Management of occult adrenocorticotropin-secreting bronchial carcinoids : limits of endocrine testing and imaging techniques

The differential diagnosis and the identification of the source of ACTH in occult ectopic Cushing's syndrome due to a bronchial carcinoid still represents a challenge for the endocrinologist. We report our experience in six patients with occult bronchial carcinoid in whom extensive hormonal, imaging, and scintigraphic evaluation was performed. All patients presented with hypercortisolism associated with high plasma ACTH values. The CRH test and high dose dexamethasone suppression test suggested an ectopic source of ACTH in three of six patients. During bilateral inferior petrosal sinus sampling, none of the patients showed a central to peripheral ACTH gradient. At the time of diagnosis, none of the patients had radiological evidence of the ectopic source of ACTH, whereas pentetreotide scintigraphy identified the lesion in two of four patients. Finally, a chest computed tomography scan revealed the presence of a bronchial lesion in all patients, and pentetreotide scintigraphy identified four of six lesions. In all patients a bronchial carcinoid was found and removed. In one patient with scintigraphic evidence of residual disease after two operations, radioguided surgery, using a hand-held \u3b3 probe after iv administration of radiolabeled pentetreotide, was performed; this allowed detection and removal of residual multiple mediastinal lymph node metastases. In conclusion, our data show that there is not a single endocrine test or imaging procedure accurate enough to diagnose and localize occult ectopic ACTH-secreting bronchial carcinoids. Radioguided surgery appears to be promising in the presence of multiple tumor foci and previous incomplete removal of the tumor

Emerging therapies in pheochromocytoma and paraganglioma: Immune checkpoint inhibitors in the starting blocks

Pheochromocytoma and paraganglioma are neuroendocrine neoplasms, originating in the adrenal medulla and in parasympathetic and sympathetic autonomic nervous system ganglia, respec-tively. They usually present as localized tumours curable with surgery. However, these tumours may exhibit heterogeneous clinical course, ranging from no/minimal progression to aggressive (progres-sive/metastatic) behavior. For this setting of patients, current therapies are unsatisfactory. Immune checkpoint inhibitors have shown outstanding results for several types of solid cancers. We therefore aimed to summarize and discuss available data on efficacy and safety of current FDA-approved immune checkpoint inhibitors in patients with pheochromocytoma and paraganglioma. After an extensive search, we found 15 useful data sources (four full-published articles, four supplements of scientific journals, seven ongoing registered clinical trials). The data we detected, even with the limit of the small number of patients treated, make a great expectation on the therapeutic use of immune checkpoint inhibitors. Besides, the newly detected predictors of response will (hopefully) be of great helps in selecting the subset of patients that might benefit the most from this class of drugs. Finally, new trials are in the starting blocks, and they are expected to shed in the next future new light on a therapy, which is considered a milestone in oncology

Long-term morphological and hormonal follow-up in a single unit on 115 patients with adrenal incidentalomas

We investigated the natural course of adrenal incidentalomas in 115 patients by means of a long-term endocrine and morphological (CT) follow-up protocol (median 4 year, range 1–7 year). At entry, we observed 61 subclinical hormonal alterations in 43 patients (mainly concerning the ACTH–cortisol axis), but confirmatory tests always excluded specific endocrine diseases. In all cases radiologic signs of benignity were present. Mean values of the hormones examined at last follow-up did not differ from those recorded at entry. However in individual patients several variations were observed. In particular, 57 endocrine alterations found in 43 patients (37.2%) were no longer confirmed at follow-up, while 35 new alterations in 31 patients (26.9%) appeared de novo. Only four alterations in three patients (2.6%) persisted. Confirmatory tests were always negative for specific endocrine diseases. No variation in mean mass size was found between values at entry (25.4±0.9 mm) and at follow-up (25.7±0.9 mm), although in 32 patients (27.8%) mass size actually increased, while in 24 patients (20.8%) it decreased. In no case were the variations in mass dimension associated with the appearance of radiological criteria of malignancy. Kaplan–Meier curves indicated that the cumulative risk for mass enlargement (65%) and for developing endocrine abnormalities (57%) over time was progressive up to 80 months and independent of haemodynamic and humoral basal characteristics. In conclusion, mass enlargement and the presence or occurrence over time of subclinical endocrine alterations are frequent and not correlated, can appear at any time, are not associated with any basal predictor and, finally, are not necessarily indicative of malignant transformation or of progression toward overt disease

clinico pathological features treatments and survival of malignant insulinomas a multicenter study

