Metastatic Endocrine Tumors Research Articles

575TiP Cabozantinib plus atezolizumab in advanced and progressive neoplasms of the endocrine system: A multicohort phase II trial (CABATEN trial / GETNE-T1914)

Antiangiogenic agents have demonstrated antitumor properties in endocrine malignancies regardless of their primary origin. Experience with immune-checkpoint inhibitors is limited in this area and early results when used as single agents are discouraging. The aim of this trial is to assess the efficacy and safety of the combination of cabozantinib and atezolizumab, which may overcome the resistance in previously treated metastatic endocrine tumors.

MANAGEMENT OF ENDOCRINE DISEASE: Cushing's syndrome due to ectopic ACTH secretion: an expert operational opinion.

Ectopic ACTH syndrome (EAS) is rare but is frequently a severe condition because of the intensity of the hypercortisolism that may be dissociated from the tumoral condition. EAS should often be considered as an endocrine emergency requiring an emergency response both in terms of diagnostic procedures and therapeutic interventions. Patient management is complex and necessitates dual skills, in the diagnosis and treatment of CS and in the specific management of neuroendocrine tumors (NET). Therefore, initial management should be performed ideally by experienced endocrinology teams in collaboration with specialized hormonal laboratory, modern imaging platforms and intensive care units. Diagnostic procedures vary according to the endocrine and tumoral contexts but should be reduced to a minimum in intense hypercortisolism. Preventive and curative treatments of cortisol-induced comorbidities, non-specific management of hypercortisolism and etiological treatments should be considered simultaneously. Therapeutic strategies vary according to (1.) the intensity of hypercortisolism, the general condition of the patient and associated comorbidities and (2.) the tumoral status, ranging from resectable ACTH secreting tumors to non-resectable metastatic endocrine tumors or occult tumors. The ideal treatment is complete excision of the ACTH-secreting tumor that can be performed rapidly or after preoperative preparation using cortisol-lowering drugs. When this is not possible, the therapeutic strategy should be discussed by a multidisciplinary experienced team in a personalized perspective and include variable combinations of pharmacological agents, bilateral adrenalectomy and non-specific tumoral interventions. Here we discuss the diagnosis and therapeutic strategies including the modern, currently available tools and emphasize on the operational effectiveness of care.

Optimizing the use of PET with selective internal radiation therapy.

