The association of testosterone with sarcopenia and frailty in chronic liver disease.

BACKGROUND: Testosterone is an important anabolic hormone responsible for maintaining body composition and muscle mass and circulates mostly albumin-bound, or sex hormone binding globulin (SHBG)-bound or free in the plasma. Of these fractions, the latter is bioactive and exerts the androgenic effects on male population. Liver cirrhosis, the advanced stage of any chronic liver disease characterized by permanent distortions to the hepatic architecture, disrupts the hypothalamic-pituitary-gonadal axis, leading to diminished levels of free testosterone and hypogonadism. METHODS: We retrieved the PubMed database to provide a synopsis of testosterone's physiology and action and summarize the effect of sarcopenia in pre-cirrhotic and cirrhotic patients. Moreover, we scoped to provide insight into the relationship of testosterone levels with sarcopenia, frailty and survival in cirrhotic and non-cirrhotic population as well as to discuss the efficacy of exogenous testosterone supplementation on the anthropometric parameters and survival of those patients. RESULTS: Low testosterone levels have been associated with sarcopenia, reduced body lean mass, decreased bone mineral density and frailty, thus leading to increased morbidity and mortality especially among cirrhotic patients. Furthermore, exogenous testosterone administration significantly ameliorated body composition on patients with chronic hepatic disease, without significant adverse effects. However, the current literature does not suggest any significant effect on survival of those patients. Moreover, the long-term safety of testosterone use remains an open question. CONCLUSION: Low serum testosterone is strongly correlated with sarcopenia, frailty, higher rate of hepatic decompensation and mortality. Nonetheless, exogenous supplementation of testosterone did not ameliorate the liver-related outcomes and complications.

High Filamin a Expression in Adrenocortical Carcinomas Is Associated with a Favourable Tumour Behaviour: A European Multicentric Study.

The insulin-like growth factor 2 (IGF2) promotes cell growth by overactivating the IGF system in an autocrine loop in adrenocortical carcinomas (ACCs). The cytoskeleton protein filamin A (FLNA) acts as a repressor of IGF2 mitogenic signalling in ACC cells. The aims of this study were to test FLNA expression by immunohistochemistry in 119 ACCs and 26 adrenocortical adenomas (ACAs) and to evaluate its relationship with clinicopathological features and outcome in ACCs. We found that 71.4% of ACCs did not express FLNA, whereas FLNA absence was a rare event in ACAs (15.4%, p < 0.001 vs. ACCs). In addition, the expression of FLNA was associated with a less aggressive tumour behaviour in ACCs. Indeed, the subgroup of ACCs with high FLNA showed a lower ENSAT stage, Weiss score, and S-GRAS score compared to ACCs with low FLNA expression (p < 0.05). Moreover, patients with high FLNA had a longer overall survival than those with low FLNA (p < 0.05). In conclusion, our data suggest that FLNA may represent a "protective" factor in ACCs, and the integration of FLNA immunohistochemical expression in ACC tissues along with other clinical and molecular markers could be helpful to improve diagnostic accuracy and prognosis prediction in ACCs.

Adrenocortical Cancer: A 20-Year Experience of a Single Referral Center in Prognosis and Outcomes.

Adrenocortical carcinoma (ACC) is a rare but very aggressive endocrine malignancy with poor survival. Histopathology is important for diagnosis, while in some cases immunohistochemical markers and gene profiling of the resected tumor may be superior to current staging systems to determine prognosis. We aimed to present the 20-year experience at a tertiary hospital in patients with ACCs and correlate the immunohistochemical characteristics of ACCs with the clinical and morphological characteristics of the tumors and the survival of the patients. Forty-five patients with ACC were included in the study. All the resections were R0. The tumor size and weight, the disease stage (ENSAT classification), Weiss score and Helsinki score were examined along with immunohistochemical expression of inhibin-A, melan A, calretinin, Ki67, synaptophysin, p53, vimentin, CKAE1/AE3. The male to female ratio was 1:1.37. The median age at diagnosis was 55.5 years (IQR 19-77). The median size of ACCs was 9 cm (IQR 3.5-22 cm) and the median weight 127 g (IQR 18-1400 g). The median follow up period was 18 months (IQR 1-96). Ki67 varied from<1% to 75% (median: 16.4%). The expression of melan-A and lower expression of Ki-67 (≤4) were independently associated with longer OS time (p=0.01 and p=0.04, respectively). In multivariable analysis, tumor volume>400 cm3 (p=0.046), Weiss score>5 (p=0.007) and overexpression of p53 (p=0.036) were independent risk factors for shorter survival. Adrenocortical carcinoma is a rare and very aggressive endocrine malignancy. The most important factors that determine long-term prognosis of ACC are the disease stage at diagnosis, the Weiss score, and the Ki67 index. Immunohistochemical markers such as melan A could also serve as prognostic factors.

