Metastatic carcinoid tumors: a clinical review

Carcinoid tumors are neuroendocrine tumors derived from enterochromaffin cells, which are widely distributed in the body. They can originate from any location in the body, but they are traditionally described as originating from the foregut, midgut, and hindgut. Although the overall incidence of carcinoid tumors appears to have increased in the past decades, the prognosis for patients with metastatic carcinoid tumors has improved during the last decade. Due to longer survival times, complications, such as carcinoid heart disease, and new metastatic patterns, like skin and bone metastases, may become more important features of carcinoid disease. Therapy focused on these complications should be part of the management. Combining new diagnostic and treatment modalities in metastatic carcinoid patients may result in better quality of life and longer survival times. The increasing number of therapeutic options and diagnostic procedures requires a multidisciplinary approach, with decisions made in multidisciplinary meetings focused on "tailor-made" therapy based on patients' specific conditions. Because carcinoid tumors are uncommon, effort should be made to treat these patients in specialized centers and for these centers to join together in multicenter studies.     

Pulmonary neuroendocrine/carcinoid tumors

Neuroendocrine tumors are a unique malignant neoplasm that can arise from the respiratory tree. Although well‐differentiated bronchial neuroendocrine tumors (also called carcinoid tumors) are reported to account for approximately 25% of all neuroendocrine tumors, they represent only 1% to 2% of all lung cancers. The epidemiology, clinical behavior, and treatment of neuroendocrine carcinoid tumors differ significantly from other lung malignancies. In this article, the recent data regarding these tumors were reviewed with attention to the treatment modalities used. Although conventional cytotoxic therapy has not been reported to demonstrate much promise in this entity over the past 4 decades, newer molecular targeted agents including those that targeted angiogenesis and the mammalian target of rapamycin (mTOR) pathway have shown encouraging results in early phase trials for advanced carcinoid tumors. Cancer 2009. © 2009 American Cancer Society.     

Pulmonary neuroendocrine (carcinoid) tumors: European Neuroendocrine Tumor Society expert consensus and recommendations for best practice for typical and atypical pulmonary carcinoids

BackgroundPulmonary carcinoids (PCs) are rare tumors. As there is a paucity of randomized studies, this expert consensus document represents an initiative by the European Neuroendocrine Tumor Society to provide guidance on their management.Patients and methodsBibliographical searches were carried out in PubMed for the terms ‘pulmonary neuroendocrine tumors’, ‘bronchial neuroendocrine tumors’, ‘bronchial carcinoid tumors’, ‘pulmonary carcinoid’, ‘pulmonary typical/atypical carcinoid’, and ‘pulmonary carcinoid and diagnosis/treatment/epidemiology/prognosis’. A systematic review of the relevant literature was carried out, followed by expert review.ResultsPCs are well-differentiated neuroendocrine tumors and include low- and intermediate-grade malignant tumors, i.e. typical (TC) and atypical carcinoid (AC), respectively. Contrast CT scan is the diagnostic gold standard for PCs, but pathology examination is mandatory for their correct classification. Somatostatin receptor imaging may visualize nearly 80% of the primary tumors and is most sensitive for metastatic disease. Plasma chromogranin A can be increased in PCs. Surgery is the treatment of choice for PCs with the aim of removing the tumor and preserving as much lung tissue as possible. Resection of metastases should be considered whenever possible with curative intent. Somatostatin analogs are the first-line treatment of carcinoid syndrome and may be considered as first-line systemic antiproliferative treatment in unresectable PCs, particularly of low-grade TC and AC. Locoregional or radiotargeted therapies should be considered for metastatic disease. Systemic chemotherapy is used for progressive PCs, although cytotoxic regimens have demonstrated limited effects with etoposide and platinum combination the most commonly used, however, temozolomide has shown most clinical benefit.ConclusionsPCs are complex tumors which require a multidisciplinary approach and long-term follow-up.     

Goblet cell carcinoid of appendix: ultrastructural features and histogenetic aspects.

Light and electron microscopic examination of a goblet cell carcinoid revealed cells with pleomorphic neurosecretory-type granules, cells containing mucin some of which also contained these granules and less differentiated cells lacking the aforementioned features. Recent embryologic and anatomic studies of developing avian and mammalian gut, respectively, show that intestinal APUD cells are probably of endodermal origin. Therefore, mixed carcinoid tumors such as the goblet cell variant could arise in crypt base stem cells.     