Future OncologyVol. 10, No. 15s Symposium PaperOptimizing the use of PET with selective internal radiation therapyPatrick FlamenPatrick Flamen*Nuclear Medicine, Institut Jules Bordet, Université Libre de Bruxelles (ULB), rue Héger Bordet, 1, B-1000 Brussels, Belgium; E-mail Address: patrick.flamen@bordet.beSearch for more papers by this authorPublished Online:5 Dec 2014https://doi.org/10.2217/fon.14.229AboutSectionsView ArticleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit View articleKeywords: FDG PET-CT responsepatient stratificationselective internal radiation therapytreatment planningReferences1 Flamen P, Vanderlinden B, Delatte P et al. Multimodality imaging can predict the metabolic response of unresectable colorectal liver metastases to radioembolization therapy with yttrium-90 labeled resin microspheres. Phys. Med. Biol. 53(22), 6591–6603 (2008).Crossref, Medline, Google Scholar2 Garin E, Lenoir L, Rolland Y et al. Dosimetry based on 99mTc-macroaggregated albumin SPECT/CT accurately predicts tumor response and survival in hepatocellular carcinoma patients treated with 90Y-loaded glass microspheres: preliminary results. J. Nucl. Med. 53(2), 255–263 (2012).Crossref, Medline, CAS, Google Scholar3 Kumar R, Sharma P, Garg P et al. Role of 68Ga-DOTATOC PET-CT in the diagnosis and staging of pancreatic neuroendocrine tumours. Eur. Radiol. 21(11), 2408–2416 (2011).Crossref, Medline, Google Scholar4 Garin E, Le Jeune F, Devillers A et al. Predictive value of 18F-FDG PET and somatostatin receptor scintigraphy in patients with metastatic endocrine tumors. J. Nucl. Med. 50(6), 858–864 (2009).Crossref, Medline, CAS, Google Scholar5 Seo S, Hatano E, Higashi T et al. Fluorine-18 fluorodeoxyglucose positron emission tomography predicts tumor differentiation, P-glycoprotein expression, and outcome after resection in hepatocellular carcinoma. Clin. Cancer Res. 13(2 Pt 1), 427–433 (2007).Crossref, Medline, CAS, Google Scholar6 Lee JW, Paeng JC, Kang KW et al. Prediction of tumor recurrence by 18F-FDG PET in liver transplantation for hepatocellular carcinoma. J. Nucl. Med. 50(5), 682–687 (2009).Crossref, Medline, Google Scholar7 Kim BK, Kang WJ, Kim JK et al. 18F-fluorodeoxyglucose uptake on positron emission tomography as a prognostic predictor in locally advanced hepatocellular carcinoma. Cancer 117(20), 4779–4787 (2011).Crossref, Medline, Google Scholar8 Lhommel R, Goffette P, Van Den Eynde M et al. Yttrium-90 TOF PET scan demonstrates high-resolution biodistribution after liver SIRT. Eur. J. Nucl. Med. Mol. Imaging 36(10), 1696 (2009).Crossref, Medline, Google ScholarFiguresReferencesRelatedDetails Vol. 10, No. 15s eToC Sign up Follow us on social media for the latest updates Metrics Downloaded 23 times History Published online 5 December 2014 Published in print November 2014 Information© Future Medicine LtdKeywordsFDG PET-CT responsepatient stratificationselective internal radiation therapytreatment planningFinancial & competing interests disclosureP Flamen has received research grants as well as honoraria for lectures from Sirtex Medical Ltd. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.The author would like to thank Rae Hobbs (of Scribe Medical) for her editorial assistance in the development of this paper, funded by Sirtex Medical Ltd.PDF download

Abstract 4063: Image-guided fluorescent endomicroscopy of glioblastoma with SVV-GFP viral labeling

Abstract We propose a novel method to improve detection of infiltrative microscopic GBM tumors during surgery, by labeling the infiltrative tumor cells in vivo by a single intravenous injection of a highly specific tumor seeking fluorescence virus, Seneca Valley Virus (SVV-GFP). The feasibility of this approach was demonstrated in a permissive pediatric GBM (IC-2305GBM) and an adult GBM (IC-A46GBM) orthotopic xenograft mouse model. Both models were derived from primary tissue of GBM from patients to preservethe histopathological and immunophenotypical characteristics of the original tumors. After establishing the xenograft tumors, SVV-GFP was injected intravenously at a dose of 5x1014 viral particles/kg. The animals were imaged at day 3 after SVV-GFP virus injection. During the imaging procedure, the animals were euthanized through anesthesia overdose and a small window was immediately drilled in the skull to introduce a 1mm outer diameter fiberoptic fluorescence probe through the tumor. Fluorescent labeled cells were recorded as a real-time video sequence along the track of the probe. Image quantification starts with low frequency temporal drift correction using Fast Fourier Transform based lowpass filtering. Air image frames (before probe insertion) were used as a zero reference and the intensity range of the video is shifted accordingly. A normal tissue fluorescence image was then estimated using a median statistics of all image frames acquired in normal brain tissue. This image was used to correct for lower detection sensitivity near the probe edge or any field inhomogeneity. The video sequence was then normalized to the normal tissue image to create a TBR map. By definition, air is used as reference with TBR=0 and normal tissue is at TBR=1. A cutoff of TBR>1.1 is used and tumor cells exceeding that threshold were classified as GFP-positive tumor cells. Fractional area occupied by the virus-labeled microscopic tumors were computed with the TBR exceeding 1.1 within the field of view. A low fractional area (<0.01%) was found in normal brain tissue using this method, demonstrating that our method is robust. To summarize, we demonstrated an innovative approach for microscopic tumor detection in glioblastoma that is two to three orders of magnitude smaller than those currently detected with in vivo imaging modalities.This method can potentially be applied to detect microscopic tumors in metastatic retinoblastoma, medulloblastoma, endocrine tumors and small cell lung cancer which are shown to be permissive to infection of this virus. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4063. doi:1538-7445.AM2012-4063

