Low-grade Neuroendocrine Tumors Research Articles

Detection of unknown primary neuroendocrine tumours (CUP-NET) using 68Ga-DOTA-NOC receptor PET/CT

This bi-centric study aimed to determine the role of receptor PET/CT using (68)Ga-DOTA-NOC in the detection of undiagnosed primary sites of neuroendocrine tumours (NETs) and to understand the molecular behaviour of the primarily undiagnosed tumours. Overall 59 patients (33 men and 26 women, age: 65 + or - 9 years) with documented NET and unknown primary were enrolled. PET/CT was performed after injection of approximately 100 MBq (46-260 MBq) of (68)Ga-DOTA-NOC. The maximum standardised uptake values (SUV(max)) were calculated and compared with SUV(max) in known pancreatic NET (pNET) and ileum/jejunum/duodenum (SI-NET). The results of PET/CT were also correlated with CT alone. In 35 of 59 patients (59%), (68)Ga-DOTA-NOC PET/CT localised the site of the primary: ileum/jejunum (14), pancreas (16), rectum/colon (2), lungs (2) and paraganglioma (1). CT alone (on retrospective analyses) confirmed the findings in 12 of 59 patients (20%). The mean SUV(max) of identified previously unknown pNET and SI-NET were 18.6 + or - 9.8 (range: 7.8-34.8) and 9.1 + or - 6.0 (range: 4.2-27.8), respectively. SUV(max) in patients with previously known pNET and SI-NET were 26.1 + or - 14.5 (range: 8.7-42.4) and 11.3 + or - 3.7 (range: 5.6-17.9). The SUV(max) of the unknown pNET and SI-NET were significantly lower (p < 0.05) as compared to the ones with known primary tumour sites; 19% of the patients had high-grade and 81% low-grade NET. Based on (68)Ga-DOTA-NOC receptor PET/CT, 6 of 59 patients were operated and the primary was removed (4 pancreatic, 1 ileal and 1 rectal tumour) resulting in a management change in approximately 10% of the patients. In the remaining 29 patients, because of the far advanced stage of the disease (due to distant metastases), the primary tumours were not operated. Additional histopathological sampling was available from one patient with bronchial carcinoid (through bronchoscopy). Our data indicate that (68)Ga-DOTA-NOC PET/CT is highly superior to (111)In-OctreoScan (39% detection rate for CUP according to the literature) and can play a major role in the management of patients with CUP-NET.

Neuroendocrine Tumors of the Ampulla of Vater

To describe the biological behavior and surgical management of ampullary neuroendocrine tumors in 7 patients. Case series and literature review. University hospital. Seven patients with ampullary neuroendocrine tumors. Clinical presentation, pathologic findings, and survival. The patients presented with jaundice (3 patients), anemia (1 patient), gastric outlet obstruction (1 patient), or incidental discovery (2 patients). No patients had neurofibromatosis. Preoperative biopsy was diagnostic in 5 of 6 patients. All of the tumors expressed chromogranin and synaptophysin. Even when the tumor expressed gastrin, vasoactive intestinal peptide, or somatostatin, no patient had a hypersecretion syndrome. Five patients were treated by pancreaticoduodenectomy, 4 for low-grade neuroendocrine tumors and 1 for high-grade neuroendocrine carcinoma. The lesions measured 1.0 to 3.5 cm in diameter. Computed tomographic scans failed to detect nodal metastases that were present in 4 patients. One patient with a high-grade malignant neoplasm died after 15 months. The rest were disease-free after 19 to 48 months. Two patients had transduodenal local resections, one for a 1.1-cm paraganglioma (disease-free, 11 years) and the other for a 0.6-cm carcinoid tumor (disease-free, 7 months). This is one of the largest series of neuroendocrine tumors of the ampulla. Preoperative biopsy was accurate, but computed tomographic scans were insensitive in detecting nodal metastases. Unlike duodenal carcinoid tumors, hypersecretion syndromes were absent and small tumor size did not preclude locoregional metastases. Tumor grade predicted survival. We recommend pancreaticoduodenectomy for this disease, with local resection reserved for mobile, superficial lesions.

