmed ACTH-dependent cortisol excess underwent investigation with IPSS during the study period. Sixty-seven patients initially had a positive IPSS result (i.e. a basal central/peripheral ACTH ratio >2·0 and >3·0 post-CRH). However, when the concurrent prolactin data were used, six patients were additionally found to have positive results suggestive of pituitary Cushing's. The Prolactin normalized ACTH IPS/Peripheral ratios were all >0·8 in patients with proven Cushing's disease, whereas they were all <0·6 in proven ectopic ACTH syndrome. The diagnosis was subsequently confirmed histologically in 72 of the patients. CONCLUSIONS: Using Prolactin as a concurrent index of pituitary venous effluent helps us recognize whether pituitary venous blood has been accurately sampled. Normalizing the IPS/peripheral ratios with Prolactin helps to improve the accuracy of the result and reduces the false-negative rate. With regards to the usefulness/validity of this test in clinical practice, it is relevant, reproducible and is easily adaptable from the existing diagnostic sequence.

The pathology of pituitary adenomas from a clinical perspective.

Pituitary adenomas present with a variety of clinical endocrine manifestations and arise in a sporadic setting or rarely as part of hereditary genetic syndromes. Molecular analysis of familial pituitary adenomas has provided significant insight into pituitary tumorigenesis. Some specific genes have been identified that predispose to pituitary neoplasia, but these are rarely involved in the pathogenesis of sporadic tumors. The number of identified genes involved in pituitary tumorigenesis is progressively increasing. The possible resulting mechanisms of action involve abnormalities in signal transduction pathways, cell cycle regulators, growth factors, chromosome stability and others. Further studies are needed to evaluate the clinical significance of genetic alterations and their implications for patient prognosis, as well as to identify targets for existing and new therapeutic options. The aim of this review is to focus on the molecular pathology of pituitary adenomas from a practical perspective and discuss the possible clinical implications which may relate to particular molecular alterations. We have summarised familial syndromes related to pituitary adenomas and considered the prognostic value of selected molecular alterations in these tumors.

Somatostatin receptor biology in neuroendocrine and pituitary tumours: part 1--molecular pathways.

Neuroendocrine tumours (NETs) may occur at many sites in the body although the majority occur within the gastroenteropancreatic axis. Non-gastroenteropancreatic NETs encompass phaeochromocytomas and paragangliomas, medullary thyroid carcinoma, anterior pituitary tumour, broncho-pulmonary NETs and parathyroid tumours. Like most endocrine tumours, NETs also express somatostatin (SST) receptors (subtypes 1-5) whose ligand SST is known to inhibit endocrine and exocrine secretions and have anti-tumour effects. In the light of this knowledge, the idea of using SST analogues in the treatment of NETs has become increasingly popular and new studies have centred upon the development of new SST analogues. We attempt to review SST receptor (SSTR) biology primarily in neuroendocrine tissues, focusing on pituitary tumours. A full data search was performed through PubMed over the years 2000-2009 with keywords 'somatostatin, molecular biology, somatostatin receptors, somatostatin signalling, NET, pituitary' and all relevant publications have been included, together with selected publications prior to that date. SSTR signalling in non-neuroendocrine solid tumours is beyond the scope of this review. SST is a potent anti-proliferative and anti-secretory agent for some NETs. The successful therapeutic use of SST analogues in the treatment of these tumours depends on a thorough understanding of the diverse effects of SSTR subtypes in different tissues and cell types. Further studies will focus on critical points of SSTR biology such as homo- and heterodimerization of SSTRs and the differences between post-receptor signalling pathways of SSTR subtypes.

The pathophysiology of pituitary adenomas.

The pathogenesis of tumour formation in the anterior pituitary has been intensively studied, but the causative mechanisms involved in pituitary cell transformation and tumourigenesis remain elusive. Most pituitary tumours are sporadic, but some arise as a component of genetic syndromes such as the McCune-Albright syndrome, multiple endocrine neoplasia type 1, Carney complex and, the most recently described, a MEN1-like phenotype (MEN4) and pituitary adenoma predisposition syndromes. Some specific genes have been identified that predispose to pituitary neoplasia (GNAS, MEN1, PRKAR1A, CDKN1B and AIP), but these are rarely involved in the pathogenesis of sporadic tumours. Mutations of tumour suppressor genes or oncogenes, as seen in more common cancers, do not seem to play an important role in the great majority of pituitary adenomas. The pituitary tumour transforming gene (PTTG; securin) was the first transforming gene found to be highly expressed in pituitary tumour cells, and seems to play an important role in the process of oncogenesis. Many tumour suppressor genes, especially those involved in the regulation of the cell cycle, are under-expressed, most often by epigenetic modulation - usually promoter hypermethylation - but the regulator of these co-ordinated series of methylations is also unclear. Cell signalling abnormalities have been identified in pituitary tumours, but their genetic basis is unknown. Both Raf/MEK/ERK and PI3K/Akt/mTOR pathways are over-expressed and/or over-activated in pituitary tumours: these pathways share a common root, including initial activation related to the tyrosine kinase receptor, and we speculate that a change to these receptors or their relationship to membrane matrix-related proteins may be an early event in pituitary tumourigenesis.