Incidental metastatic endocrine tumor diagnosed at laparoscopic radical prostatectomy and bilateral lymph node dissection

The introduction and expansion of laparoscopic and robotic radical retropubic prostatectomy (LRRP and RRRP) for organ-confined prostate cancer have led to an increase in pelvic lymphadenectomy specimens. Extended lymph node dissection (eLND) involves removing nodes over the obturator fossa, external ileac vessels as well as the internal iliac and increases the number of nodes examined. This has the potential to increase incidental nonprostatic nodal pathology identified in prostatectomy specimens. For the first time in the current literature we report the incidental diagnosis of a metastatic small bowel endocrine tumor in a 69-year-old gentleman, made at the time of LRRP and bilateral lymph node dissection. This report suggests that the benefit of an extended lymph node dissection is not only to prostate cancer control and staging, but also to the possibility of diagnosing potentially treatable incidental disease. It is a possibility that both pathologists and urologists alike should be aware of.

Treatment of Liver Metastases in Patients with Neuroendocrine Tumors

Neuroendocrine tumours may originate from the lungs, thymus, stomach, gastrointestinal tract and endocrine pancreas. A majority of the tumours are malignant. Metastases occur to regional and distal lymph nodes, liver, bones, lungs, mammary glands, subcutaneous tissue, central nervous system and adrenal glands. Although most neuroendocrine tumours are relatively slowly growing, poorly differentiated neuroendocrine carcinomas are fast growing neoplasms with high proliferative activity. A characteristic feature of many neuroendocrine tumours is the ability to produce and secrete various hormones and peptides, leading to endocrine symptoms that can be very disabling and cause substantial morbidity. Small bowel carcinoids, for example, produce serotonin giving rise to the classical carcinoid syndrome with flushing, diarrhea, right-sided heart disease and asthma. A prerequisite for the carcinoid syndrome to occur is usually the presence of liver metastases. Lung carcinoids rarely produce serotonin, but may instead secrete histamine causing an atypical carcinoid syndrome with generalized flushing, diarrhea, periorbital oedema, lacrimation and asthma. They may also produce adrenocorticotropic hormone or corticotropin-releasing factor, resulting in an ectopic Cushing's syndrome. Endocrine pancreatic tumours may as well secrete various hormones, such as gastrin, insulin, glucagon, vasoactive intestinal polypeptide (VIP) or somatostatin, resulting in the corresponding syndrome. The treatment of patients with metastatic neuroendocrine tumours is based on primary tumour origin, tumour biology, stage and grade and includes debulking by surgery, liver embolization with particles, chemoembolization, radioembolization, radiofrequency ablation and peptide receptor radionuclide therapy (PRRT) with 90Yttrium-DOTATOC or 177Lutetium-DOTATATE. Medical treatment consists of biotherapy with alpha-interferon and somatostatin analogues, various chemotherapy regimens, angiogenesis inhibitors, tyrosine kinase inhibitors and mTOR inhibitors. In this special issue in the International Journal of Hepatology, focus is on the various specific treatment possibilities for patients with neuroendocrine tumours metastatic to the liver. There are two papers describing the role of surgery in these patients, and one clinical study reporting the results of liver transplantation. Surgical debulking should always be considered, and liver transplantation may in selected cases be an option. Because of the immunosuppression, it is however of utmost importance that every effort is made to exclude remaining tumour outside the liver before transplantation. Three papers deals with hepatic arterial embolization, one of them reviews the role of hepatic arterial embolization for debulking of liver metastases. Another paper is about a clinical study and a review of radioembolization, which is a promising alternative for this patient group with possible long-lasting effect and few serious adverse effects. An important disadvantage (also with particle and chemoembolization) is that most patients with neuroendocrine tumours metastatic to the liver in addition have spread of the tumour to lymph nodes and/or other distant organs such as the bones, necessitating systemic therapy. In patients with normal bone marrow and renal function, PRRT is thus often preferred to radioembolization, which however may be considered if the patient shows progression later after PRRT. A randomized clinical trial comparing the various embolization methods, particle embolization, chemoembolization and radioembolization, would nevertheless be highly desirable. Three papers review the possible systemic therapies for patients with liver metastases from neuroendocrine tumours. This year, two new drugs have been approved for treatment of patients with metastatic endocrine pancreatic tumours, everolimus and sunitinib. This represents an important progress in the therapeutic arsenal for patients with neuroendocrine tumours. There is however still a need for more new drugs, and especially for patients with midgut carcinoids, in whom the therapeutic options are limited after progression. In addition, there is an urgent need to learn how to use, combine and sequence the various therapeutic alternatives, including chemotherapy, biotherapy, newer drugs and PRRT. Dan Granberg Wouter de Herder Dermot O'Toole Larry Kvols

