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Neuroendocrine neoplasms (NENs) are derived from neuroendocrine cell system and can have benign or malignant characteristics. They are rare tumors, but have been increasing in incidence over the past 40 years. Patients with NENs may develop symptoms due to primary tumor invasion, metastasis, or from secretion of hormonally active tumor substances. Multiple imaging modalities are used for diagnosis and staging, including specialty scans such as 111In pentetreotide (Octreoscan) and 68Gallium-DOTATATE, along with endoscopy, endoscopic ultrasound, and biochemical marker testing. Treatment involves both surgical approach, for both primary and metastatic lesions, as well as medical management for symptom management and disease progression. This article will review the current clinical knowledge regarding the diagnosis, treatment, and prognosis of these fascinating neoplasms and the associated hormonal syndromes.

Since their first description in 1882, malignant neoplasms of the appendix still remain rare. Malignant carcinoid tumours are the most common accounting for 85% of all appendiceal neoplasms. Preoperative diagnosis is invariably difficult, and precise treatment protocols for these neoplasms remain unclear. We reviewed our experience and searched published evidence to produce management guidelines. A retrospective review of all malignant carcinoid tumours diagnosed in our hospital between April 1994 and December 2003 was performed. Patient demographics, operative details, histological types and clinical outcomes were retrieved from case notes supplemented by a questionnaire to the patient's General Practitioner. A literature search was then performed. Nine patients were identified with classical carcinoid tumours (CCT); (M = 3 and F = 6, mean age: 43, range 14-81) and two patients with goblet-cell morphology (F = 2, age 46 and 76). Mean follow-up was 63 months (range 1-125 months). Nine patients were alive at the end of follow-up. Appendicectomy was performed for acute appendicitis. Other appendiceal pathologies were identified following hemicolectomy and oophorectomy. CCT are the most common tumours and have the better prognosis. From our experience and subsequent review of the literature, we recommend right hemicolectomy as the treatment of choice for malignant carcinoid tumours. However, small CCTs less than 2 cm in diameter at the tip of the appendix, with a low proliferative index, without angiolymphatic or mesoappendiceal extension can be treated by appendicectomy. Following oncological assessment, further adjuvant therapy should be considered for patients with advanced disease.

Background Appendiceal carcinoid tumours are found in 0·3–0·9 per cent of patients undergoing appendicectomy. Controversy exists over the management following appendicectomy, especially with regard to the role of right hemicolectomy in patients with tumours smaller than 2 cm in diameter. Methods and results The literature pertaining to the behaviour of appendiceal carcinoids was reviewed in order to formulate indications for right hemicolectomy. Metastatic disease from appendiceal carcinoids is a rare occurrence, but is more common when lesions are larger than 2 cm in diameter. The risk–benefit balance of right hemicolectomy needs to be better defined, and an improved understanding of tumour cell biology may aid prognostic accuracy and decision-making. Conclusion There is limited evidence on which to base clear indications for right hemicolectomy in patients with a diagnosis of appendiceal carcinoid. Acceptable indications are carcinoids larger than 2 cm in size, any high-grade malignant carcinoid (including those with a high mitotic index), mesoappendiceal invasion, lesions at the base of the appendix with tumour-positive margins, and goblet cell adenocarcinoid tumours.

Carcinoid tumors arise from argentaffine cells or from a primitive stem cells which may differentiate into anyone of a variety of adult endocrine-secreting cells. Carcinoid tumor of the pancreas is a very rare tumor with less than 50 cases reported in world literature. In literature it is denoted "pancreatic serotoninoma" or "serotonin-producing pancreatic tumor". Due to its rarity the tumor is an unusual cause of carcinoid syndrome. As the carcinoid tumor of the pancreas does not always causes carcinoid syndrome its absence does not necessarily exclude the existence of the tumor. The tumor is frequently malignant. Over 50% of patients have metastases at the time of surgery. This is the reason why radical surgery is not possible in a number of patients. Excisional surgery offers the best chance for recovery or long term survival. We report on a 57-year-old woman with carcinoid syndrome caused by malignant carcinoid tumor of the head of the pancreas without liver or other distant metastases; it was successfully excised with pylorus preserving cephalic duo-denopancreatectomy (after Longmire-Traverso) and radical lymphadenectomy. The diagnosis was established on the basis of histologic and immunohistochemical findings. The patient is symptom free for more than eight months.