A phase II clinical and biological study of lithium carbonate (Li) in patients with low-grade neuroendocrine tumors

e15662 Background: Low-grade neuroendocrine tumors (NETs), such as carcinoid, islet cell tumors, and medullary thyroid carcinomas, respond poorly to chemotherapy, and effective, less toxic therapies are needed. Glycogen Synthase Kinase (GSK)-3β, a multifunctional protein kinase, has been shown to regulate growth and hormone production in NETs. Use of lithium carbonate (Li) in murine models suppressed carcinoid cell growth, reduced GSK-3β levels and reduced expression of chromogranin A. This study assessed the efficacy of Li in patients with NETs. Methods: Eligible pts had pathologically-proven, measurable low-grade NETs. Prior treatment was allowed if completed &gt;4wks prior to registration. Standard eligibility criteria were used, and use of medications affecting Li metabolism or levels were prohibited. A single-arm, open-label, two-stage Phase II design was used. Li was dosed at 300mg orally TID with meals, titrated to a target serum level of 0.8–1.0mmol/L. The primary endpoint was objective tumor response by RECIST. Secondary endpoints included overall survival, progression-free survival, decrease of serum tumor markers, toxicity, and quality of life. Results: 15 pts were enrolled between 10/3/07and 7/17/08; 6 men, 9 women. The median age was 58 (range 47–74). Patients’ diagnoses were carcinoid tumor for 8 subjects, islet cell tumor for 5 subjects, and 2 unknown primary sites. ECOG PS was 0 (6 patients) or 1 (9 patients). Two pts came off study due to side effects (tremor, dizziness/abdominal pain). There were no radiographic responses. Due to an early stopping rule requiring at least 1 objective response in the first 13 evaluable pts, the study was closed to further accrual. 13 patients had pre- and post-therapy biopsies. Evaluation of quality of life and GSK-3β levels in tumor tissue is ongoing. Conclusions: Li was ineffective at obtaining a radiographic response in our 13 evaluable patients who were treated as part of this study. We will determine from tumor biopsies whether Li was effective at phosphorylating GSK-3β in order to make conclusions about GSK-3β as a therapeutic target for future NET treatment strategies. Funded through NIH grant R21CA117117- 01A2 and CTRC grant 1ULRR025011. No significant financial relationships to disclose.

Detection of unknown primary neuroendocrine tumors (CUP-NET) using 68Ga DOTA-NOC receptor PET/CT

4599 Background: This bi-centric study aimed at determining the role of receptor PET/CT using 68Ga-DOTA-NOC in the detection of undiagnosed primary sites of neuroendocrine tumours (NETs). Methods: Overall 59 patients (M: F 33:26, age 65±9 yr) with documented NET and unknown primary, were enrolled. PET/CT was performed after injection of approximately 100 MBq (46–260 MBq) of 68Ga-DOTA-NOC. The maximum standardised uptake values (SUVmax) were calculated and compared with SUVmax in known pancreatic NET (pNET) and ileum / jejunum / duodenum (SI-NET). The results of PET/CT were also correlated with CT alone. Results: In 35/59 (59%) of patients, 68Ga-DOTA-NOC PET/CT localised the site of the primary: ileum/jejunum (14), pancreas (16), rectum (2), lungs (2) and paraganglioma (1). CT alone (on retrospective analyses) confirmed the findings in 12/59 (20%) patients. The mean SUVmax of identified previously unknown pNET and SI-Net were 18.6 ± 9.8 (range 7.8–34.8) and 9.1± 6.0 (range 4.2–27.8), respectively. SUVmax in patients with previously known pNET and SI-NET were 26.1± 14.5 (range 8.7–42.4) and 11.3±3.7 (range 5.6- 17.9). The SUVmax of the unknown pNET and SI-NET were significantly lower (p&lt; 0.05) as compared to the ones with known primary tumour sites. 19% of the patients had high grade, and 81% low grade NET. In 4/59 patients the primary tumour was subsequently resected (2 pancretic, one ileal and one rectal tumour). Conclusions: Our data indicate that 68Ga- DOTA-NOC PET/CT is highly superior to 111In Octreoscan (17% detection rate for CUP according to literature) and can play a major role in the management of patients with CUP-NET. No significant financial relationships to disclose.