Hypophysitis (Including IgG4 and Immunotherapy).

Hypophysitis is characterized by inflammation of the pituitary gland that can be primary (PH) or secondary (SH) to other diseases or following drug administration. It may also be classified according to anatomical and histopathological criteria, leading to variable degrees of hypopituitarism and/or compressive symptoms to nearby structures. There has recently been an increase in the number of hypophysitis cases, raising the interest on the spectrum of its pathogenesis, clinical, biochemical/endocrinological, and imaging features. However, the use of conventional biomarkers, including currently utilized pituitary autoantibodies, has relatively limited diagnostic accuracy. Lymphocytic hypophysitis (LH) is the commonest cause of PH, whereas IgG4-related hypophysitis is increasingly being recognized. Histiocytosis and granulomatous diseases are the most frequent causes of SH, although infections and lymphoma have also been reported. The increasing use of immune checkpoint inhibitors in oncology is associated with a high incidence of hypophysitis, providing further understanding of its pathogenesis. Hypophysitis can occur silently and be easily missed, potentially leading to substantial morbidity or mortality due to adrenal insufficiency, requiring a high index of clinical suspicion and timely initiation of appropriate treatment. In most cases of LH or drug-induced hypophysitis, active surveillance along with replacement of established hormonal deficiencies is needed. In the presence of compressive and/or evolving symptoms, treatment with glucocorticoids either alone or in combination with other immunosuppressive agents can be used. Surgical decompression is reserved for nonresponsive cases with threatened vital structures. Timely diagnosis and intervention are important to minimize disease-related morbidity and mortality. We aimed to review current concepts and recent developments in the pathogenesis, diagnosis, and management of hypophysitis.

Lung Metastases in Patients with Well-Differentiated Gastroenteropancreatic Neuroendocrine Neoplasms: An Appraisal of the Validity of Thoracic Imaging Surveillance.

BACKGROUND/AIMS: To evaluate the impact of lung metastases (LM) on overall survival (OS) in well-differentiated (WD) stage IV gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) patients along with developing surveillance strategies for thoracic imaging. METHODS: Thirty-four patients with LM, from 3 centres, were identified (22 small intestine/12 pancreatic; 17 grade 1/15 grade 2/2 of unknown grade). For comparison, we used 106 stage IV WD, grade 1 and 2 GEP-NEN patients with metastatic disease confined in the abdomen. RESULTS: LM prevalence was 4.9% (34/692). Eleven patients (32%) presented with synchronous LM whereas 23 (68%) developed metachronous LM at a median of 25 months (range 1-150 months). Patients with metachronous LM had already established liver and/or para-aortic lymph node metastases. Eighteen of 23 patients (78%) with metachronous LM exhibited concomitant progression in the abdomen. Median OS of WD GEP-NEN patients with LM was shorter than for those with stage IV disease without extra-abdominal metastases (56 [95% CI 40.6-71.6] vs. 122.7 [95% CI 70.7-174.8] months; log-rank p = 0.001). Among patients with progressive stage IV disease, the subset of patients with LM exhibited shorter OS (log-rank p = 0.005). LM were also confirmed as an independent prognostic factor for survival in multivariable analysis (HR 0.18; 95% CI 0.07-0.45; p < 0.0001). CONCLUSION: LM, although relatively rare in patients with WD stage IV GEP-NENs, may impact patients' outcome. The development of metachronous LM is associated with concomitant disease progression in established abdominal metastases in most patients. These patient-related parameters could be utilized for a stratified surveillance approach, mainly reserving thoracic imaging for GEP-NEN patients with progressive disease in the abdomen.

Activity and Safety of Standard and Prolonged Capecitabine/Temozolomide Administration in Patients with Advanced Neuroendocrine Neoplasms.