TTF-1 positive small cell cancers: Don’t think they’re always primary pulmonary!

Thyroid transcription factor 1 (TTF-1) plays a key role in morphogenesis of the lungs and is expressed in up to 90% of pulmonary small cell carcinomas. This explains why this marker is frequently used in the search for the primary origin of metastatic endocrine tumours. Here we report on a TTF-1 expressing mixed endocrine-exocrine carcinoma of the common bile duct in a patient with pulmonary nodules that did not appear to be neoplastic. TTF-1 positivity in pulmonary and extrapulmonary neuroendocrine tumours is reviewed, and we conclude that TTF-1 expression in neuroendocrine tumours of the small-cell type are not uncommon at extrapulmonary locations. Therefore, immunohistochemistry for TTF-1 in such tumours should be interpreted with caution.

Liver transplantation for primary or secondary endocrine tumors

Endocrine tumors comprise a heterogeneous group of rare neoplasms. Liver metastatic endocrine tumors (MET) are amenable to various therapeutic modalities including liver transplantation (LT). However, LT for MET remains controversial because of the lack of clear selection criteria. The purpose of this study based on thorough perusal of English and French literature since 1989 was to identify prognostic factors and propose recommendations for selecting patients most likely to benefit LT for primary and secondary endocrine tumors.

Hepatic Metastases From Neuroendocrine Tumors With a “Thin Slice” Pathological Examination

To prospectively compare the results of the pathologic examination including thin 3- to 4-mm thick serial slices of the surgical specimen in a well-defined anatomic part of the liver with those of 4 different liver imaging techniques. BACKGROUNDS SUMMARY DATA: Liver metastases (LM) of neuroendocrine origin are frequent and accuracy of pretherapeutic liver imaging in detecting small-sized LM is questioned, but no study has compared the different techniques used to image large liver specimens and meticulous pathologic examination. Eleven patients with a metastatic endocrine tumor were selected before undergoing a right hepatectomy or a left hepatectomy passing along the median hepatic vein. Before the hepatectomy, patients underwent somatostatin receptor scintigraphy, computed tomography, magnetic resonance imaging, and ultrasonography (US). An intraoperative assessment (palpation and US) was also performed. Liver specimens were systematically cut into thin serial slices, 3- to 4-mm thick. A final histologic count of the total number of LM was obtained and compared with findings from each imaging technique. Compared with the final histologic count of LM, fewer than 50% of the LM were detected preoperatively. The accuracy was 24% for somatostatin receptor scintigraphy, 38% for computed tomography and US, and 49% for magnetic resonance imaging (the only imaging technique that detected half the number of LM). The size of the smallest LM was not greater than 2 mm in 54% of the patients. Half the number of LM from neuroendocrine tumors are undetectable on preoperative imaging.