A “live” biopsy in a small-cell lung cancer patient by detection of circulating tumor cells

A 71-year-old patient with a pulmonary lesion was diagnosed with a low-grade neuroendocrine tumor following examination of a fine needle aspiration biopsy. Analysis of a peripheral blood sample with the CellSearch™ system revealed the presence of putative circulating tumor cells (CTC) that were positive for EpCAM and cytokeratin (CK) expression. Since EpCAM is not usually expressed in neuroendocrine tumors, we performed a biopsy of liver metastases. Morphological and immunophenotypical characterization revealed that the patient had an EpCAM and CK positive small-cell lung cancer (SCLC). By using the CellSearch™ apparatus, EpCAM/CK positive CTC were detected in peripheral blood samples from 3 out of 4 additional SCLC patients. This study is the first to demonstrate that CTC can be identified in SCLC patients by using the CellSearch™ system.

Primary hepatic carcinoid: A case report and literature review

Carcinoids are tumors derived from neuroendocrine cells and often produce functional peptide hormones. Approximately 54.5% arise in the gastrointestinal tract and frequently metastasize to the liver. Primary hepatic carcinoid tumors (PHCT) are extremely rare; only 95 cases have been reported. A 65-year-old man came to our attention due to occasional ultrasound findings in absence of clinical manifestations. His previous medical history, since 2003, included an echotomography of the dishomogeneous parenchymal area but no focal lesions. A computed tomography scan performed in 2005 showed an enhanced pseudonodular-like lesion of about 2 cm. Cholangio-magnetic resonance imaging identified the lesion as a possible cholangiocarcinoma. No positive findings were obtained with positron emission tomography. Histology suggested a secondary localization in the liver caused by a low-grade malignant neuroendocrine tumor. Immunohistochemistry was positive for anti chromogranin antibodies, Ki67 antibodies and synaptophysin. Octreoscan scintigraphy indicated intense activity in the lesion. Endoscopic investigations were performed to exclude the presence of extrahepatic neoplasms. Diagnosis of PHCT was established. The patient underwent left hepatectomy, followed by hormone therapy with sandostatine LAR. Two months after surgery he had a lymph nodal relapse along the celiac trunk and caudate lobe, which was histologically confirmed. The postoperative clinical course was uneventful, with a negative follow-up for hematochemical, clinical and radiological investigations at 18 mo post-surgery. Diagnosis of PHCT is based principally on the histopathological confirmation of a carcinoid tumor and the exclusion of a non-hepatic primary tumor. Surgical resection is the recommended primary treatment for PHCT. Recurrence rate and survival rate in patients treated with resection were 18% and 74%, respectively.

Immunohistochemical basis for adjuvant anti-angiogenic targeted therapy for renal carcinoid: Initial case report

Objectives To evaluate the immunohistochemical profile of a carcinoid (low grade neuroendocrine tumor of the kidney) from a patient with lymph node positive disease who remains disease free for 31 months after radical nephrectomy, lymph node dissection, and adjuvant therapy with sunitinib malate. Methods Immunohistochemical staining was performed for chromogranin, synaptophysin, CD31, VEGF, HIF-1α, HIF-2, and Glut-1. Staining was evaluated in 3 high-power fields and samples scored as strongly positive (3+), moderately positive (2+), weakly positive (1+), or negative (0). A clear cell renal cell carcinoma was used as positive control. Results Immunohistochemical staining was strongly positive VEGF, weak to moderately positive for HIF-2, and negative for HIF-1α and Glut-1. Conclusions Our case of primary renal carcinoid stained intensely for VEGF and HIF-2, consistent with a VHL-HIF1-HIF2-Glut1 independent pathway for VEGF activation. These data suggest that like other neuroendocrine tumors, primary renal carcinoid is a potential target for anti-angiogenic therapy with sunitinib.