BACKGROUND: Capecitabine and temozolomide combination (CAPTEM) is associated with high response rates in patients with advanced neuroendocrine neoplasms (NENs). We evaluated the real-world activity and safety of CAPTEM from 3 NEN centers. METHODS: Clinicopathological characteristics and outcomes of patients treated with CAPTEM for bulky or progressive disease (PD) were retrospectively analyzed. -Results: Seventy-nine patients with gastroenteropancreatic (grades 1-2 [n = 38], grade 3 [n = 24]) and lung/thymic (n = 17) NENs were included. Median treatment duration was 12.1 months (range 0.6-55.6). Overall, partial responses (PRs) occurred in 23 (29.1%), stable (SD) in 24 (30.4%), and PD in 28 (35.4%) patients. Median progression-free survival (PFS) and overall survival (OS) were 10.1 (6-14.2) and 102.9 months (43.3-162.5), respectively. On univariate analysis, NENs naive to chemotherapy and low Ki67 were associated with favorable responses (partial response [PR] + SD; p = 0.011 and 0.045), PFS (p < 0.0001 and 0.002) and OS (p = 0.005 and 0.001). Primary site (pancreas and lung/thymus) was also a significant prognostic factor for PFS (p < 0.0001) and OS (p < 0.0001). On multivariate analysis, gastrointestinal and unknown primary NENs (hazard ratio [HR] 0.3, 95% CI 0.1-0.8, p = 0.009 and p = 0.018) and prior surgery (HR 2.4, 95% CI 11-4.9, p = 0.021) were independent prognostic factors for PFS. Ki-67 was a poor predictor for favorable response in receiver operating characteristic analysis (area under the curve 0.678). Safety analysis of CAPTEM indicated rare events of serious (grades 3-4) toxicities (n = 4) and low discontinuation rates (n = 8) even in patients with prolonged administration (>12 months). CONCLUSIONS: CAPTEM treatment can be an effective and safe treatment even after prolonged administration for patients with NENs of various sites and Ki67 labeling index, associated with significant favorable responses and PFS.

Diagnosis, Pathophysiology and Management of Hypercalcemia in Malignancy: A Review of the Literature.

Hypercalcemia of malignancy is the most common life-threatening metabolic disorder in patients with advanced stage cancers and is a sign of poor prognosis. It usually presents with markedly elevated calcium level and is severely symptomatic. It is associated with hematological malignancies, such as multiple myeloma, non-Hodgkin lymphoma, leukemias and solid cancers, particularly renal and breast carcinomas as well as squamous cell carcinomas of any organ. Several mechanisms have been implicated in the development of hypercalcemia of malignancy amongst them the osteolytic related hypercalcemia, parathyroid hormone-related peptide (PTHrP) mediated hypercalcemia, extrarenal 1,25 dixydroxyvitamin D (calcitriol) mediated hypercalcemia and parathyroid hormone (PTH) related hypercalcemia either ectopic in origin or in patients with parathyroid carcinoma. Clinical history and and physical examination could point towards the correct diagnosis confirmed by the above-mentioned biochemical mediators of hypercalcemia. Early diagnosis and treatment lowering calcium levels in the blood can improve symptoms and the quality of life of these patients and avoid delays for further antitumor therapy.

Magnetic Resonance Imaging or Endoscopic Ultrasonography for Detection and Surveillance of Pancreatic Neuroendocrine Neoplasms in Patients with Multiple Endocrine Neoplasia Type 1?

Our aim was to compare the clinical utility of Magnetic Resonance Imaging (MRI) and Endoscopic Ultrasonography (EUS) in identifying Pancreatic Neurondocrine Neoplasms (PanNENs) and monitoring size alterations in Multiple Endocrine Neoplasia type 1 (MEN1) patients. Thirty-one MEN1 patients with PanNENs and concurrent screening by EUS and abdominal MRI were included and 129 pancreatic lesions were detected in total. MRI detected fewer lesions than EUS (n=73 vs. 110, p=0.006). MRI sensitivity and specificity compared to EUS at 20 and 10 mm cut-offs of maximal lesion diameter were 96 and 88% (20 mm cut-off) and 90 and 82%(10 mm cut-off), respectively (concordance rates of 97 and 87% and Cohen's kappa=0.912 and 0.718, respectively). Lesions<1 cm were more often detected with EUS (p=0.025). Data from sequential concurrent imaging on lesion growth rate [n=7 (mean±SD: 2 mm/year±3.4 mm vs. 1.9 mm/year±3.6 mm)] over a period of at least two years as well as pathology data in connection to preoperative concurrent imaging were available in a small number of patients (n=7, p=0.933 for mean differences in maximal lesion diameter). MRI of the pancreas was more readily available and less expensive than EUS in an outpatient setting. In conclusion, MRI performs well compared to EUS for the detection and subsequent surveillance of MEN1-related panNENs larger than 10 mm and seems to be cost-effective. Both modalities could be used at initial assessment and MRI alone could be utilized thereafter in patient surveillance. EUS retains its value in surgical planning and the detection of small mostly functional PanNENs.

