Classical Carcinoid Research Articles

Comment on the Article by Chetty et al on Combined Classical Carcinoid and Goblet Cell Carcinoid Tumor

Comment on the Article by Chetty et al on Combined Classical Carcinoid and Goblet Cell Carcinoid Tumor

Neuroendocrine tumors of the gallbladder: a case report and review of the literature

IntroductionPrimary gallbladder neuroendocrine tumors are extremely rare, representing 0.2% of all neuroendocrine tumors. The diagnosis is incidental in most cases.Case presentationWe describe the case of a 57-year-old Caucasian man who underwent laparoscopic cholecystectomy for the evaluation of a gallbladder polyp that had been incidentally detected by ultasonography. Histologically, his lesion was composed of monomorphic cells that contained small round nuclei and that were organized in small nodular, trabecular, and acinar structures. His cells were positive for chromogranin A and synaptophysin, and a diagnosis of "typical" carcinoid of the gallbladder was made. His post-operative computerized axial tomography, 111In-pentetreotide scintigraphy, and hormone-specific marker results were negative. He is disease-free 45 months after surgical treatment.ConclusionsCharacteristic pathological findings of the gallbladder neuroendocrine tumors predict the prognosis. Whereas classical carcinoids of the gallbladder only rarely have a metastatic or invasive phenotype, the "atypical" variants are more aggressive and are associated with a poorer prognosis. Given the difficulty in distinguishing between benign and malignant lesions in the pre-surgical setting, we tend to consider each polypoid-like lesion of the gallbladder to be a high-risk lesion if it is larger than 1 cm and, as a result, to emphasize the need for cholecystectomy in all cases, relying on the pathological and immunohistochemistry analyses for the final diagnosis.

Resektionsausmaß bei neuroendokrinen Tumoren des Dünndarms

Neuroendocrine tumors of the small intestine have been diagnosed with increasing frequency over the past 35 years and presently account for approximately 2% of all gastrointestinal neoplasms. While most of these tumors are discovered incidentally during emergency laparotomy or in the clinical setting of unknown primary cancer with hepatic metastases, the growing awareness of this rare entity and improved diagnostic methods promote earlier diagnosis. The classical carcinoid syndrome with flush, diarrhea and cardiac strain is observed only in 20-30% of patients. The clinical symptoms necessitate a special preoperative preparation of the patient including evaluation of cardiac function.Prospective studies assessing the efficacy of surgical treatment strategies for neuroendocrine neoplasms of the small intestine do not exist. However, retrospective studies have demonstrated that curative as well as palliative resection of the primary tumor improves the prognosis and the quality of life of patients. Besides limited resection of the small bowel in order to avoid postoperative short bowel syndrome an effective clearance of the regional lymph nodes is essential. A primary tumor site in the terminal ileum requires dissection of the lymph nodes on the right side of the ileocolic artery which usually implies an additional resection of the right colon. In cases of a primary tumor site located in the lower ileum up to the distal jejunum, a cone-shaped resection of the mesenterium of the small bowel with extension of lymphadenectomy into adjacent segments with preservation of vascularization is performed.

Combined Classical Carcinoid and Goblet Cell Carcinoid Tumor: A New Morphologic Variant of Carcinoid Tumor of the Appendix