Carcinoids are rare neuroendocrine tumors encountered most commonly in the gastrointestinal tract and bronchopulmonary tree. While carcinoids are perhaps best distinguished by their ability to cause the carcinoid syndrome through secretion of vasoactive peptides and amines, the vast majority are asymptomatic. We herein describe the case of a 68 year-old woman who presented with weight gain and local compressive symptoms from a known pelvic cystic teratoma, which was found to contain a well-differentiated malignant carcinoid at the time of surgical excision.

A 47 year old male patient came to our attention for severe anaemia. Although Gujak test for occult blood in the stool was repeatedly positive, x-ray films and endoscopic methods did not yield a definite diagnosis. Ultrasound only was able to identify a mass in the small intestine. Intraoperatively the diagnosis was confirmed; the tumour was a highly malignant carcinoid on pathologic examination.

PURPOSE: To describe the clinical and histopathologic findings in a patient with corticosteroid-induced open-angle glaucoma attributable to an adrenocorticotropin-secreting malignant carcinoid of the thymus. METHODS: Case report. In a 33-year-old man, the clinical course, laboratory findings, and imaging results as well as the histopathologic findings are described. RESULTS: Increased intraocular pressure in this patient represented a manifestation of severe hypercortisolism attributable to a malignant adrenocorticotropin-secreting carcinoid tumor. Surgical removal resulted in return of the intraocular pressure values to normal levels. CONCLUSION: Thymic carcinoid is a rare cause of Cushing syndrome, which can lead to increased intraocular pressure.

During the last year, Journal of Clinical Oncology (JCO) celebrated its first 25 years of publication by reproducing articles from 1983, JCO’s first year of publication, with concurrent commentary by the original authors of those articles. With little editorial direction, all of the authors wrote pieces that inform the history of oncology. Each took a unique approach, giving each article a truly personal perspective on the evolution of our specialty. As a body of literature, they represent the history of oncology. As such, they should be required reading for all who care for patients with cancer, and most particularly for those who have trained recently and may not have known or interacted with the people who defined oncology as a discipline. For each article, at least one of the original authors wrote a commentary, with the exception of Charles (Chuck) G. Moertel’s “Treatment of the Carcinoid Tumor and the Malignant Carcinoid Syndrome.” This is one of the best examples of medical writing in JCO or in any other medical journal. Larry K. Kvols, who worked with Chuck Moertel at the Mayo Clinic for 18 years, was gracious enough to write the commentary for the original 1983 article. When Chuck died, we lost one of our best writers, teachers, and clinical researchers. For those unfortunate enough not to have heard his Karnofsky Memorial Lecture on the topic of gut neuroendocrine tumors, “An Odyssey in the Land of Small Tumors,” JCO published the text of his lecture in 1987. This is not the place to review the entire series of articles—we hope that you will read your print copy or go to www.jco.org and access these articles under “25th Anniversary Celebration” on the home page. Their breadth reflects the amazing job Joe Bertino, MD, JCO’s first Editor-in-Chief, did in attracting seminal papers in oncology. In his editorial published in the January 1, 2008, edition of the Journal, Joe Bertino reflected on what then seemed a daunting task: “...by begging and calling and twisting arms, we persuaded some outstanding investigators to send their ‘good stuff ’ to JCO. So the first issue had a number of seminal papers/reviews by Gianni Bonadonna, Saul Rosenberg, Ray Warrell and Joe Burchenal, and Ian Tannock and Kevin Murphy.” Joe Bertino certainly succeeded. The fledgling JCO published many outstanding articles that likely would have gone to more established journals, making my task of selecting articles to be reproduced throughout this anniversary year—save this last issue— really quite easy. The current editors of JCO will be interested to see whether future editors will recapitulate this series or the concept of it for JCO’s 50th Anniversary Celebration. More importantly, we hope that all of the current readers and editors have had or will have the same pleasure in reading the articles and commentaries as we did throughout 2008.