Clock genes alterations and endocrine disorders.

BACKGROUND: Various endocrine signals oscillate over the 24-hour period and so does the responsiveness of target tissues. These daily oscillations do not occur solely in response to external stimuli but are also under the control of an intrinsic circadian clock. DESIGN: We searched the PubMed database to identify studies describing the associations of clock genes with endocrine diseases. RESULTS: Various human single nucleotide polymorphisms of brain and muscle ARNT-like 1 (BMAL1) and Circadian Locomotor Output Cycles Kaput (CLOCK) genes exhibited significant associations with type 2 diabetes mellitus. ARNTL2 gene expression and upregulation of BMAL1 and PER1 were associated with the development of type 1 diabetes mellitus. Thyroid hormones modulated PER2 expression in a tissue-specific way, whereas BMAL1 regulated the expression of type 2 iodothyronine deiodinase in specific tissues. Adrenal gland and adrenal adenoma expressed PER1, PER2, CRY2, CLOCK and BMAL1 genes. Adrenal sensitivity to adrenocorticotrophin was also affected by circadian oscillations. A significant correlation between the expression of propio-melanocorticotrophin and PER 2, as well as between prolactin and CLOCK, was found in corticotroph and lactosomatotroph cells, respectively, in the pituitary. Clock genes and especially BMAL1 showed an important role in fertility, whereas oestradiol and androgens exhibited tissue-specific effects on clock gene expression. Metabolic disorders were also associated with circadian dysregulation according to studies in shift workers. CONCLUSIONS: Clock genes are associated with various endocrine disorders through complex mechanisms. However, data on humans are scarce. Moreover, clock genes exhibit a tissue-specific expression representing an additional level of regulation. Their specific role in endocrine disorders and their potential implications remain to be further clarified.

The value of prolactin in predicting prolactinοma in hyperprolactinaemic polycystic ovarian syndrome.

BACKGROUND: To identify a serum prolactin (PRL) cut-off value indicative of a PRL-producing adenoma in women with polycystic ovarian syndrome (PCOS) and hyperprolactinaemia and characterize such patients. MATERIALS AND METHODS: In the present retrospective case-control study, the medical records of 528 PCOS women were reviewed. Pituitary magnetic resonance imaging (MRI) was performed in PCOS patients with PRL levels ≥94.0 ng/mL and/or symptoms suspicious of a pituitary adenoma (PA). Prolactinoma diagnosis was made in the presence of an MRI-identifiable PA with biochemical and radiological response to dopamine agonists. Receiver operating characteristic (ROC) curve analysis was performed to determine a serum PRL threshold that could identify hyperprolactinaemic PCOS subjects with prolactinomas. Clinical, metabolic and endocrine parameters were also analysed. RESULTS: Among 528 patients with PCOS, 60 (11.4%) had elevated PRL levels. Of 44 (73.3%) patients who had pituitary imaging, 19 had PAs, 18 normal MRI and 7 other abnormalities. Patients harbouring prolactinomas had significantly higher PRL levels compared to patients without adenomas (median PRL 95.4 vs 49.2 ng/mL, P < .0001). A PRL threshold of 85.2 ng/mL could distinguish patients with prolactinomas with 77% sensitivity and 100% specificity [Area Under the curve (AUC) (95%) 0.91(0.8-1.018), P = .0001]. PCOS women with prolactinomas were younger and had lower LH levels compared to women without prolactinomas. CONCLUSIONS: In women with PCOS, PRL levels exceeding 85.2 ng/mL are highly suggestive of a prolactinoma warranting pituitary imaging. Pituitary MRI could also be considered in young PCOS patients with milder PRL elevation and low LH levels.