A rare surgical case of multiple liver resections for recurrent liver metastases from pancreatic gastrinoma: liver and vena cava resection

Pancreatic gastrinoma is a rare non-beta islet cell tumor. Approximately 60% of gastrinomas are malignant; despite the fact that they are usually slow growing, liver metastases have a major impact on prognosis. Most authors have advocated aggressive surgical management as being the only potentially curative therapy to improve survival as well as to provide outstanding relief from symptoms. We present a case of a 57-year-old man referred to our hospital with a diagnosis of liver metastases from pancreatic gastrinoma, with suspected involvement of the inferior vena cava (IVC). At the age of 37 years, he was diagnosed in his local hospital as having a pancreatic gastrinoma, with liver metastases, and he underwent distal pancreatectomy, splenectomy and enucleation of liver metastases. A liver tumor recurred twice, 7 and 9 years after the first surgery, for which double liver resections were performed: the first time he underwent enucleation of multiple liver metastases in segments II, III, IV, V, VI, VII and VIII, with resection of the right hepatic vein and partially resection of the diaphragm; the second time he underwent enucleation of multiple liver metastases in segments II, III, IV, and V. In our hospital, 8 years after the last surgery, the patient underwent right extended trisectionectomy, resection of segment I, combined resection of the IVC, and partial removal of the diaphragm. To the best of our knowledge, from a review of the literature, this is the first case to achieve successful long-term survival through aggressive surgical management of this type of metastatic endocrine tumor. The patient described here is still alive, free of disease and leading a normal life, 20 years after the initial diagnosis and 3 years after the last surgery.

Plasma Chromogranin A as Marker for Survival in Patients With Metastatic Endocrine Gastroenteropancreatic Tumors

The prognostic role of plasma chromogranin A in patients with neuroendocrine tumors is unclear. We investigated the role of chromogranin A in predicting survival and hypothesized that chromogranin A mirrors tumor burden and that a rapid increase after a phase of stable plasma chromogranin A levels might predict exploding tumor growth. Three hundred forty-four patients with metastatic, well-differentiated neuroendocrine tumors were included. A subsample of 102 patients was investigated to correlate radiologically classified tumor burden with plasma chromogranin A. Hepatic tumor burden (0%, 0%-25%, 25%-50%, >50%) was assessed from computed tomography/magnetic resonance imaging scans. Follow-up information until death was generated in regular intervals. Plasma chromogranin A levels (U/L) vary between tumor entities (Kruskal-Wallis, P < .001) and were associated with survival time (hazard ratio [hours], 2.14 per one unit in the log10 CgA level scale; 95% confidence interval [CI], 1.75-2.62; P < .001). Chromogranin A levels correlated with hepatic tumor burden (Spearman P = .57; 95% CI, 0.44-0.70; P < .001). Additional extrahepatic tumor load did not relevantly affect plasma chromogranin A. A sudden increase observed in individual patients was paralleled by rapid tumor progress and short survival. Increased plasma chromogranin A in patients with metastatic neuroendocrine tumors is predictive for shorter survival. There was a modest correlation between chromogranin A levels and hepatic tumor burden. We hypothesized further that a sudden increase in individual chromogranin A levels indicates unfavorable outcome.

Predictors of Long-Term Survival After Liver Transplantation for Metastatic Endocrine Tumors: An 85-Case French Multicentric Report

Liver transplantation (LTx) for metastatic endocrine tumors (MET) remains controversial due to the lack of clear selection criteria. From 1989 to 2005, 85 patients underwent LTx for MET. The primary tumor was located in the pancreas or duodenum in 40 cases, digestive tract in 26 and bronchial tree in five. In the remaining 14 cases, primary location was undetermined at the time of LTx. Hepatomegaly (explanted liver > or =120% of estimated standard liver volume) was observed in 53 patients (62%). Extrahepatic resection was performed concomitantly with LTx in 34 patients (40%), including upper abdominal exenteration (UAE) in seven. Postoperative in-hospital mortality was 14%. Overall 5-year survival was 47%. Independent factors of poor prognosis according to multivariate analysis included UAE (relative risk (RR): 3.72), primary tumor in duodenum or pancreas (RR: 2.94) and hepatomegaly (RR: 2.63). After exclusion of cases involving concomitant UAE, the other two factors were combined into a risk model. Five-year survival rate was 12% for the 23 patients presenting both unfavorable prognostic factors versus 68% for the 55 patients presenting one or neither factor (p < 10(-7)). LTx can benefit selected patients with nonresectable MET. Patients presenting duodeno-pancreatic MET in association with hepatomegaly are poor indications for LTx.