Prognostic indicators for carcinoid neuroendocrine tumors of the gastrointestinal tract

Factors that determine the clinical course and outcome of patients with gastrointestinal (GI) carcinoid tumors are complex and multifaceted. These include the site of origin within the GI tract, the size of the primary tumor, and the anatomical extent of disease, whether localized, regional, or metastatic to distant sites. The new World Health Organization (WHO) histological classification of endocrine tumors, including carcinoids, represents a significant advance in terms of providing a consistent framework for histopathological interpretation that should facilitate multicenter research on treatment outcomes. Histochemical indicators of a poorer prognosis are the degree of expression of the proliferation protein Ki-67 and the p53 tumor suppressor protein. Adverse clinical indicators are the malignant carcinoid syndrome, carcinoid heart disease, and high concentrations of the tumor markers, urinary 5-HIAA and plasma chromogranin A.     

Primary carcinoid tumor of the ovary: report of an unusual case

Carcinoid tumors are endocrine malignancies that are often associated with a characteristic syndrome, the malignant carcinoid syndrome, which is most common in patients with small bowel tumors and liver metastases. In the rare instances when the syndrome is present without liver metastases the primary tumor is usually localized to the bronchus or ovary and secretes hormones directly into the systemic circulation. About two thirds of patients with carcinoid syndrome have evidence of carcinoid heart disease. We report on a case of a primary ovarian carcinoid tumor with an unusual clinical presentation.     

Primary Hepatic Carcinoid in a Renal Transplant Patient

There seems to be a world-wide increase in the incidence of tumors among immunosuppressed patients. Of 1350 renal allografts transplanted in the past 23 years at the Department of Transplantation and Surgery, 56 cases were malignant tumors. The case of a 58-year-old female patient is reported, with disseminated primary carcinoid in the liver detected 86 days after renal transplantation. According to the literature only 39 patients with primary liver carcinoids have been reported until 1997, but this is the first where the carcinoid developed in an immunosuppressed patient. The rapid progression of the carcinoid could be associated with the immunosuppression.     

Extrapulmonary small cell: a novel case of small cell carcinoma of the thyroid gland

Neuroendocrine tumors comprise a large group of malignancies which share unique morphological features and are characterized by the presence of neuroendocrine markers such as synaptophysin, chromogranin-A, and CD56 (N-CAM), ranging from indolent tumors, such as carcinoid tumors, to aggressive tumors, such as small cell carcinoma. The lung is the most common site for primary neuroendocrine tumors. Extrapulmonary primary sites of small cell carcinoma are rare but have been documented arising from various sites including esophagus, stomach, colon and rectum, gallbladder, thymus, salivary gland, ovary, cervix, bladder, prostate, and skin. We present a case of small cell carcinoma arising from the thyroid gland, a site not previously described in the literature. A 59-year-old woman presented with a thyroid mass, which, after resection, showed small cell morphology and positive immunostains for TTF-1, synaptophysin, chromogranin-A, CD56, etc. Five months after diagnosis, she had widely metastatic disease. After a near-complete response to the first chemo-treatment, her disease progressed. Following local radiation and more rounds of chemotherapy, she succumbed to the disease, 15?months after diagnosis. Our patient had no pulmonary lesions at the time of diagnosis to suggest metastasis from the lung. Much like its pulmonary counterparts, this small cell carcinoma of primary thyroid origin displayed an aggressive clinical course and poor outcome. Although it shows early sensitivity to chemotherapy, small cell carcinoma remains a difficult-to-treat cancer with a poor prognosis and can rarely be seen originating in organs outside of the lung.     

Pathologic findings at orchiectomy following chemotherapy for disseminated testicular cancer

Patients with testicular cancer who have disseminated disease at presentation do not always undergo orchiectomy for diagnosis of staging before initiation of chemotherapy. Between October 1978 and November 1982 orchiectomy was performed following cisplatin combination chemotherapy in 20 patients with disseminated germ cell tumors. There were three patients with residual carcinoma in the removed testis and six patients with teratoma. Therefore, in patients with evidence of a primary testicular neoplasm that was not resected initially, orchiectomy should be performed after chemotherapy. Furthermore, the testis may be a sanctuary site for germ cell malignancies during systemic treatment.     