New Molecular, Biological, and Immunological Agents Inducing Hypophysitis.

Hypophysitis is a relatively rare disease that exerts a strong autoimmune component encompassing different etiologies. Immunomodulatory drugs, such as interferon-α, are known to rarely induce hypophysitis. In recent years, a large number of new biological and immunomodulatory agents have been introduced into clinical practice. Although immune-suppressing agents used for the treatment of autoimmune disorders only rarely are associated with hypophysitis, it is commonly encountered with immunomodulatory agents used for the treatment of cancer. Hypophysitis related to anti-cytotoxic T-lymphocyte-associated antigen-4 antibodies (anti-CTLA-4 Abs) occurs with a prevalence ranging from 0 to 18% and is considered a distinctive side effect of anti-CTLA-4 Abs treatment. Hypophysitis due to the programmed cell death protein-1 antibodies and their ligand is less common, its frequency ranging from 0 to 0.8%. No cases of hypophysitis have been described with molecular targeted agents. Diagnosis of hypophysitis still remains clinical since anti-pituitary antibodies are not a sensitive marker and thus its true prevalence is probably underestimated. The pathophysiology of hypophysitis induced by anticancer agents is not fully clarified. In most cases, treatment requires dose adjustment of the offending drug and pituitary hormone replacement. This mini-review aims to present currently available information regarding hypophysitis related to new molecular, biological, and immunological agents.

Clinical, Endocrine and Imaging Characteristics of Patients with Primary Hypophysitis.

Primary hypophysitis (PH) is a rare disease with a poorly-defined natural history. Our aim was to characterise patients with PH at presentation and during prolonged follow-up. Observational retrospective study of 22 patients was conducted from 3 centres. In 14 patients, PH was confirmed histologically and in the remaining 8 clinically, after excluding secondary causes of hypophysitis. All patients had hormonal and imaging investigations before any treatment. Median follow up was 48 months (25-75%: 3-60). There was a female predominance with a female/male ratio: 3.4:1. Eight out of 22 patients had another autoimmune disease. Headaches and gonadal dysfunction were the most common symptoms. Five patients presented with panhypopituitarism; 17 patients had anterior pituitary deficiency, and 7 had diabetes insipidus. At presentation, 9 patients were treated surgically, 5 received replacement hormonal treatment, and 8 high-dose glucocorticoids from whom 5 in association with other immunosuppressive agents. Six patients showed complete recovery of pituitary hormonal deficiencies while 6 showed a partial recovery during a 5-year follow-up period. No difference was found between patients treated with surgery and those treated medically. The overall relapse rate was 18%. PH can be manifested with a broad spectrum of clinical and hormonal disturbances. Long-term follow-up is required to define the natural history of the disease and response to treatment, since pituitary hormonal recovery or relapse may appear many years after initial diagnosis. We suggest that surgery and immunosuppressive therapy be reserved for exceptional cases.

Chemotherapy in NETs: When and how.

The majority of neuroendocrine tumours (NETs) are well-differentiated tumours that follow an indolent course, in contrast to a minority of poorly differentiated neuroendocrine carcinomas (NECs) which exhibit an aggressive course and assocaited with an overall short survival. Although surgery is the only curative treatment for NETs it is not always feasible,necessitating the application of other therapies including chemotherapy. Streptozotocin (STZ)-based regimens have long been used for advanced or metastatic well-to-moderately differentiated (G1-G2) NETs, especially those originating from the pancreas (pNETs). In poorly differentiated grade 3 (G3) tumours, platinum-based chemotherapy is recommended as first-line therapy, albeit without durable responses. Although data for temozolomide (TMZ)-based chemotherapy are still evolving, this treatment may replace STZ-based regimens in pNETs due to its better tolerability and side effect profile. In addition, there is evidence that TMZ could also be used in the subgroup of well-differentiated G3 NETs. There is less clear-cut evidence of a benefit for chemotherapy in intestinal NETs, but still evolving data suggest that TMZ may be efficacious in particular patients. In lung and thymic carcinoids, chemotherapy is reserved for patients with progressive metastatic disease in whom other treatment options are unavailable. Overall, chemotherapy is indicated in patients who have progressed on first-line treatment with somatostatin analogues, have extensive tumour load or exhibit rapid growth following a period of follow-up, and/or have a high proliferative rate; it may occasionally can be used in a neo-adjuvant setting. Prospective randomised studies are awaited to substantiate the role of chemotherapy in the therapeutic algorithm of NETs along with other evolving treatments.