Treatment with Combined Streptozotocin and Liposomal Doxorubicin in Metastatic Endocrine Pancreatic Tumors

Treatment with combined streptozotocin and liposomal doxorubicin is safe and efficient in patients with endocrine pancreatic tumors (EPTs). No cardiac toxicity was reported. Background: The combination of streptozotocin and doxorubicin has been shown to be superior to streptozotocin and fluorouracil in the treatment of metastatic EPTs. However, the risk of cardiac toxicity from anthracyclins hampers the usefulness of the drug combination. Liposomal doxorubicin has a lower frequency of cardiac adverse events compared to doxorubicin. We wanted to assess the efficacy and safety of combined streptozotocin and liposomal doxorubicin in patients with metastatic EPTs. Methods: Thirty patients with metastatic EPTs were recruited from three medical centers in Norway and Sweden during a time period of 3 years. All patients had histopathologically confirmed diagnoses and bidimensionally measurable lesions. 30 mg/m² of liposomal doxorubicin was administered on day 1 of each cycle. During the first course, 1 g of streptozotocin was given on 5 consecutive days. Thereafter, 2 g of streptozotocin was given on day 1 only. Treatment was repeated every 3 weeks. Results: Twelve of 30 patients (40%) achieved an objective radiological response with a median duration of 9 months. Stabilization of disease was achieved in 17 of 30 patients (57%) for a median duration of 11 months. Only one patient had progressive disease as best response. The 2-year progression-free survival was 18% and the 2-year overall survival was 72%. The treatment was well tolerated. None of the patients experienced cardiac toxicity. Conclusion: We conclude that combined streptozotocin and liposomal doxorubicin is a safe and efficient treatment for EPTs. The efficacy seems to be comparable to that of combined streptozotocin and doxorubicin, whereas the cardiac toxicity clearly favors using the liposomal drug combination.

18-FDG-PET and somatostatin receptor scintigraphy (SRS) can predict disease progression and survival in patients with metastatic endocrine tumors: Results of a prospective study

4577 Background: Appropriate treatment for metastatic endocrine tumors (MET) depends on the aggressiveness of the disease. We wanted to know whether PET and SRS can predict early disease progression and patient survival. Methods: A prospective exploration protocol was applied for new cases of untreated MET diagnosed between September 2003 and January 2006 who gave their written informed consent. Explorations included: computed tomography (CT), SRS, PET, review of histological data (WHO grade, p53 and Ki67 IH); CT was repeated every three months to assess: disease-free survival (PFS), the risk of early (first 6 months) progressive disease (PD6m)and overall survival (OS). Results: The series included 38 patients (60±15y) with a primary digestive tract (n=24), lung (n=2) or unknown (n=12) tumor. Histologically, 4 patients had a high-grade tumor and 34 a low-grade tumor. Visual analysis of PET and SRS was positive in 15 and 27 patients respectively. The 2-year OS and DFS were 73% and 45%; 16 patients had PD6m. PET exhibited an excellent positive predictive value for PD6m (14/15 PET+ and 2/23 PET- were PD6m) and was correlated with DFS (p&lt;0.0001; at 2 yr 75% DFS for PET- and 0% for PET+) and OS (p&lt;0.0001; at 2 yr 95% vs 42%) even when considering only low-grade tumors. Positive SRS was associated with DFS (p&lt;0.001) and OS (p&lt;0.03). Among patients with positive PET, the SRS-positive patients had a better DFS than the SRS-negative patients. At univariate analysis DFS and OS were correlated with: PET, SRS, WHO grade, Ki67 and p53. At multivariate analysis only PET was predictive of DFS. Conclusions: PET and SRS exhibit excellent predictive value for rapid tumor progression. There results are correlated with DFS and OS even for histologically low-grade tumors. Tumors progressed within 6 months in 14/15 patients with a positive PET. These explorations should be included in the initial work-up for MET. No significant financial relationships to disclose.