Breast implant-associated anaplastic large cell lymphoma: A comprehensive review

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a recently recognized non-Hodgkin lymphoma of T-cell origin. Despite the low incidence of this new disease, the increasing use of breast implants for cosmetic or post-mastectomy reconstruction purposes places BIA-ALC as an emerging and compelling medical challenge. The real BIA-ALCL pathogenesis has not been fully uncovered so far, while different putative causal factors have been proposed. Breast implants with textured surfaces seem to be associated with nearly all cases of BIA-ALCL, while the real the risk of disease development has not been well estimated so far. Late onset, persistent seroma around breast implant represents the classical clinical presentation. Most of the BIA-ALCL patients presents with localized disease, which confers an excellent prognosis. Unlike other non-Hodgkin lymphomas, surgical excision of the mass has a key role in the treatment. For patients with advanced and disseminated diseases, the treatment did not differ from other types of T-cell lymphoma. For these reasons, BIA-ALCL represents an emerging disease which requires multidisciplinary team approach to well define diagnostic workup and treatment for each patient. This review article aims to summarize available data on BIA-ALCL. First, we will outline available data on BIA-ALCL epidemiology, pathogenesis, diagnostic work-up, and treatment. Second, we will point out the potential psychological implications as well as the risk of perception distortion for women with breast implants, especially for those with previous breast cancer. Lastly, we will summarize the current national recommendations regarding textured breast implants and discuss the diagnostic-therapeutic algorithm for BIA-ALCL management.     

Ileal carcinoid tumor with liver metastases and cardiac involvement treated with intraarterial liposomal doxorubicin and valve replacement

Unless carcinoid are in general slow-growing tumors, some cases could be frankly malignant. The commonest cause of death in patients suffering a carcinoid tumor is liver failure due to tumor progression. When tumors have a fast evolution a multidisciplinary approach must be perform. This case report is an example of this specific situation.     

Bronchopulmonary neuroendocrine tumors

Bronchopulmonary neuroendocrine tumors (BP-NETs) comprise approximately 20% of all lung cancers and represent a spectrum of tumors arising from neuroendocrine cells of the BP-epithelium. Although they share structural, morphological, immunohistochemical, and ultrastructural features, they are separated into 4 subgroups: typical carcinoid tumor (TC), atypical carcinoid tumor (AC), large-cell neuroendocrine carcinoma (LCNEC), and small-cell lung carcinoma (SCLC), which exhibit considerably different biological characteristics. The clinical presentation includes cough, hemoptysis, and obstructive pneumonia but varies depending on site, size, and growth pattern. Less than 5% of BP-NETs exhibit hormonally related symptoms such as carcinoid syndrome, Cushing, acromegaly, and SIADH. SCLC is the most common BP-NET, while LCNEC is rare, approximately 10% and < or =1%, respectively, of all lung cancers. Both SCLC and LCNEC progress rapidly, are aggressively metastatic, and exhibit a poor prognosis. The incidence of BP-carcinoids (TC and AC) in the US was 1.57 of 100,000 in 2003 (an unexplained and substantial increase over the last 30 years, approximately 6% per year). No curative treatment except for radical surgery (almost never feasible) exists. The slow-growing TC exhibit a fairly good prognosis ( approximately 88%, 5-year survival), whereas AC demonstrate a 5-year survival of approximately 50%, and the highly malignant LCNEC and SCLC5-year survival of 15% to 57% and <5%, respectively. This review provides a broad overview on BP-NETs and focuses on the evolution of the disease, general features, and current diagnostic and therapeutic options.     

Diagnosis and management of multifocal gliomas

Patients who present with multiple cerebral tumors are usually considered as having metastatic disease. If they have a history of a primary cancer in another site, the brain tumors are considered metastases and are usually managed with standard whole-brain radiotherapy. If no primary cancer site is known, a diagnostic work-up is performed, but if no primary site is found, they are still considered as brain metastases from an unknown primary site. Thus, such patients can either have brain biopsy (recommended) for further diagnostic consideration or, occasionally, they can be treated with whole-brain radiotherapy, depending on the age, performance status and wish of the patient. However, in some of these patients the multiple brain tumors represent multifocal glioma rather than metastases, resulting in incorrect treatment. In such cases, various MRI characteristics may be helpful in directing towards the correct diagnosis. Thus, patients who present with multiple brain tumors should not always be considered to have metastatic disease even if they have a previous diagnosis of systemic cancer, and multifocal glioma should be ruled out.     

Neuroendocrine Tumors of the Pancreas

This literature review briefly summarizes the epidemiology, pathophysiology, clinical management, and outcomes of patients with pancreatic neuroendocrine tumors (PNETs) and highlights recent advances in PNET research. PNETs are rare neoplasms, compared with carcinomas arising from pancreatic exocrine tissue. They, like other neuroendocrine tumor types, display variable malignant potential, hormone‐related syndromes (functionality), localization, and genetic background. Although tumor origin and molecular pathogenesis remain poorly understood, recently established grading and staging systems facilitate patient risk stratification, and thereby directly impact clinical decision making. Although the optimal clinical management of PNETs involves a multidisciplinary approach, surgery remains the only curative treatment for early‐stage disease. Surgery may also have a role in patients with advanced‐stage disease, including those with hepatic metastases. Alternative therapeutic approaches applied to PNETs, including chemotherapy, radiofrequency ablation, transarterial chemoembolization, biotherapy, polypeptide radionuclide receptor therapy, antiangiogenic therapy, and selective internal radiotherapy, have failed to demonstrate a long‐term survival benefit. Surgery remains the primary therapeutic option for patients with PNETs. Research on PNETs is desperately needed to improve the therapeutic options for patients with this disease.     