Carcinoid tumors are the most common neoplasms of the appendix. Histologically they have been categorized as classical, tubular, or goblet cell types. Goblet cell carcinoid has been regarded as a distinctive tumor type, not related to classic carcinoids, and to our knowledge combinations of these 2 tumor types have not been described in detail. In this report, we describe 5 cases of combined classical carcinoid and goblet cell carcinoid (GCC) tumors of the appendix. Four men and 1 woman, (mean age 53.4 y) presented with acute appendicitis (4 cases), whereas 1 presented with a pelvic mass owing to widespread pelvic disseminated disease. The tumors (0.6 to 6.0 cm) were located in the mid-portion and the tip of the appendix. Four patients were treated with right hemicolectomies (the patient with disseminated pelvic and ovarian metastases also had a pelvic exenteration), and 1 was treated with an appendectomy only. Four patients are alive and asymptomatic, whereas the patient with disseminated pelvic disease died 6 months after surgery. All 5 appendiceal tumors had microscopic features of both classical carcinoid and GCC, either intimately admixed or separate but closely apposed. The extent of the 2 components varied, with classical carcinoid representing 60% to 90% of the tumor. Both components stained for the general neuroendocrine markers, however, staining in the classic component was greater. The Mib-1 proliferation index varied from 1-15%, again with higher Mib-1 indices seen in the GCC component of all 5 cases. The pelvic soft tissue and ovarian metastases in case 4 consisted predominantly of a signet ring cell carcinoma with a minor component of goblet cells and was interpreted as an adenocarcinoma ex-GCC. In view of the fact that these combined carcinoid tumors appear to behave more as goblet cell carcinoids, detailed microscopic examination of classical carcinoid tumors of the appendix is suggested and larger series with longer follow-up is required to ascertain the true biologic potential of this unique form of combined carcinoid tumor of the appendix. The occurrence of both carcinoid types in the same appendices suggests a closer histogenetic relationship than previously believed, although the possibility that the 2 components represent separate, independent primaries ("collision tumors") can also be considered.

The NANETS Consensus Guideline for the Diagnosis and Management of Neuroendocrine Tumors

Well-differentiated neuroendocrine tumors (NETs) of the jejunum, ileum, and appendix are also collectively known as midgut carcinoids. Similar to NETs in general, the diagnosed incidence of the midgut NETs is on the rise. Their presenting symptoms vary depending on stage and primary site. Local-regional NETs often present with vague and nonspecific symptoms. Classic carcinoid syndrome is more likely to appear in patients with advanced disease. Local-regional NETs of the small bowel should be resected whenever possible. With the exception of small well-differentiated NETs of the appendix, NETs of the midgut have substantial risk of relapse after resection and need to be followed for at least 7 years.Metastatic/advanced NETs of the midgut are incurable. Optimal management requires a multidisciplinary approach. Somatostatin analogs are effective in the management of carcinoid syndrome. Octreotide long-acting release has also recently been shown to delay disease progression. Liver-directed therapy and surgical debulking can improve quality of life in selected patients. Pivotal phase 3 studies with bevacizumab targeting vascular endothelial growth factor and everolimus targeting mTOR (mammalian target of rapamycin) are ongoing and may lead to improved outcome. Further studies of novel approaches such as peptide receptor radiotherapy are also warranted.

Gastrointestinal neuroendocrine (carcinoid) tumours: current diagnosis and management

Neuroendocrine tumours (NETs) are increasing in both incidence and prevalence and, as a group, are more prevalent than either gastric, pancreatic, oesophageal or hepatobiliary adenocarcinomas, or any two of these cancers combined. Clinical awareness of the protean and intermittent symptoms of NETs (eg, sweating, flushing, diarrhoea, and bronchospasm) is critical for timely diagnosis; however, the classical carcinoid syndrome is relatively uncommon. The most useful diagnostic test for gastrointestinal NETs is measurement of plasma chromogranin A (CgA) levels. Disease extent is assessed by both anatomical imaging, and nuclear imaging with radiolabelled somatostatin analogues. Pathological evaluation comprises tumour-node-metastasis classification, a minimum pathological dataset, CgA and synaptophysin immunostaining, as well as mitotic count or Ki-67 index (a marker of cell proliferation) to define grading. Resection of the primary lesion and as much metastatic disease as possible increases the efficacy of medical therapy. Other management strategies include hepatic embolisation and peptide receptor radionuclide therapy. Patients with tumours expressing somatostatin receptors should be treated with somatostatin analogues. Depending on the tumour grade, other effective agents include cytotoxics, tyrosine kinase inhibitors, and antiangiogenics. The overarching requirement for best management of patients with NETs is to ensure that they have ready access to experienced multidisciplinary clinician groups located within centres of appropriate subspecialty expertise.