9657 Background: Human chorionic gonadotropin (hCG) is not by itself sensitive or specific for malignancy. However, in multiple carcinomas multivariate analysis indicates that preoperative serum hC...

We present a case of malignant carcinoid initially diagnosed as rosacea. This patient was later found to have an additional functioning parathyroid tumour. Although a pituitary tumour was not identified, the association represents a probable case of multiple endocrine neoplasia type 1 (MEN 1). This autosomal dominant syndrome is characterized by tumours of the pancreas, parathyroid and pituitary. Inoperable carcinoid tumour is best treated with a long-acting somatostatin analogue, octreotide. A diagnosis of MEN 1 has important connotations for the proband's first-degree relatives, who should be entered into an appropriate screening programme.

A 64-year-old woman with a malignant carcinoid tumor began receiving monthly treatment with 30 mg long-acting Sandostatin suspension injected intramuscularly in the buttocks along with 200 μg Sandostatin (Novartis, Hanover, NJ) subcutaneously once per day in 1994. Tc-99m MDP bone imaging showed areas of extensive metastases. To better characterize the extent of disease, In-111 pentetreotide imaging was performed, with images acquired at 24 hours. In addition to widespread disease, unusual uptake was shown in the upper outer quadrants of both buttocks, apparently at the sites of intramuscular Sandostatin injection. Recent studies of single-dose intramuscular injections have shown that Sandostatin injection may lead to localized granulomatous myositis and granuloma formation. In this patient, two large areas of increased uptake located in both buttocks are seen at the sites of repeated intramuscular injection of Sandostatin.

Twenty-five cases of neuroendocrine tumors of lung, including bronchial carcinoids (eight), malignant (atypical) carcinoids (nine), and large cell undifferentiated carcinomas (LCAC) with neuroendocrine differentiation (eight) were analyzed. All carcinoids (BC) could be diagnosed by light microscopy; all patients with these tumors are alive without disease. Five of nine malignant carcinoids (MC) could be recognized histologically; four of nine were called LCAC and required electron microscopy for diagnosis. Survival correlated best with stage of diagnosis. High-grade neuroendocrine carcinomas (LCAC-NE) required electron microscopy for their diagnosis. Seven were LCAC histologically; one was diagnosed as malignant carcinoid (MC). Such tumors resemble small cell anaplastic carcinomas ultrastructurally and behaviorally. All eight patients with such high-grade tumors died of their disease; three of eight had no nodal metastases at the time of resection. This experience suggests it is clinically important to distinguish neuroendocrine neoplasms since behavior is predictable on the basis of morphology.

An undifferentiated small cell tumor of the colon that was found by light- and electron-microscopic study to possess features of a malignant carcinoid merged into keratinizing squamous cell carcinoma. Single cells contained both dense-core secretory granules and tonofilaments. The implications of this combination in relation to theories of tumor origin and differentiation are briefly discussed.

Gastrointestinal carcinoid tumors arising from the foregut and hindgut may metastasize within the abdomen. Bone metastases are rare, but their occurrence is well established. Both osteoblastic and osteolytic metastases can occur in the same patient without any bone symptoms. Three patients with malignant carcinoid tumors had no bone symptoms but demonstrated extensive bone metastases on radionuclide bone scans. Some of these lesions were abnormal on corresponding roentgenograms and some areas were negative on roentgenograms. The use of radionuclide bone scanning in the evaluation of patients with malignant carcinoid tumor is emphasized.

In a retrospective review, we were able to identify records for 18 patients who were treated for malignant carcinoid in our Departments of Radiation Oncology from 1974-1985. At postmortem examination, one was found not to have malignant carcinoid. In 4 cases irradiation was administered postoperatively to patients whose subsequent courses did not permit assessment of objective response. Using standard criteria for objective response, an objective response rate of 54% was observed in the 13 cases whose records were adequate to make this assessment. Of the 7 responses, 3 were complete within the treated field as judged by clinical findings (2 patients) or postmortem examination (1 patient). Of the 6 nonresponders, 2 interrupted treatment prematurely, 2 were treated to a planned dose of only 2000 and 2500 cGy, and 2 were treated palliatively to limited ports which included only partial volumes of tumor. We conclude that radiation therapy is an effective treatment modality with a high rate of objective response in the management of those patients with malignant carcinoid tumors who require non-surgical, anti-neoplastic therapy.