软组织肉瘤治疗现状

软组织肉瘤是一类主要起源于胚胎中胚层的恶性肿瘤，全球每年发病率在1．8～5．0／10万，约占成人恶性肿瘤的1％，占儿童恶性肿瘤的7％～10％[1]。该肿瘤可以发生在任何部位，以四肢最为多见（上下肢包括肢带骨占近60％）[2]。可以发生在任何年龄，但发病率会随着年龄的增长而升高，美国一项基于疾病登记机构的17364例患者研究显示，患者平均诊断年龄为57．4岁。     

Delay in diagnosis of high-grade osteosarcoma of the extremities. Has it any effect on the stage of disease?

In 965 patients with high-grade osteosarcoma of the extremities, we investigated the correlation between diagnostic delay and the stage of the tumor at presentation. The mean interval between the onset of first symptoms and the final diagnosis was significantly shorter in patients with metastatic disease than in patients with localized disease at the time of the diagnosis. The difference was due to a late presentation of patients with localized disease to the physician and not to delays in performing radiologic examinations or in referring patients to a specialized hospital for biopsy and treatment. We conclude that in high-grade osteosarcoma of the extremity the shorter interval between onset of symptoms and diagnosis observed in patients with disseminated disease at the time of the diagnosis reflects a more aggressive behavior of tumors that are metastatic at presentation.     

原发性肺类癌的治疗进展与展望

原发性肺类癌(pulmonary carcinoid,PC)是一种较为少见的肺部肿瘤。在2015年世界卫生组织(WHO)最新的肿瘤分类中,PC包括典型类癌(typical carcinoid,TC)和非典型类癌(atypical carcinoid,AC)。PC与大细胞神经内分泌癌(large cell neuroendo? crine carcinoma,LCNEC)和小细胞肺癌(small cell lung carcinoma,SCLC)均属于肺部神经内分泌肿瘤(neuroendocrine tumor,NET)。由于发病率较低,且缺乏特异性的临床表现,PC的诊断和管理相对较复杂。对于整体健康状况和肺储备可以耐受手术的早期局限型PC患者,外科手术切除是首选的治疗方法。而晚期或不可切除PC患者,目前各种指南推荐的标准系统治疗缺乏统一的共识。本文拟对PC最新的诊断及多学科治疗进展进行综述。      

Challenges in the Diagnosis and Management of Well‐Differentiated Neuroendocrine Tumors of the Lung (Typical and Atypical Carcinoid): Current Status and Future Considerations

Neuroendocrine tumors (NET) of the lung represent approximately 25% of all primary lung tumors and can be classified as low grade (typical carcinoids), intermediate grade (atypical carcinoids), or high grade (large cell neuroendocrine carcinoma or small cell lung carcinoma). Low- and intermediate-grade lung NET are increasingly recognized as biologically distinct from high-grade lung NET based on clinical behavior and underlying molecular abnormalities. This review summarizes current knowledge and challenges in the diagnosis and management of low- and intermediate-grade lung NET. Accurate histopathologic classification of lung NET is critical to determining appropriate treatment options but can be challenging even for experts. For low- and intermediate-grade lung NET, surgery remains the mainstay of treatment for localized disease. Although no standard systemic therapy has been established for the treatment of advanced, unresectable disease, a number of promising treatment options are emerging, including somatostatin analogs, temozolomide-based chemotherapy, targeted therapy with mammalian target of rapamycin or vascular endothelial growth factor inhibitors, and peptide receptor radionuclide therapy. Given the difficulty in accurately diagnosing these tumors, and the paucity of data supporting establishment of standard systemic therapy options, management of patients within the setting of a multidisciplinary team, including specialists with expertise in NET, is recommended. Ongoing and future clinical trials hopefully will provide stronger evidence to support treatment recommendations for low- and intermediate-grade lung NET.

Implications for Practice:

Treatment of neuroendocrine tumors (NET), particularly those of lung origin, continues to evolve. This review seeks to educate oncologists on the most up-to-date options and supporting data regarding management of two rare lung neoplasms, typical and atypical carcinoid tumors. Although surgical resection has been the mainstay of treatment, several systemic options have been studied in the treatment of NET of various origins that may potentially play a role in treating typical carcinoid tumors and atypical carcinoid tumors.