Cervical and Endometrial Metastases of Appendiceal Goblet Cell Carcinoid

Appendiceal goblet cell carcinoid (GCC) is a rare tumor with histologic features of both adenocarcinoma and neuroendocrine tumor (carcinoid). Clinically, it behaves more aggressively than classic appendiceal carcinoid and commonly presents with peritoneal carcinomatosis. We report 2 cases of appendiceal GCC, one with uterine cervical involvement and the other with endometrial involvement as the initial presentations. The first patient's invasive cervical signet ring cell carcinoma was diagnosed on routine screening. The second patient presented with abnormal uterine bleeding, and endometrial curettage showed an adenocarcinoma with signet ring cell features. Primary appendiceal GCC was demonstrated in both cases after systematic clinical investigations. Metastatic appendiceal GCC to uterine cervix and endometrium can potentially be misinterpreted as primary cervical or endometrial signet ring cell carcinoma. Therefore, for any uterine cervical/endometrial signet ring cell carcinoma, a metastatic appendiceal GCC should be considered in the differential diagnosis, especially after excluding other primary sites.

Neuroendocrine gastroenteropancreatic tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Neuroendocrine gastroenteropancreatic tumours : ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Pitfalls in neuroendocrine tumor diagnosis

Pitfalls in neuroendocrine tumor diagnosis

Endocrine Tumor of the Pancreas

Clinicopathological findings and pancreatograpy of thirteen patients (male: female = 7:6) with nonfunctioning endocrine tumors (ET) of the pancreas were reviewed. Abnormal endoscopic retrograde pancreatography (ERP) findings were observed in eight 22 cases (62%). Tumors with lymphatic invasion, venous invasion and/or splenic vein invasion were defined as malignant ET. Four malignant ET showed abnormal ERP findings, while five ET without any ERP findings were all histologically benign. A relationship between ERP findings and histological malignant potential is suggested. Histological examination revealed that changes of the main pancreatic duct (MPD) could be classified into three patterns; 1) tumor compression of the MPD (n = 3), 2) tumor infiltration into the MPD (n = 2), 3) tumor with fibrous stroma proliferating around the MPD (n = 3). Tumors showing the last histological findings were all immunoreactive to serotonin antibody, therefore these tumors were those of classical enterochromaffin cell carcinoid tumors.

Neuroendocrine gastroenteropancreatic tumors: ESMO Clinical Recommendation for diagnosis, treatment and follow-up

Neuroendocrine gastroenteropancreatic tumors : ESMO clinical recommendation for diagnosis, treatment and follow-up

Goblet Cell Carcinoid of the Appendix

A goblet cell appendiceal carcinoid (GCAC) is an uncommon tumor. It shares the histologic features of both adenocarcinoma and conventional carcinoids. The metastatic potential of GCAC is higher than that of classic appendiceal carcinoids. Their management, whether an appendectomy alone is an adequate treatment or whether a right hemicolectomy is indicated, is still under debate. The metastatic potential of GCAC is similar to that of classic appendiceal carcinoids and depends on the tumor size and the mitosis rate. Therefore, some authors advocate a simple appendectomy, not expanding beyond the appendix adventitia, for selected patients with tumors less than 1 cm in diameter with a low mitosis rate (<2/10 HPF). Otherwise, a right hemicolectomy is indicated for all other patients to reduce the risk of developing metastatic disease. Chemotherapy is the usual treatment option for metastatic disease, but more data are required if an optimal regimen is to be determined. Finally, colonoscopy plays an important role in patients with an appendiceal adenocarcinoid because of their high risk of developing a colorectal adenocarcinoma. Recently, we discovered one case of a GCAC that was diagnosed incidentally at appendectomy. A 48-yr-old man visited the emergency department with the symptom of right lower quadrant abdominal pain. Acute appendicitis was suspected after evaluation, and a laparoscopic appendectomy was performed. The type of appendicitis was gangrenous, and there were no obvious signs of malignancy. However, a pathologic diagnosis of a goblet cell carcinoid was made. A laparoscopic right hemicolectomy was subsequently performed. The patient received 5 cycles of chemotherapy applied to the goblet cell carcinoid and has shown no other remarkable indispositions during the last 12 mo.