Introduction Management of malignant insulinomas is challenging due to the need to control both hypoglycaemic syndrome and tumor growth. Literature data is limited to small series. Aim of the study To analyze clinico-pathological characteristics, treatments and prognosis of patients with malignant insulinoma. Materials and methods Multicenter retrospective study on 31 patients (male: 61.3%) diagnosed between 1988 and 2017. Results The mean age at diagnosis was 48 years. The mean NET diameter was 41 ± 31 mm, and 70.8% of NETs were G2. Metastases were widespread in 38.7%, hepatic in 41.9% and only lymph nodal in 19.4%. In 16.1% of the cases, the hypoglycaemic syndrome occurred after 46 ± 35 months from the diagnosis of originally non-functioning NET, whereas in 83.9% of the cases it led to the diagnosis of NET, of which 42.3% with a mean diagnostic delay of 32.7 ± 39.8 months. Surgical treatment was performed in 67.7% of the cases. The 5-year survival rate was 62%. Overall survival was significantly higher in patients with Ki-67 ≤10% (P = 0.03), insulin level <60 µU/mL (P = 0.015) and in patients who underwent surgery (P = 0.006). Peptide Receptor Radionuclide Therapy (PRRT) was performed in 45.1%, with syndrome control in 93% of patients. Conclusions Our study includes the largest series of patients with malignant insulinoma reported to date. The hypoglycaemic syndrome may occur after years in initially non-functioning NETs or be misunderstood with delayed diagnosis of NETs. Surgical treatment and Ki67 ≤10% are prognostic factors associated with better survival. PPRT proved to be effective in the control of hypoglycaemia in majority of cases

Ectopic Cushing' syndrome caused by a neuroendocrine carcinoma of the mesentery

BACKGROUND: ACTH overproduction within the pituitary gland or ectopically leads to hypercortisolism. Here, we report the first case of Cushing' syndrome caused by an ectopic ACTH-secreting neuroendocrine carcinoma of the mesentery. Moreover, diagnostic procedures and pitfalls associated with ectopic ACTH-secreting tumors are demonstrated and discussed. CASE PRESENTATION: A 41 year-old man presented with clinical features and biochemical tests suggestive of ectopic Cushing's syndrome. First, subtotal thyroidectomy was performed without remission of hypercortisolism, because an octreotide scan showed increased activity in the left thyroid gland and an ultrasound revealed nodules in both thyroid lobes one of which was autonomous. In addition, the patient had a 3 mm hypoenhancing lesion of the neurohypophysis and a 1 cm large adrenal tumor. Surgical removal of the pituitary lesion within the posterior lobe did not improve hypercortisolism and we continued to treat the patient with metyrapone to block cortisol production. At 18-months follow-up from initial presentation, we detected an ACTH-producing neuroendocrine carcinoma of the mesentery by using a combination of octreotide scan, computed tomography scan, and positron emission tomography. Intraoperatively, use of a gamma probe after administration of radiolabeled (111)In-pentetreotide helped identify the mesenteric neuroendocrine tumor. After removal of this carcinoma, the patient improved clinically. Laboratory testing confirmed remission of hypercortisolism. An octreotide scan 7 months after surgery showed normal results. CONCLUSION: This case underscores the diagnostic challenge in identifying an ectopic ACTH-producing tumor and the pluripotency of cells, in this case of mesenteric cells that can start producing and secreting ACTH. It thereby helps elucidate the pathogenesis of neuroendocrine tumors. This case also suggests that patients with ectopic Cushing's syndrome and an octreotide scan positive in atypical locations may benefit from explorative radioguided surgery using (111)In-pentetreotide and a gamma probe

A comprehensive overview of radioguided surgery using gamma detection probe technology

The concept of radioguided surgery, which was first developed some 60 years ago, involves the use of a radiation detection probe system for the intraoperative detection of radionuclides. The use of gamma detection probe technology in radioguided surgery has tremendously expanded and has evolved into what is now considered an established discipline within the practice of surgery, revolutionizing the surgical management of many malignancies, including breast cancer, melanoma, and colorectal cancer, as well as the surgical management of parathyroid disease. The impact of radioguided surgery on the surgical management of cancer patients includes providing vital and real-time information to the surgeon regarding the location and extent of disease, as well as regarding the assessment of surgical resection margins. Additionally, it has allowed the surgeon to minimize the surgical invasiveness of many diagnostic and therapeutic procedures, while still maintaining maximum benefit to the cancer patient. In the current review, we have attempted to comprehensively evaluate the history, technical aspects, and clinical applications of radioguided surgery using gamma detection probe technology

Analysis of histological and immunohistochemical patterns of benign and malignant adrenocortical tumors by computerized morphometry