Extensive Expression of Collapsin Response Mediator Protein 5 (CRMP5) is a Specific Marker of High-grade Lung Neuroendocrine Carcinoma

The diagnosis of high-grade neuroendocrine tumors has strong clinical relevance because it identifies patients at higher risk of an unfavorable outcome who should receive multimodal treatment. However, these tumors can be mistaken for poorly differentiated nonsmall cell carcinoma or carcinoid lung tumors. In fact, no immunohistochemical marker can currently distinguish between histologic lung subtypes. Because the collapsin response mediator protein (CRMP) family is involved in an autoimmune disease associated with small cell lung carcinoma, we explored the relationship between CRMP5 expression and lung tumor behavior. Using World Health Organization morphologic criteria, 123 lung neuroendocrine tumors and 41 randomly selected non-neuroendocrine tumors were classified. CRMP5 protein expression in tumors, metastases, and healthy lung tissue was assessed using immunostaining method. Strong and extensive CRMP5 expression was seen in 98.6% of high-grade neuroendocrine lung tumors, including small cell lung carcinoma and large cell lung neuroendocrine carcinoma, but not in any of the squamous cell carcinomas or lung adenocarcinomas in our series. In contrast, the majority of low-grade neuroendocrine lung tumors were negative for CRMP5 staining, although weak CRMP5 expression was seen in some, with 2 different staining patterns of either scattered positive cells or small foci of positive cells. Our findings point at CRMP5 as a novel marker for routine pathologic evaluation of lung tumors surgical samples in distinguishing between highly aggressive neuroendocrine carcinoma and the other lung cancers.

Sandostatin Desensitization

Purpose: Currently there are no guidelines to manage patients with carcinoid tumors who would benefit from sansdostatin but are unable to tolerate it. We attempt a desensitizing strategy in such patients. Methods: 49-year old white male was evaluated for a history of painless jaundice of 1-week duration. He reported facial flushing, lasting years. Asymptomatic otherwise, and had no other significant personal or family history or physical examination findings other than facial flushing. Work up revealed distension of the gall bladder and dilatation of the common bile duct (CBD) (1.9 cm), hepatic ducts and a 3.5 cm hypodense lesion in the head of the pancreas. Patient underwent multiple endoscopic retrograde cholangiopancreatographies (ERCP) with stent placement; CBD biopsies and brushings did not reveal malignancy. Subsequent CT scan of the abdomen revealed multiple 10–15 mm ill-defined hepatic lesions and increased fullness in the pancreatic head. Biopsy of the pancreas revealed a low-grade neuroendocrine tumor of the pancreas head and neck. Octreotide uptake was noted in the head and neck of the pancreas and two hepatic lesions. Patient had an elevated chromogranin-A level of 6. While the patient was waiting for surgery (whipple procedure), he was started on sandostatin 150 mcg SQ bid, to be continued for 2 weeks, followed by long acting sandostatin once every month. However, patient reported severe nausea, vomiting, diarrhea, abdominal cramps after each dose of 150 mcg and was challenged a few days apart with 3 doses. There is no literature to guide management of these patients in terms of strategies for desensitizing patients as sandostatin can cause disease stabilization as well as minimize anesthesia complications during the peri-operative period and ultimately benefit the patient. We attempted a trial of gradually increasing the dose of sandostatin, starting at less than 1/3rd of the recommended dose, at 25 mcg subcutaneously (SQ) twice a day. Results: As the patient tolerated the dose, it was doubled every 3 days to eventually reach a dose that is within the lower range of recommended for achieving steady state concentrations. Upon reaching the targeted dose of 150 mcg SQ bid, he tolerated it without the intial severe gastrointestinal effects. Following this he was given a long acting sandostatin LAR injection of 20 mg deep intramuscularly, which he tolerated well, with some relief of his flushing as well. Conclusion: There are no guidelines to manage patients with carcinoid tumors who are unable to tolerate sandostatin. We report a desensitizing strategy that can be useful in such patients and situations where sandostatin is indicated for therapy of tumor (as a disease stabilizing agent) or for control of carcinoid symptoms.