Prognostic value of the apoptotic index analysed jointly with selected cell cycle regulators and proliferation markers in non-small cell lung cancer.

In a previous small series of surgically treated non-small cell lung cancer patients (NSCLC), we found that higher apoptotic index (AI) negatively influenced survival (Dworakowska D, Jassem E, Jassem J, Karmolinski A, Dworakowski R, Wirth T, et al. Clinical significance of apoptotic index in non-small cell lung cancer: correlation with p53, mdm2, pRb and p21WAF1/CIP1 protein expression. J Cancer Res Clin Oncol 2005; 131:617-623.). In this study we attempted to verify our previous finding in larger group of 170 NSCLC cases, additionally correlating AI to selected cell cycle regulators as well as a proliferation marker. Apoptosis was assessed with the use of the TUNEL technique, whereas the expression of p53, pRb, mdm2, p21(WAF1/CIP1), cyclin D1 and PCNA were assessed immunohistochemically. The mean and the median AI was 12 and 8, respectively. The expression of p53, pRb, mdm2, p21(WAF1/CIP1) proteins and cyclin D1 was found in 47%, 71%, 37%, 65% and 40% of cases, respectively. The mean and the median PCNA labeling index (PCNA LI) was 34 and 35, respectively. AI was not correlated with any patient characteristic or other tumor markers. In uni- and multivariate analysis AI, analysed separately or jointly with cell cycle regulators and PCNA LI, did not influence disease-free or over-all survival. However, patients with "very high AI/very high PCNA LI" had a particularly poor prognosis (P=0.001). Patients with "very low AI/negative pRb" phenotype survived for a shorter time in comparison to others (P=0.04). In addition, patients with the highest PCNA LI had a worse outcome in comparison to patients with the lowest PCNA LI (P=0.04), especially those with concomitant p53 protein expression (P=0.026) or lacking pRb protein expression (P=0.04). This study demonstrates that joint analysis of several factors involved in apoptosis, proliferation and cell cycle regulation, but not AI alone, might provide additional prognostic information in NSCLC patients.

Are neuroendocrine tumours a feature of tuberous sclerosis? A systematic review.

Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disorder characterised by the development of multiple hamartomas in numerous organs. It is caused by mutations of two tumour suppressor genes, TSC1 on chromosome 9q34 and TSC2 on chromosome 16p13.3, which encode for hamartin and tuberin respectively. The interaction between these two proteins, the tuberin-hamartin complex, has been shown to be critical to multiple intracellular signalling pathways, especially those controlling cell growth and proliferation. TSC may affect skin, central nervous system, kidneys, heart, eyes, blood vessels, lung, bone and gastrointestinal tract. Small series and case reports have documented that in tuberous sclerosis patients many endocrine system alterations might occur, affecting the function of the pituitary, parathyroid and other neuroendocrine tissue. There have been scattered reports of the involvement of such tissue in the pathological process of TSC, but no systematic review as to whether this is a true association. We have therefore systematically assessed all available published literature in this area. We conclude that there may be an association with pituitary and parathyroid tumours, and two recent descriptions of Cushing's disease are especially intriguing. However, the evidence seems more firm in the case of islet cell tumours, particularly insulinomas. As these latter may cause changes in mental state that may be confused with the cerebral manifestations of TSC per se, it is particularly important for physicians working with these patients to be aware of the putative and indeed likely association.

Multimodality palliative treatment of (111)In-pentetreotide negative/(123)I-MIBG positive metastatic carcinoid - a case report.

Patients with carcinoid tumours frequently present with metastatic disease. There are only a few therapeutic options for these patients, and the main goal of palliative treatment is to reduce symptoms and thus to improve quality of life. Current therapy includes surgical resection, hepatic artery embolisation, chemotherapy and somatostatin analogue treatment; however, all these options have limitations. It seems probable that therapeutic modalities based on radiopharmaceuticals may provide better therapy, not only in relation to symptom reduction but may also improve patient survival. In this case report we present a 46-year-old woman with a symptomatic carcinoid, who at the time of diagnosis had liver and abdominal lymph node metastases, the primary tumour being located in the terminal ileum. (111)In-pentetreotide scanning was negative, whereas (123)I-MIBG scanning showed high avidity in the tumour tissue. After right hemicolectomy, two courses of (131)I-MIBG treatment were given (12.95 GBq and 12 GBq, respectively). After the second dose of (131)I-MIBG temporary pancytopenia was present. Octreotide therapy was given empirically only for a short time and was stopped because of drug intolerance. The patient underwent tricuspid and pulmonary valve replacement because of her carcinoid heart disease, followed by two courses of embolisation of liver metastases. While (131)I-MIBG therapy reduced the patient's symptoms of flushing and diarrhoea, there has not yet been any effect on tumour response or 5-HIAA production. This case illustrates the multimodality and multidisciplinary approach to such patients.