Management of neuroendocrine tumors of unknown primary.

Neuroendocrine neoplams (NENs) are mostly relatively indolent malignancies but a significant number have metastatic disease at diagnosis mainly to the liver. Although in the majority of such cases the primary origin of the tumor can be identified, in approximately 11-22% no primary tumor is found and such cases are designated as NENs of unknown primary origin (UPO). This has significant therapeutic implications with respect to potentially resectable hepatic disease and/or application of appropriate medical therapy, either chemotherapeutic agents or targeted treatment, as the response to various treatments varies according to the origin of the primary tumor. This lack of tumor specific orientated treatment may also account for the relatively poorer prognosis of NENs of UPO compared to metastatic NENs with a known primary site. In the majority of cases the primary tumors are located in the small bowel and the lung, but a number may still elude detection. Occasionally the presence of a functional syndrome may direct to the specific tissue of origin but in the majority of cases a number of biochemical, imaging, histopathological and molecular modalities are utilized to help identify the primary origin of the tumor and direct treatment accordingly. Several diagnostic algorithms have recently been developed to help localize an occult primary tumor; however, in a number of cases no lesion is identified even after prolonged follow-up. It is expected that the delineation of the molecular signature of the different NENs may help identify such cases and provide appropriate treatment.

Sequential Everolimus and Sunitinib Treatment in Pancreatic Metastatic Well-Differentiated Neuroendocrine Tumours Resistant to Prior Treatments.

OBJECTIVE: Alternating treatment with sunitinib and everolimus has been shown to be efficacious in renal cell carcinoma. However, no data currently exist for the role of alternate sequence administration of these agents in well-differentiated pancreatic neuroendocrine tumours (pNETs). METHODS: Thirty-one patients were administered one compound and upon progression were switched to the other. All patients had grade 1 or 2 tumours and stage IV disease with similar metastatic load. The primary end point included estimation of the median overall progression-free survival (mPFS) along with each drug's mPFS as a first-line (mPFS1) and a second-line treatment (mPFS2); tolerability and serious adverse events were also evaluated. Secondary end points included overall survival (OS), 2-year mortality rate, and incidence of disease progression. RESULTS: Overall, mPFS did not differ between the everolimus to sunitinib group (36.5 months) and the sunitinib to everolimus group (31.6 months) with a hazard ratio of 0.94 ([95% CI, 0.45-1.97], p = 0.7). Although mPFS1 after first-line everolimus was longer (16.3 months) compared to sunitinib (9 months), this was not statistically significant (p = 0.15). Sequential second-line treatment showed no difference in the mPFS2 (p = 0.3). No difference in OS between the 2 groups was observed. Tolerability was better for everolimus compared to sunitinib. CONCLUSIONS: Treatment with sequential molecular target agents was well tolerated and associated with similar overall mPFS in both schemes of administration. Larger prospective studies are required to investigate the long-term efficacy and sequence of administration of alternate therapy with molecular targeting agents in metastatic pNETs and their effect on OS.

Lipofuscin Accumulation in Cortisol-Producing Adenomas With and Without PRKACA Mutations.

The adrenal cortex accumulates lipofuscin granules with age. Lipofuscin accumulation is also seen in adrenocortical tumors associated with Cushing syndrome (CS), particularly those with PRKAR1A mutations, such as in primary pigmented nodular adrenocortical disease (PPNAD). We investigated the presence of lipofuscin in cortisol-producing adenomas (CPAs) responsible for CS with and without the PRKACA (pLeu206Arg) somatic mutation. Ten paraffin-embedded sections of CPAs from cases with overt CS with (n=4) and without (n=6) a PRKACA mutation were microscopically examined through three detection methods, the hematoxylin-Eosin (H & E) staining, the Fontana Masson (FM) staining using light microscopy, and lipofuscin autofluorescence, using confocal laser scanning microscopy (CLSM). Sections were examined quantitatively according to the intensity of the pigmentation, as well as qualitatively based on the total number of granular pigments at all visual fields per tissue slide. Tissues from CPAs were compared to peritumoral adjacent tissues (n=5), to Conn adenomas (n=4), and PPNAD (n=3). CPAs had significantly higher number of lipofuscin-pigment granules compared to peritumoral adrenal tissue and Conn adenomas (46.9±9.5 vs. 3.8±4.8, p=0.0001). The presence of the PRKACA mutation did not increase the chances of pigmentation in the form of lipofuscin granules within CPAs associated with CS. Thus, all CPAs leading to CS accumulate lipofuscin, which presents like pigmentation sometimes seen macroscopically but always detected microscopically. PPNAD caused by PRKAR1A mutations is the best known adrenal lesion leading to CS associated with intense lipofuscin pigmentation and this was confirmed here; CPAs harboring PRKACA mutations did not have statistically significantly more pigmentation than CPAs without mutation, but a larger study might have shown a difference.