Diagnosis of benign and purely localized malignant adrenocortical lesions is still a complex issue. More-over, histology-based diagnosis may suffer of a moment of subjectivity due to inter- and intra-individualvariations. The aim of the present study was to assess, by computerized morphometry, the morphologicalfeatures in benign and malignant adrenocortical neoplasms.Eleven adrenocortical adenomas (ACA) were compared with 18 adrenocortical cancers (ACC). Allspecimens were stained with H&E, cellular proliferation marker Ki-67 and reticulin. We generated amorphometric model based on the analysis of volume fractions occupied by Ki-67 positive and nega-tive cells (nuclei and cytoplasm), vascular and inflammatory compartment; we also analyzed the surfacefraction occupied by reticulin. We compared the quantitative data of Ki-67 obtained by morphometrywith the quantification resulting from pathologist\u2019s visual reading.The volume fraction of Ki-67 positive cells in ACCs was higher than in ACAs. The volume fraction ofnuclei in unit volume and the nuclear/cytoplasmic ratio in both Ki-67 negative cells and Ki-67 positivecells were prominent in ACCs. The surface fraction of reticulin was considerably lower in ACCs.Our computerized morphometric model is simple, reproducible and can be used by the pathologist inthe histological workup of adrenocortical tumors to achieve precise and reader-independent quantifica-tion of several morphological characteristics of adrenocortical tumors

Adrenocortical Cancer: Use of New ENSAT Staging System and Re-Evaluation of Old and New Markers of Prognosis

A modification of the TNM classification (WHO-UICC 2004) for adrenocortical cancer (ACC) has been recently proposed in order to improve the prognostic value as to the disease-free and disease-specific survival.(1) So far an increasing number of molecular markers has been proposed for early detection, confirmation of malignancy and/or outcome prediction, but none of them is considered as reliable as the Weiss score morphological system.(2,3) Aim: to compare the prognostic value of WHO-UICC 2004 and new ENSAT TNM staging classification in a single Institution ACC series as to the disease-free and disease-specific survival and to compare these findings with tumor Weiss score and ki67 expression. Methods: Clinical and pathological data of 26 pts (19F, 7M, median age 52 yrs, range 25-78) surgically treated for ACC, were retrospectively reviewed; the follow up period was 26 months (median, range 6-192). ACC staging was performed according to both WHO-UICC 2004 and ENSAT classification, tumor malignancy was assessed according to Weiss system. A multivariate analysis of disease-free and overall survival in ACC according to Weiss score and ki67 (IHC, monoclonal Mib1 Ab) was performed. Results: 70% of tumors were hypersecreting ; mean size was 10,7cm (range 50-2500), mean weight was 512g (range 50-2500). WHO-UICC identified 2 stage I, 11 stage II, 4 stage III and 9 stage IV disease (Kaplan-Meyer, log-rank test: p=0,0004). Two pts with stage IV WHO-UICC and good prognosis switched to stage III ENSAT (Kaplan-Meyer, log-rank test: p=0,0002). In our series ki67>7% (sensitivity 85,7%, specificity 62,5%, ROC analysis) and Weiss score>4 (sensitivity 100%, specificity 50%) were the best cut-off values suggestive for a poor prognosis (Kaplan-Meyer, p=0,06 and p=0,04 respectively); taken together the two risk factors showed a significant effect on survival probability (Cox-regression, p= 0,04). Ki67>7% and Weiss score>4 showed a slight correlation also with disease-free survival (Kaplan-Meyer, p=0,06 and p=0,04 respectively); when both risk factors were concomitantly present, the correlation with probability of disease recurrence was higher (Cox-regression, p=0,02). Conclusions: The outcome of pts with ACC is strictly related to the stage of the disease, being new ENSAT proposal a valuable tool to improve the power of the stage-related prognostic value. Ki67 expression and Weiss score combined may play a role of interest, but more reliable molecular markers are needed

Quantitative Assessment By Computerized Morphometry of Ki-67 and Intratumoral Inflammatory Infiltrate in Benign and Malignant Adrenocortical Tumors