Combined goblet cell carcinoid and mucinous cystadenoma of the vermiform appendix

Goblet cell carcinoid is an uncommon primary tumor of the vermiform appendix, characterized by dual endocrine and glandular differentiation. Whether goblet cell carcinoid represents a morphological variant of appendiceal classical carcinoid or a mucin-producing adenocarcinoma is a matter of conjecture. Rare cases of goblet cell carcinoid with other concomitant appendiceal epithelial neoplasms have been documented. In this report, we describe a rare case of combined appendiceal goblet cell carcinoid and mucinous cystadenoma, and discuss the possible histopathogenesis of this combination.

Large Cell Neuroendocrine Cancer (LCNEC) of uterine cervix: A case study and review of literature

Large cell neuroendocrine carcinoma (LCNEC) of the uterine cervix is a very rare malignancy (less than 5% of all cervical malignancies) that is highly aggressive and usually results in unfavorable outcomes1,2. These tumors have been classified into four categories: small cell, large cell, classic carcinoid, and atypical carcinoid. Most patients with early stage disease develop metastatic disease. Frequent metastatic sites include the central nervous system, lung, and bone3. Despite aggressive surgical therapy, even in early-stage patients, mortality is high. This propensity for rapid, local and distant spread in early-stage disease emphasizes the need for systemic treatment2. In some cases, the initial diagnosis may be confused with either poorly differentiated squamousor adeno-carcinomas3.

Goblet cell carcinoid of the appendix: a specific type of carcinoma

Goblet cell carcinoid is a poorly understood tumour of the appendix. The aim of this study was to determine whether it should be regarded as a separate entity or as a variant of classical carcinoid. The immunohistochemical expression pattern of 21 markers and the mutation status of KRas codon 12 were determined in 16 goblet cell carcinoids and compared with 14 classical carcinoids, 19 colonic adenocarcinomas and 10 appendiceal mucinous cystadeno (carcino)mas. The results were subjected to a stepwise linear discriminant analysis. Goblet cell carcinoids were significantly different from the control groups. The most important markers for discriminating between the groups were CEA (classical carcinoid versus all others), KRas mutation (present in all mucinous cystadeno (carcino)mas), beta-catenin (goblet cell carcinoid versus left sided colonic adenocarcinoma) and chromogranin (goblet cell carcinoid versus right sided colonic adenocarcinoma). Expression of Math1 and HD5 was similar in goblet cell carcinoid and colonic adenocarcinoma but absent in classical carcinoid. The results suggest that goblet cell carcinoids should be regarded as a separate entity. The formerly used term 'crypt cell carcinoma' may be more appropriate because it reflects the more aggressive clinical behaviour of these tumours as well as their greater similarity to adenocarcinomas rather than to carcinoids.

CK19 and CD99 Immunoexpression Profile in Goblet Cell (Mucin-Producing Neuroendocrine Tumors) and Classical Carcinoids of the Vermiform Appendix