A combination of cisplatin, etoposide and slow-release lanreotide is effective for the treatment of patients with metastatic endocrine tumours,

A combination of cisplatin, etoposide and slow-release lanreotide is effective for the treatment of patients with metastatic endocrine tumours,

Chemo-hormone therapy of non-well-differentiated endocrine tumours from different anatomic sites with cisplatinum, etoposide and slow release lanreotide formulation

We report the results of a phase II trial in patients with metastatic endocrine tumours from different sites, which aimed to evaluate the anti-tumour activity and toxicity of a cisplatinum and etoposide regimen administered in combination with the somatostatin agonist lanreotide given in slow release formulation. Between January 1999 and November 2003, 27 patients with histological diagnoses of endocrine tumours with different degrees of differentiation, excluding well differentiated carcinoid neoplasms, received intravenous (i.v.) administration of cisplatinum (30 mg m−2) and etoposide (100 mg m−2) on days 1–3 and intramuscular administration of 60 mg lanreotide on day 1, in a 21-day cycle. All of the patients were evaluable for toxicity and response. The treatment was very well tolerated as no grade 4 toxicity was observed. Four patients achieved a complete response, six a partial response, 12 experienced disease stabilisation and five disease progression. The average time to progression and to survival were 9 and 24 months respectively. These results suggest that this chemo-hormone therapy regimen is well tolerated and active in patients with non-well differentiated endocrine tumours.

Liver transplantation for patients with metastatic endocrine tumors: Single-center experience with 15 patients

In contrast to other secondary liver malignancy, orthotopic liver transplantation (OLT) is considered as a treatment modality for nonresectable endocrine liver metastases in selected patients. However, only few series have assessed patient selection criteria and long-term results, and no reports have focused on the impact of new technologies in this regard. Between 1992 and 2004, 28 patients with malignant endocrine tumors underwent evaluation for OLT according to our protocol. Data were entered into a prospective database. During pretransplant evaluation, somatostatin receptor scintigraphy detected extrahepatic metastases not diagnosed in standard imaging in 10 patients. Of them, 3 showed aberrant Ki67 labeling results. One patient was excluded from further evaluation due to severe carcinoid heart. Thus far, 15 patients, 10 men and 5 women, aged 37 to 67 years, were subjected to the transplant procedure (11 deceased donor OLT, 3 living donor liver transplantations, and 1 cluster transplantation). Four patients died during the hospital treatment. The median follow-up of the discharged patients was 60.8 months. The actuarial patient survival was 78.3% at 1 year and 67.2% at 5 years. The actuarial 1-, 2-, and 5-year tumor-free survival amounted to 69.4%, 48.3%, and 48.3%, respectively. Two patients underwent surgery for isolated tumor recurrence. In 2 patients, peptide receptor radiotherapy was carried out because of multilocular recurrent disease. In conclusion, liver transplantation is a realistic therapeutic option for highly selected patients with hepatic metastases of endocrine tumors. Our strategy, which implements strict pretransplant selection and aggressive surgical approach, in case of disease recurrence, in addition to systemic radiopeptide treatment, led to an excellent long-term survival cure, however, is unlikely to be achieved.

Metastatic mammary carcinomas with endocrine features: Potential diagnostic pitfalls

Mammary carcinomas with endocrine differentiation (MCED) are an uncommon subtype of breast carcinomas that are morphologically indistinguishable from low-grade endocrine neoplasms arising in other organs. Aspirates of MCED yield relatively monotonous cells with eccentrically placed nuclei containing characteristic "salt and pepper" chromatin. In the breast, these features represent MCED. In extramammary sites, the differential is more extensive, and diagnosing MCED metastases to the lung, a common location for primary and metastatic endocrine tumors, can be a challenging task, with significant clinical implications. Although primary MCED have been described extensively in the cytology literature, secondary pulmonary MCED have not been reported to the best of our knowledge. We report three cases of MCED metastatic to the lung and present the cytological and immunohistochemical features.