High mitotic index and high nuclear grade are part of representative hallmarks of adrenocortical cancer (ACC), but the analysis of these parameters is known to be operator-dependent. A characteristic neutrophil/T-lymphocytes infiltrate ratio has been often implicated in carcinogenesis, progression and clinical outcome of several cancer types. However, its role in adrenal cortical tumors is unclear. Aim: to assess by computerized morphometry morphological features, vascular and inflammatory pattern in adrenocortical adenomas (ACAs) and carcinomas. Methods: A single Institution series of 11 ACAs and 18 ACCs samples was analyzed using a Kontron-Zeiss KS400 image analyzer. Four consecutive sections 4 \ub5m thick were obtained with a total of 250\u2013300 HPF examined for each case. Immunohistochemistry for Ki67 and CD8/CD15 was obtained to assess proliferation index and inflammatory infiltrate respectively. To minimize subjectivity, particularly relevant when quantitative results are expected, we generated a morphometric model based on analysis of volume fractions occupied by Ki67 positive and negative cells (nuclei, cytoplasm) and inflammatory compartments (CD15+ granulocytes, CD8+ lymphocytes). Lastly, the assessment of Ki-67 by computerized morphometry was compared with pathologist\u2019s evaluation. Results: volume fraction of Ki-67+ cells was higher in ACCs (ACC .11951, ACA .06637; p<0.001); nuclei volume fraction resulted higher in ACCs, in both Ki-67- (ACC .11951, ACA .06637; p<0.001) and Ki-67+ cells (ACC .01293, ACA .00104; p<0.001). Nuclear/cytoplasmic ratio was higher in ACCs, both Ki-67- (ACC .20535, ACA .09260; p<0.001) and Ki-67+ cells (ACC .66141, ACA .27281; p<0.001). Volume fractions of CD15+ (ACC .00312, ACA .00098; p<0.001) and CD8+ cells (ACC .00731, ACA .00356; p<0.05) were also significantly higher in ACCs. Moreover, when comparing morphometric analysis of Ki67+ cells to pathologist\u2019s scores, the data of the point grid analysis revealed significantly lower values compared to conventional histopathology. Conclusions: Our computerized morphometric model is simple, repeatable (lacking observer bias) and flexible, as it can be upgraded to include newly described histological or immunohistochemical features. This method could be integrated into a classification tool to complement conventional histological analysis to achieve quantification of morphological characteristics and histological biomarkers of adrenocortical tumors. In our experience, nuclear/cytoplasmic ratio differs mostly between ACCs and ACAs, both in Ki-67+ and Ki-67- cells. We speculate that neutrophils may play a role in ACC milieu and that the quantitative assessment of inflammatory infiltrate may find a place in the diagnostic algorithm of adrenal benign and malignant tumors

A Computerized, Operator-Independent Morphometric Model for the Histological Assessment of Adrenal Neoplasia: Preliminary Data

Specific biomarkers for diagnosis and prognosis of adrenocortical carcinomas (ACCs) are still lacking.(1) The proliferation marker Ki-67 is under evaluation for validation as a reliable IHC marker of malignancy for ACCs.(2) Although a well defined diagnostic cutoff has not been demonstrated yet, Ki-67 staining between 5-7% is thought to be a feature of AT malignant behavior.(3) As for the morphological markers currently used in the determination of AT malignancy, also for Ki-67 an interobserver variability is frequently reported. The aim of this pilot study was to determine, with an operator independent and repeatable technique, the proliferative activity and cell morphology of AT histological samples; a preliminary comparison with visual perception was also attempted. METHODS IHC study of 14 ACCs and 7 adrenal adenomas (AAs) samples was done (Rabbit anti-human Ki-67 monoclonal Ab, Clone SP6, 1:400); two pathologists performed a blinded examination with a consensus determination and according to Weiss score. We generated a computerized morphometric model on AT slices to evaluate the volume fractions occupied by nuclei (nVF) and cytoplasm (cVF) of both Ki-67(+)/Ki-67(-) neoplastic cells, and by inflammatory infiltrate. All morphometric variables were obtained by a computerized image analyzer (Kontron-Zeiss KS400) with a color camera attached to a light microscope (40x objective) for microscopic fields examination. More than 200 fields were systematically selected and examined by an automatically controlled procedure to assure unbiased sampling. The method of point counting by using a counting frame was used to determine the relative volume proportion of the investigated structures. Statistics: t-test. RESULTS nVF (p<0.0001), cVF (p<0.0001), nuclear/cytoplasmic ratio (p<0.0001) were the most discriminatory features between ACCs/AAs. Moreover nVF of Ki-67(+) cells was more prominent in ACCs than in AAs (p<0.0001) but in some cases an overlapping was still evident. When compared with computerized analysis, Ki-67 pathologist's evaluation in ACCs showed a marked overestimation and a wide range (average of 9,9% vs 1,4%, range 1-25 % and 0,2-4,2% respectively; p=0,00036). CONCLUSIONS Based on these preliminary data our computerized morphometric method could be considered in the future as an helpful tool for pathologists in the histological assessment of ACCs/AAs, particularly minimizing subjectivity and possibly integrating the actual morphologic Weiss criteria