The immunoexpression of CK19 recently has been identified as a marker of poor prognosis in pancreatic endocrine tumors and hepatocellular carcinoma. Conversely, the loss of expression of CD99 has been suggested to play a role in the tumorigenesis and dedifferentiation and is associated with poor outcome in some malignancies. The purpose of this study was to explore CK19 and CD99 immunostaining in mucin-producing neuroendocrine (goblet cell) and classical carcinoids of the appendix. Eighteen goblet cell carcinoids (GCCs) and 20 classic carcinoids were stained with CK19, CD99, and Ki-67, and these results were correlated with known pathological features of aggression: extent of invasion, mitoses, necrosis, and histological pattern. All 18 GCCs were CK19 strongly positive, whereas 16/20 classic carcinoids were also CK19 positive. Fourteen of 18 GCCs and 14/20 classic carcinoids were CD99 positive. CK19/CD99 immunoexpression did not correlate with extent of tumor invasion and mesoappendiceal extension, mitotic activity, Ki-67 labeling index, presence of extracellular mucinous pools dissecting muscle, and angiolymphatic and perineural/neural invasion. There is no difference in the immunostaining for CK19 and CD99 between GCCs and classic carcinoids, and both types of neuroendocrine tumor show the same extent of expression of both markers.

Retrospective analysis of pulmonary neuroendocrine/carcinoid tumors at Ohio State University

18176 Background: Neuroendocrine tumors are a unique malignant neoplasm which can arise from the respiratory tree. Bronchial neuroendocrine tumors account for 25% of all neuroendocrine tumors, but only about 1–2% of all lung cancers. The epidemiology, clinical behavior, treatment, and prognosis of carcinoid tumors differ from other lung malignancies in significant ways. Located most often in the major bronchi, these tumors secrete neuroendocrine granules such as serotonin, histamine, and prostaglandins. Classic carcinoid syndrome (diarrhea, flushing, palpitations, wheezing), however, is rare in these patients. Treatment is primarily surgical resection for cure. The purpose of our study was to identify the experience with these malignancies at our institution and compare it to other series. Methods: A total of 64 patients were identified using diagnostic codes via our institutional cancer registry from 1980–2006. Poorly-differentiated neuroendocrine tumors and small cell lung cancer cases were excluded from analysis. Data collected included survival after diagnosis, staging, epidemiologic characteristics, and treatment. Additional variables included smoking history, laterality, and tumor staging. Results: The patient age distribution ranged from 17 years old to 82 years old, with a median age of 57 years old. Most of the patients were female (73%). Tobacco use is variable in carcinoid - 54% of our patients were never smokers, whereas 17% were previous smokers, 20% were current smokers, and history was unknown in 7%. Staging was unknown in over half of the patients. Treatment was generally surgical; lobectomy (40%) was the most common intervention, followed by wedge resection (17%), radiation therapy (14%), bronchial sleeve resections (3.5%), and pneumonectomies (3.5%). Survival was generally good - at the time of last contact, 50 patients (78%) were still alive with a median follow up of 39 months since diagnosis. Conclusion: Neuroendocrine tumors of the bronchial tree remain a unique and uncommon malignancy among lung cancers. The findings at our medical center are consistent with reported series as far as epidemiologic characteristics, treatments, and outcomes. The future direction of non-surgical therapy in this malignancy remains investigational. No significant financial relationships to disclose.

Cytokeratins 7 and 20 Immunoexpression Profile in Goblet Cell and Classical Carcinoids of Appendix