Diagnosis and Management of Hereditary Adrenal Cancer.

Benign adrenocortical tumours (ACT) are relatively frequent lesions; on the contrary, adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with unfavourable prognosis. Recent advances in the molecular understanding of adrenal cancer offer promise for better therapies in the future. Many of these advances stem from the molecular elucidation of genetic conditions predisposing to the development of ACC. Six main clinical syndromes have been described to be associated with hereditary adrenal cancer. In these conditions, genetic counselling plays an important role for the early detection and follow-up of the patients and the affected family members.

Expression of sodium iodide symporter in human breast tissues.

PURPOSE: Sodium iodide symporter (NIS) expression in breast cancer (BC) tissues suggests the possibility of using radioiodine for diagnostic and therapeutic purposes. This study evaluated NIS protein expression in primary BC samples and its association with BC prognostic markers and thyroid functional parameters. METHODS: Fifty-six breast tissue samples from 52 operated women (41 BC, 11 benign breast diseases (BBD) and 4 peritumoral adjacent to the carcinoma tissues samples) were analyzed by immunohistochemistry using monoclonal anti-NIS antibody. Measurements of baseline levels of thyroid hormones and antibodies were also analysed in association with NIS protein expression. RESULTS: NIS presented positive cytoplasmic immunoreactivity in the majority of BBD samples (45% ) and in 3 out of 4 breast tissues adjacent to carcinoma. Immunoreactivity was extremely faint in BC samples. Mean thyroid hormones levels and thyroid antibodies positivity did not differ statistically between patients with NIS positive (faint expression) and NIS negative BC. NIS expression appeared to be independent of estrogen (ER) and progesterone receptor (PR) expression as well as of lymph node status. CONCLUSIONS: BC samples expressed only faintly and mainly cytoplasmic NIS protein, suggesting the presence of a non-functional NIS protein. The hypothesis of the downregulation of NIS expression during carcinogenesis cannot be excluded.

Metastatic pheochromocytoma and paraganglioma.

BACKGROUND: Metastatic pheochromocytomas (PCs) and paragangliomas (PGLs) are rare neuroendocrine tumours with a strong genetic background. DESIGN: We searched the PubMed database through February 2015 to identify studies characterizing metastatic PCs/PGLs as well as currently established and evolving therapies. RESULTS: Large size tumours (> 5 cm), PASS score > 6 and Ki-67 labelling index > 3% are the most robust indices of metastatic PCs/PGLs albeit with great variability. Germline succinate dehydrogenase complex, subunit B (SDHB) mutation constitutes the main reliable molecular predictor of malignancy. Plasma and urinary methoxytyramine are the biochemical markers characterizing metastatic PCs/PGLs along with evolving molecular markers such as miRNAs and SNAIL. Conventional imaging is used for tumour localization, whereas (18)F-FDG-PET for staging of metastatic PCs/PGLs especially those related to SDHB gene mutations. In addition, (68)Ga-DOTATATE PET/CT is emerging as a highly sensitive alternative. Surgery remains the gold standard treatment in reducing tumour bulk and/or controlling the clinical syndrome. Treatment with (131)I-MIBG or radiolabelled somatostatin analogues is considered for unresectable disease. Conventional chemotherapy is reserved for more advanced and refractory to other therapies disease although new schemes are currently evolving. Recent genetic studies have highlighted a number of pathways involved in PCs/PGLs pathogenesis directing towards the use of targeted therapies which have still to be validated in clinical practice. CONCLUSIONS: Metastatic PCs/PGLs remain an orphan disease that is only curable by surgery. However, advances in genomic analyses have improved the pathogenesis of these tumours and may lead to effective and more personalized treatments in the near future.