Pulmonary Carcinoid Tumours: Indolent but Not Benign

Background: The aim of this retrospective study was to analyse the malignant behaviour of low-grade pulmonary neuroendocrine tumours (NETs) treated at our institution. Patients and Methods: We reviewed 48 consecutive patients with pulmonary NETs referred to our Medical Oncology Unit between 1998 and 2006, including 33 subjects with typical carcinoids (TCs) and 15 with atypical carcinoids (ACs). Results: At diagnosis, there were 37 metastatic and 11 non-metastatic patients. Medical treatments used were somatostatin analogues, combined chemotherapy, within study protocols, 5-fluorouracil/dacarbazine/epiadriamycin (FDE), and oxaliplatin plus capecitabine (XELOX). Median disease-free survival was 72 months for the TC patients and 38 months for the AC patients. Actuarial 5-year survival was 93% for those with TCs and 73% for those with ACs. The mean overall survival was 68 months for the non-metastatic patients (78 months for TC patients and 58 months for AC patients) and 36 months for patients with advanced disease (42 and 32 months, respectively). Conclusion: Cell type is the strongest determinant of prognosis, and the degree of malignancy increases from TCs to ACs. Moreover, the prognosis of metastatic pulmonary carcinoids is not as good as expected. Our analysis suggests that patients with advanced disease should receive first-line therapy with a somatostatin analogue, with chemotherapy regimens (FDE, XELOX) used in progressing cases.

Functional imaging of neuroendocrine tumors with combined PET/CT using 68Ga‐DOTATATE (DOTA‐DPhe1,Tyr3‐octreotate) and 18F‐FDG

The aim was to assess the relevant distribution of the novel PET tracer (68)Ga-DOTATATE in neuroendocrine tumors (NETs) with combined positron emission tomography / computed tomography (PET/CT) and compare its performance with that of (18)F-FDG PET/CT. The imaging findings with (68)Ga-DOTATATE and (18)F-FDG on 38 consecutive patients with a diagnosis of primary or recurrent NET were compared and correlated with tumor grade on histology based on ki67 and mitotic index. The sensitivity of (68)Ga-DOTATATE PET/CT was 82% (31 of 38) and that of (18)F-FDG PET/CT was 66% (25 of 38). The sensitivity of combined (68)Ga-DOTATATE and (18)F-FDG PET/CT was 92% (35 of 38). There was greater uptake of (68)Ga-DOTATATE than (18)F-FDG in low-grade NET (median SUV 29 vs 2.9, P < .001). In high-grade NET there was higher uptake of (18)F-FDG over (68)Ga-DOTATATE (median SUV 11.7 vs 4.4, P = .03). There was a significant correlation with predominant tumor uptake of (68)Ga-DOTATATE or (18)F-FDG and tumor grade on histology (P < .0001). (68)Ga-DOTATATE PET/CT is a useful novel imaging modality for NETs and is superior to (18)F-FDG for imaging well-differentiated NET. Functional imaging with both (68)Ga-DOTATATE and (18)F-FDG has potential for a more comprehensive tumor assessment in intermediate- and high-grade tumors.

Elevated expression of vascular endothelial growth factor correlates with increased angiogenesis and decreased progression‐free survival among patients with low‐grade neuroendocrine tumors

Vascular endothelial growth factor (VEGF) is a critical proangiogenic factor in solid tumors. However, its expression and role in human neuroendocrine tumor development and progression remains unclear. Using immunohistochemistry, VEGF and Sp1 expression patterns were investigated in 50 cases of human gastrointestinal neuroendocrine tumor having various clinicopathologic characteristics. It was found that strong VEGF expression was detected in tumor cells, whereas no or very weak VEGF expression was detected in stromal cells surrounding or within the tumors. The levels of VEGF expression directly correlated with the expression levels of Sp1 and microvessel density. Strong, weak, and negative VEGF expression was observed in 32%, 54%, and 14% of cases, respectively. Compared with the group with negative VEGF expression, VEGF (weak/strong) expression was associated with metastasis (14% versus 58%; P = .03). The median progression-free survival (PFS) durations of patients with strong and weak VEGF expression were 29 months and 81 months, respectively. With a median follow-up duration of 50 months, the median PFS duration for the group with negative VEGF expression has not been reached. Compared with the log-rank test, VEGF expression was associated with poor PFS (P = .02). Using in vitro and in vivo models, human carcinoid cell lines were treated with bevacizumab, a monoclonal antibody targeting VEGF. Bevacizumab did not inhibit the growth of carcinoid cells in vitro but significantly reduced tumor angiogenesis and impaired tumor growth in animals. The data suggest that overexpression of VEGF promotes the growth of human neuroendocrine tumors in part through up-regulation of angiogenesis.