Goblet cell carcinoid (GCC) of the vermiform appendix is an uncommon neoplasm and its histogenesis is controversial. Whether GCC represents a morphological variant of classical appendiceal carcinoid or a mucin-producing adenocarcinoma is still conjectural. Little is known about the immunohistochemical expression of cytokeratins 7 (CK7) and 20 (CK20) in appendiceal neuroendocrine tumors. In this study, we compared the expression of CK7 and CK20 in 17 cases of appendiceal GCC and 25 cases of classical carcinoid. The tumors were also evaluated for Ki-67 proliferation index, mitotic activity, tumor necrosis, extracellular pools of mucin, obvious intestinal type adenocarcinomatous foci, angiolymphatic permeation, perineural/neural infiltration, and the depth of invasion of the appendix wall. Mesoappendiceal extension was present in 14 of 17 (82.3%) cases of GCC, whereas angiolymphatic and perineural/intraaneural involvement were found in 10 of 17 (58.8%) and 14 of 17 (82.3%) cases, respectively. The mitotic count ranged from 0 per 10 high power fields to 6 per 10 high power fields, with an average of 1.4 per 10 high power fields. Necrosis was not seen in any case and pools of extravasated mucin were present in 5 of 17 (29.4%) cases. Immunohistochemically, all 17 (100%) of GCC exhibited strong and diffuse immunopositivity for CK20, whereas expression of CK7 was present in 12 cases (70.5%), ranging from 5 to 50% of tumor cells being labeled. The Ki-67 labeling index ranged from 0 to 75% and showed no correlation to mitotic activity, angiolymphatic invasion or perineural/intraneural permeation. On the other hand, 25 cases of classical carcinoid tumors were consistently negative for CK7; however, 4 cases (16%) showed immunolabeling for CK20 in 25-50% of the tumor cells. The Ki-67 labeling index in classical carcinoids ranged from 0 to 5%. This study shows that in addition to the morphological differences, GCC (CK7/CK20-positive) and classical carcinoid (CK7/CK20-negative) differ in their expression of CK7 and CK20. In addition, GCC shows the same CK7/CK20 immunoexpression as colorectal adenocarcinoma. Goblet cell carcinoid should be regarded as a crypt cell or an amphicrine carcinoma rather than a variant of carcinoid tumor, a lesion that has benign connotations.

Pax-5 Expression in Nonhematopoietic Tissues

We evaluated 123 formalin-fixed, paraffin-embedded samples, including neuroendocrine tumors, adult brain, mesonephric tissues, and from various other sites. A pre-B lymphoma cell line, Daudi, and a small cell carcinoma cell line, NCL-H128, were evaluated by Western blot. All tissues were immunostained by mouse monoclonal anti-Pax-5 antibody by using standard, synthetic polymer-based detection methods. Our study describes for the first time distribution of Pax-5 in adult brain tissue, including periaqueductal gray matter of the midbrain, area postrema of the medulla oblongata, and occasional cells of the spinal trigeminal nucleus (caudal nucleus). We confirm that Pax-5 is expressed regularly in poorly differentiated neuroendocrine tumors but never in well-differentiated classic carcinoid tumors. Pax-5 expression also was found readily in benign and malignant mesonephric tissues and focally in müllerian duct-derived tissues and tumors. Expression of Pax-5 in the Daudi and NCL-H128 cell lines was confirmed by Western blot. Together, these results are important for correct interpretation of results in immunophenotyping of undifferentiated tumors, for diagnosis of mesonephric carcinoma, and, potentially, for correct classification of neuroendocrine tumors in small biopsy samples.

Neoplastic lesions of the appendix.

Neoplasms occur in 0.5 per cent of appendices. Ultrasonography or computed tomography is beneficial, but preoperative detection is rare. At operation, the diagnosis is considered in under half of cases. Mucocele, localized pseudomyxoma peritonei, benign tumours and most appendiceal carcinoids are cured by appendicectomy alone. Right hemicolectomy is indicated for: (1) invasive adenocarcinoma; (2) tumours close to the caecum; (3) lesions larger than 2 cm; (4) mucin production; (5) invasion of the lymphatics, serosa or mesoappendix; and (6) cellular pleomorphism with a high mitotic rate. Tumours of 1-2 cm, small mucinous carcinoids, adenocarcinoma confined to the mucosa, and tumours in children may be treated by appendicectomy alone at the surgeon's discretion. The 5-year survival rate associated with classical carcinoid is more than 90 per cent. The prognosis of mucinous carcinoid is intermediate between that of classical carcinoid and well differentiated adenocarcinoma. The prognosis of adenocarcinoma is determined by Dukes' stage and is similar, stage for stage, to that of colorectal carcinoma.