We report a case of a presacral teratoma containing a malignant carcinoid component associated with an anterior sacral meningocele that presented in a 35-year-old woman. The clinical, radiographic, and pathological features of these rare tumors, of presacral meningoceles, and of the hereditary presacral teratoma syndrome are discussed. (Neurosurgery 22:581-588, 1988)

Postmortem examination in a patient with a widely disseminated pulmonary carcinoid tumor revealed invasion of a fibroblastic meningioma by metastatic tumor cells. To the authors' knowledge, this case represents the first example of a malignant carcinoid tumor that has metastasized to a primary intracranial neoplasm. The literature concerning metastasis of extracranial to primary intracranial tumors is briefly reviewed.

This paper presents a unique apudoma variant--a malignant carcinoid of mid and lower oesophagus in an elderly man. It was remarkable in the short duration of the clinical symptoms, its rather easy resectability despite its large size and the local perigastric lymph node metastases. On light microscopy, the neoplasm was composed entirely of atypical but uniform round cells lacking argentaffin and argyrophilic staining, arranged in a carcinoid pattern. On electron microscopy, they exhibited dense-core neurosecretory granules.

A case of primary malignant laryngeal carcinoid with dual endocrine and mucous differentiation i s reported. Histologically the tumor showed a characteristic organoid pattern and exhibited Alcian-blue, periodic acidschiff, and Grimelius silver positivity. By the immunoperoxidase technique cal citoni n, ACTH, and or-hCG subunit were demonstrated in the tumor cells. ELectron microscopy revealed two different types of endocrinelike cells: mucous cells and occasional cells containing both endocrinelike granules and mucin droplets. Diagnostic morphologic criteria of this rare tumor entity are discussed and reference t o biologic behavior and possible h istogenesis is made.

The malignant carcinoid syndrome (MCS) is a rare complication of malignant carcinoid neoplasms, fewer than 200 cases having been reported since its description by Thorson in 1954. Its signs and symptoms vary with the site of the primary neoplasm, and MCS is now recognized as one member of the large family of endocrine tumors - APUDOMAS). Although MCS remains uniformly fatal, significant palliation can be provided some patients with current surgical and chemotherapeutic management. All signs and symptoms in MCS, except evidence of the destruction of the tricuspid and pulmonic valves, can be reproduced experimentally. The factor causing this lethal complication has not been identified. Two previously unreported cases of MCS, each from the gastrointestinal (GI) tract, are presented. This brings the world's total reported cases to approximately 210.

The medical management of metastatic endocrine tumors, such as malignant insulinoma, adrenal carcinoma, and malignant carcinoid, involves the use of both anticancer and antihormonal chemotherapy. The former is directed against the primary tumor and its metastases, while the latter offers palliation through the inhibition of synthesis, release, or direct cellular action of the specific secretory product. The current clinical results with the use of streptozotocin in malignant insulinoma, and o,p′DDD in the treatment of adrenocortical carcinoma are reviewed.

Summary 1. The pathogenesis, incidence, location and pathology of carcinoid tumors (argentaffinomas) of the gastrointestinal tract were discussed. 2. Twelve cases of carcinoid tumors were tabulated. Two cases, a malignant carcinoid of the rectum and a benign gastric carcinoid, were reported in detail.

A case of congenital pulmonary stenosis with tricuspid insufficiency and a peculiar type of cyanosis in an 19-year-old boy is described. The patient died in connection with angiocardiography. At autopsy, the clinical diagnosis was verified; in addition to the cardiac lesion there was a malignant carcinoid of the jejunum with metastases to the liver. The findings are briefly discussed and an explanation of the type of cyanosis is suggested.