Bronchial Typical Carcinoid Tumors

The current WHO classification of lung tumors recognizes bronchial typical carcinoid as low-grade neuroendocrine tumors. These tumors grow slowly but can metastasize to regional nodes (4 to 20%) and more rarely to extrathoracic sites. Symptoms are usually related to local compression and obstruction of the bronchial tree. Paraneoplastic syndrome can be present (carcinoid syndrome, Cushing's syndrome, acromegaly). Preoperative diagnosis is usually obtained with bronchoscopic biopsy. Computed tomography and somatostatin receptor scintigraphy are useful in the preoperative staging. Only selected cases can be treated endoscopically with laser resection. The complete surgical resection remains the only therapy with curative intent in the majority of patients. Parenchyma-sparing resections are indicated whenever possible. Overall survival after surgery is excellent (5-year rate, 87 to 100%) with low recurrence rate (2 to 11%). N-status and type of resection seem not to affect prognosis. Local relapse can be treated successfully with surgery, whereas distant metastases have a poor prognosis even after chemotherapy.

Fine-Needle Aspiration of Adrenal Cortical Carcinoma

We reviewed the cytologic features of 20 adrenal cortical carcinomas (ACCs; 9 primary and 11 metastatic) from 19 patients and highlighted diagnostic pitfalls. The mean size of primary ACCs was 11.9 cm, and that of metastatic ACCs was 3.0 cm. The metastatic sites were liver, lung, lymph node, soft tissue, and bone. Primary and metastatic ACCs were cytologically similar and showed a wide range of features varying from well-differentiated tumor resembling a benign cortical lesion or low-grade neuroendocrine tumor to poorly differentiated pleomorphic tumor mimicking poorly differentiated carcinoma, melanoma, or high-grade sarcoma. The common cytologic features were hypercellularity (70% of cases), necrotic debris in the background (70%), moderate to marked nuclear pleomorphism (80%), mitotic figures (90%), and prominent nucleoli (60%). Twenty percent of cases exhibited all 5 features; 40% exhibited 4 features, and 40% exhibited 3 features. Necrosis and/or mitosis were found in all cases, even in tumors with bland cytologic features. Cytologic, immunophenotypic, and ultrastructural findings should be correlated with clinical and radiologic information for achieving a proper cytologic diagnosis.

Fine-Needle Aspiration of Adrenal Cortical Carcinoma: Cytologic Spectrum and Diagnostic Challenges

We reviewed the cytologic features of 20 adrenal cortical carcinomas (ACCs; 9 primary and 11 metastatic) from 19 patients and highlighted diagnostic pitfalls. The mean size of primary ACCs was 11.9 cm, and that of metastatic ACCs was 3.0 cm. The metastatic sites were liver, lung, lymph node, soft tissue, and bone. Primary and metastatic ACCs were cytologically similar and showed a wide range of features varying from well-differentiated tumor resembling a benign cortical lesion or low-grade neuroendocrine tumor to poorly differentiated pleomorphic tumor mimicking poorly differentiated carcinoma, melanoma, or high-grade sarcoma. The common cytologic features were hypercellularity (70% of cases), necrotic debris in the background (70%), moderate to marked nuclear pleomorphism (80%), mitotic figures (90%), and prominent nucleoli (60%). Twenty percent of cases exhibited all 5 features, 40% exhibited 4 features, and 40% exhibited 3 features. Necrosis and/or mitosis were found in all cases, even in tumors with bland cytologic features. Cytologic, immunophenotypic, and ultrastructural findings should be correlated with clinical and radiologic information for achieving a proper cytologic diagnosis.

Are capecitabine and oxaliplatin (XELOX) suitable treatments for progressing low-grade and high-grade neuroendocrine tumours?