Hypoechoic focal liver lesions: Characterization with contrast enhanced ultrasonography

To evaluate the late sinusoidal phase of contrast enhancement with a 2nd-generation ultrasound contrast enhanced medium in the characterization of hypoechoic focal liver lesions. We studied 88 hypoechoic liver lesions (diameter range, 1-18 cm; with 18 lesions 2 cm or less) found on conventional grayscale sonography (US) with contrast-enhanced ultrasonography (CEUS). Final diagnosis was made using contrast enhanced helical CT, contrast enhanced MR, angiography (DSA), and/or histopathic confirmation or clinical imaging follow-up. There were 37/88 benign lesions demonstrated: 17 cavernous hemangiomas, 3 capillary hemangiomas, 11 focal nodular hyperplasias (FNH), 3 focal areas of sparing in hepatic steatosis, 2 adenomas, and 1 intrahepatic necrotic area. Malignant lesions demonstrated included 51/88: 27 hepatocellular carcinomas (HCC) in cirrhosis, 11 metastatic carcinomas, 10 metastatic endocrine tumors, 2 cholangiocellular carcinomas (CCC) and 1 non-Hodgkin's lymphoma (NHL). CEUS characterized 30/37 (81%) benign lesions and 45/51 (88%) malignant lesions. On the basis of the results obtained during the sinusoidal contrast enhanced phase of CEUS, diagnosis of benignancy was possible in 35/37 (95%) of benign liver lesions and diagnosis of malignancy in 49/51 (96%) of malignant liver lesions. The enhancement pattern of 13 small (< or = 2 cm in diameter) hypervascular liver lesions (3 capillary hemangiomas, 2 FNHs, 4 HCCs, 4 metastatic endocrine tumors) was better demonstrated on CEUS than on helical CT. In these cases the hyper vascularization of the lesions shown on CEUS was not confirmed on CT. CEUS distinguished malignant from benign hypoechoic liver lesions with an accuracy of 95%.

Neuroendocrine secretory protein-55 (NESP-55) expression discriminates pancreatic endocrine tumors and pheochromocytomas from gastrointestinal and pulmonary carcinoids.

Neuroendocrine secretory protein-55 (NESP-55), the latest addition to the chromogranin family, is a product of a genomically imprinted gene transcribed exclusively from the maternal allele. Initial studies have shown it to have a less widespread distribution than that of chromogranin A in normal tissues. It has also been suggested that NESP-55 may be a marker of neuroendocrine tumors differentiating toward the adrenal chromaffin and pancreatic islet cells. Metastatic gastrointestinal and pulmonary carcinoids may occasionally be difficult to distinguish from pancreatic endocrine tumors (PETs) and pheochromocytomas on morphologic grounds alone. We studied neuroendocrine tumors from these sites to see if NESP-55 expression could reliably discriminate pulmonary and gastrointestinal carcinoids from neuroendocrine tumors arising in the pancreas or the adrenal medulla. Sixty-three neuroendocrine tumors positive for one or more immunohistochemical marker of neuroendocrine differentiation (chromogranin A, chromogranin B, synaptophysin, secretogranin II, neuron-specific enolase) were selected for the study and consisted of 34 typical carcinoids (15 pulmonary, 11 ileal, 4 gastric, and 4 rectal), 19 PETs, and 10 pheochromocytomas (4 sporadic, 3 MEN-2, 2 neurofibromatosis type 1, and 1 VHL). All cases were stained for NESP-55 after microwave antigen retrieval using a rabbit polyclonal antibody at a dilution of 1:1000. Sections of normal adrenal medulla were used as positive controls for NESP-55 staining. Negative controls consisted of omission of primary antibody and replacement with normal rabbit serum at an equivalent concentration. NESP-55 immunoreactivity was seen as brown finely granular cytoplasmic staining with prominent perinuclear accentuation. All gastric and ileal carcinoids studied were completely negative for NESP-55. One of four rectal and 1 of 15 pulmonary carcinoids showed focal positivity for it in less than 5% of tumor cells. In contrast, all 10 pheochromocytomas and 14 of 19 PETs showed strong immunohistochemical staining in a variable proportion of tumor cells. Diffuse positivity (>75% of tumor cells) was seen in 6 of 14 PETs and 8 of 10 pheochromocytomas. Our results indicate that, in contrast to the other granins, NESP-55 reactivity is restricted to endocrine tumors of the pancreas and the adrenal medulla. Immunohistochemical expression of NESP-55 may thus be useful in assigning a pancreatic or adrenal origin to metastatic endocrine tumors of unknown origin.