During the course of anaesthesia, in patients with malignant carcinoid disease, sudden episodes of hypotension may occur. These are apparently due to the failure of compensatory mechanisms in the cardiovascular system to adjust rapidly to the effects of sudden serotonin release.

WE recently recognized distinctive ophthalmic consequences of the carcinoid syndrome that have not been reported. Patients with malignant carcinoid were studied during their hospital courses at the National Institutes of Health. Their ocular changes form the basis of this report. Material and Methods The subjects were 16 patients from thirty-three to sixty-nine years old. The diagnosis of carcinoid tumor was established histologically by biopsy, pharmacologically by flushes induced with epinephrine1 2 3 and chemically by the demonstration of abnormally large concentrations of serotonin (5-hydroxytryptamine) in platelets and of 5-hydroxyindoleacetic acid (5-HIAA) in the urine. Epinephrine hydrochloride (2 to 10 μg.) was diluted . . .

SummaryA malignant carcinoid of the small intestine, presenting the syndrome described by Thorson and coll. : argentaffine tumour of the intestine, variable cutaneous erythema and cyanosis, valvular heart disease acquired in some cases.It is now demonstrated that these tumours are secreting 5 hydroxytryptamine, 5-HT, also called Enteramine or Serotonin, cause of the symptomatology.

In this paper we have attempted to define the relationships between clinical medicine and diagnostic or, as it is more frequently termed, clinical biochemistry. We have indicated first, the role that general biochemistry has played in elucidating mechanisms of disease and in providing the clinician with procedures that aid him in the diagnosis of disease and in the care of the patient. We have illustrated this role by reviewing very briefly some of the recent contributions such as the expanded diagnostic use of serum enzymes; the correlation of subcellular structure in human tissues with function at enzymatic levels; the investigation of enzyme variants; the metabolism of epinephrine and norepinephrine in pheochromocytoma; the metabolism of tryptophan in malignant carcinoid; and enzyme defects in hereditary disease. We noted the reservations with which the clinician frequently views the specific results that he obtains from the diagnostic biochemistry laboratory and have attempted to analyze the bases for these reservations. In this connection we considered the phenomenon of interlaboratory variability, the nature of the random and the constant errors that may exist within a laboratory, and the measures that the clinical biochemist may take to counteract these errors. We have tried to indicate the steps the clinician may take in a fuller and more knowledgeable utilization of the data from the diagnostic biochemistry laboratory. These involve a recognition of the efforts and advances that are being made in increasing precision and accuracy within the laboratory and the role that the clinician himself can play in contributing to this precision and accuracy. The phenomenon of intraindividual and interindividual variability of biochemical parameters, and the significance of this phenomenon in diagnosis, are also worthy of the clinicians attention. Finally, the clinician should abjure the concept that a seeming discrepancy between his formulation and laboratory results usually means a laboratory error. Thoughtful review, in cooperation with the biochemist, of such discrepancies are of value both for clinical medicine and clinical biochemistry.

This is the case of a 52-year-old man with regional enteritis treated by ileal resection. Recurrent symptoms led to further resection and the surgical specimen showed persistent regional enteritis and malignant carcinoid tumor. A recent review which discussed all tumors reported to occur concomitantly with Crohn’s disease did not include this particular combination.

Of a group of 13 patients with carcinoid tumours, 10 were investigated biochemically during life, and 3 tumours were discovered post mortem. Nine of the 10 patients had significantly elevated levels of 5-hydroxytryptamine in blood platelets, but only 7 showed markedly increased levels of 5-hydroxyindoleacetic acid in urine. One of these patients excreted the precursor 5-hydroxytryptophpn, as well as 5-hydroxytryptamine and 5-hydroxyindoleacetic acid. Analysis of tumour tissue from this patient showed only low levels of 5-hydroxytryptamine (16 μg/g) when compared with the levels from other carcinoid tumours (50-500 μg/g). A primary tumour in this patient could not be located at autopsy. In another patient with widely disseminated metastases, a small primary tumour was found in a Meckel's diverticulum, a rare site of development. Of the 3 carcinoid tumours discovered post mortem, the first involved the appendix and right ovary; in the second case, multiple primary tumours occurred in the jejunum, while in t...