The aim of this trial was to evaluate the safety and efficacy of oxaliplatin and capecitabine (XELOX) in neuroendocrine tumours' (NETs) treatment. Forty patients (pts) with advanced NETs were treated. Of these, 13 had untreated poorly differentiated NETs, 27 had well-differentiated NETs in progression after somatostatin analogues. Patients received oxaliplatin e.v. 130 mg/mq i.v. and capecitabine 2,000 mg/mq/die. The primary sites of the disease were: lung (10 pts), pancreas (15 pts), small bowel (8 pts), unknown (1 pt), others (6 pts). In 13 pts with poorly differentiated NETs objective responses (OR) were: 3 PR (23%), 1 SD (7%), 9 PD (70%). Biochemical responses were 11%. In 27 patients with well-differentiated NETs the OR were: 8 PR (30%), 13 SD (48%) and 6 PD (22%). Biochemical and symptomatic responses were 20 and 50%, respectively. The XELOX regimen is effective and tolerated in well-differentiated NETs after progression following somatostatin analogues.

Leiomyomatoid angiomatous neuroendocrine tumor (LANT) of the pituitary: a distinctive biphasic neoplasm with primitive secretory phenotype and smooth muscle-rich stroma

We describe a hitherto undocumented variant of dimorphic pituitary neoplasm composed of an admixture of neurosecretory cells and profuse leiomyomatous stroma around intratumoral vessels. Radiologically perceived as a macroadenoma of 3.8 cm in diameter, this pituitary mass developed in an otherwise healthy 43-year-old female. At the term of a yearlong history of amenorrhea and progressive bitemporal visual loss, subtotal resection was performed via transsphenoidal microsurgery. Discounting mild hyperprolactinemia, there was no evidence of excess hormone production. Histologically, solid sheets, nests and cords of epithelial-looking, yet cytokeratin-negative cells were seen growing in a richly vascularized stroma of spindle cells. While strong immunoreactivity for NCAM, Synaptophysin and Chromogranin-A was detected in the former, the latter showed both morphological and immunophenotypic hallmarks of smooth muscle, being positive for vimentin, muscle actin and smooth muscle actin. Architectural patterns varied from monomorphous stroma-dominant zones through biphasic neuroendocrine-leiomyomatous areas, to pseudopapillary fronds along vascular cores. Only endothelia were labeled with CD34. Staining for S100 protein and GFAP, characteristics of sustentacular cells, as well as bcl-2 and c-kit was absent. Except for alpha-subunit, anterior pituitary hormones tested negative in tumor cells, as did a panel of peripheral endocrine markers, including serotonin, somatostatin, calcitonin, parathormone and vasoactive intestinal polypeptide. Mitotic activity was absent and the MIB-1 labeling index low (1-2%). While assignment of this lesion to any established neoplastic entity is not forthcoming, we propose it is being considered as a low-grade neuroendocrine tumor possibly related to null cell adenoma.

Is the new WHO classification of neuroendocrine tumours useful for selecting an appropriate treatment?

Neuroendocrine tumours (NETs) are a rare and heterogeneous group of neoplasms. The most recent WHO classification provides clinical tools and indications to make the diagnosis and to suggest the correct treatment in different subgroups of patients. The aim of this trial was to apply the new classification criteria in clinical practice and, accordingly, to choose the most appropriate treatment. Thirty-one evaluable patients, not previously treated, classified as advanced well differentiated NETs according to the new classification, were given long-acting release octreotide 30 mg every 28 days until evidence of disease progression. The treatment activity was evaluated according to objective, biochemical and symptomatic responses. Safety and tolerability were also assessed. Two partial objective tumour responses were obtained (6%), stabilization occurred in 16 patients (52%) and 95% of patients had a disease stabilisation lasting > or =6 months. However, eight patients showed rapid disease progression within 6 months of therapy and six patients after 6 months. Biochemical responses, evaluated by changes in serum chromogranine A levels were reported in 20/24 patients (83%). Symptomatic responses were observed in 6/14 patients (43%): a complete syndrome remission in one patient, partial syndrome remission in five patients, no change in four patients and progressive disease in four patients. The median overall survival was not reached, and the median time to disease progression was 18 months (range 1-49 months). The treatment was well tolerated, no severe adverse events were observed and no patient withdrew from the study because of adverse events. The WHO classification enables identification of low-grade NET patients who may be suitable for hormonal treatment. Octreotide LAR was seen to be effective in controlling the disease and was well tolerated. However, eight patients failed to respond to the treatment, despite histological evidence of a well differentiated tumour according to the new classification. This suggests that further histological examination should be carried out, especially in patients with visceral metastases and a short disease-free interval.

Effective treatment of neuroendocrine tumors With temozolomide and capecitabine

4216 Background: Low grade neuroendocrine tumors (NET), which are differentiated and metastatic, have a poor response to chemotherapy (<10%). This group (7000 cases per year in the U.S.) includes carcinoid tumors, pancreatic endocrine tumors (PETs), catecholamine-secreting tumors (e.g. pheochromocytomas), medullary carcinoma of the thyroid and excludes small cell cancers of the lung and GI tract. In our lab, we have found that capecitabine (5-FDUR), an oral pro-drug for 5-FU, and temozolomide are synergistic for induction of apoptosis in 2 human NET cell lines when given in a specific sequence and schedule. Our hypothesis is that the DNA damage induced by capecitabine, by incorporation of 5-FdUTP into DNA and reducing thymidine pools by inhibition of thymidylate synthase via 5-FdUMP, synergistically potentiates the effect of temozolomide on O6-alkylguanyl alkyl-transferase (O6-AGAT). Methods: We have treated ten patients with progressive metastatic NET who had failed chemotherapy and/or octreotide. Treatm...

ZOLLINGER-ELLISON SYNDROME WITH NORMAL SERUM GASTRIN LEVEL

Introduction: Zollinger-Ellison syndrome is characterized by gastric acid hypersecretion leading to refractory/recurrent peptic ulceration due to non-beta islet cell tumor. Diagnosis of Zollinger-Ellison syndrome is made by elevated serum gastrin levels or secretin stimulation test in appropriate clinical setting. We describe a case of Zollinger-Ellison that had near normal serum gastrin levels. Diagnosis was made with endoscopic ultrasound and confirmed by octreotide receptor scintigraphy and histopathology. Case Report: 53-year-old white male with history of 40 lbs weight loss over four months and peptic stricture was referred for evaluation of abdominal pain, diarrhea and symptoms of gastroesophageal reflux despite being on omeprazole 40 mg twice daily. Abdominal exam did not show any evidence of fluid or masses. The patient underwent an esophageal gastroduodenoscopy, which showed diffuse ulceration of esophagus, erosions in the stomach, ulceration in the duodenal bulb and second part of the duodenum. Liver enzymes were elevated and a trans abdominal ultrasound showed dilated pancreatic duct. A CT scan obtained at the same time did not reveal any abnormalities. Serum gastrin level initially was 37 pg/ml and later rose to 161 pg/ml; normal (40–200 pg/ml). Patient refused secretin stimulation test because of fear of symptoms off proton pump inhibitors. An endoscopic ultrasound (EUS) was performed which showed a 25 mm × 30 mm mass in the head of the pancreas. Fine needle aspirate of that mass suggested endocrine tumor. Octerotide scan showed high uptake in the mid epigastric area consistent with gastrinoma. The patient underwent a Whipple procedure and resection of low grade neuroendocrine tumor of the pancreas which stained positive for chromogranin, synaptophysin and pancytokeratin consistent with gastrinoma. The patient was discharged home after one week stay in the hospital. Currently patient is doing well without any complaints of gastroesophageal reflux, one-month post surgery. Discussion: Our case illustrates the fact that normal serum gastrin levels do not rule out the diagnosis of Zollinger-Ellison syndrome. When clinical suspicion of Zollinger- Ellison syndrome is high additional testing i.e. secretin stimulation test (which shows a paradoxical rise in the gastrin levels) or EUS should be done to confirm or refute the diagnosis. A EUS can be very helpful in such situations by not only establishing the diagnosis but also localizing the tumor for surgery.