Fibrosis and Carcinoid Syndrome — From Causation to Future Therapy

Carcinoid tumors are part of a heterogeneous group of gastrointestinal and pancreatic endocrine tumors that are characterized by their capacity to produce and secrete hormones, 5-hydroxytryptamine, tachykinins and other mediators. These substances are thought to be responsible for the collection of symptoms, which include diarrhea, flushing and wheezing, that is known as carcinoid syndrome. Fibrosis that occurs either local to or distant from the primary tumor is one of the hallmarks of carcinoid tumors that originate from the midgut. The fibrotic process can occur in the mesentery as a desmoplastic response and may lead to obstruction of the small bowel, but it can also occur in the lungs, skin or retroperitoneum. Importantly, up to one-third of patients develop cardiac valvulopathy. One or more products that are secreted by the tumor and enter into the circulation are likely to have a role in this process. This review discusses the incidence and prevalence of fibrosis in carcinoid syndrome and explores evidence to date for causative agents, in particular the roles of 5-hydroxytryptamine and elements of the downstream signaling pathway. Improved understanding of the etiology of carcinoid-tumor-related fibrosis may lead to better treatments for this condition than those we currently have.

Introduction

The term ‘karzinoide tumoren’ was first introduced by Oberndorfer in 1907 to describe a particular type of intestinal tumor—one that has a less aggressive natural history than intestinal adenocarcinoma. These growths are part of a heterogeneous group of gastrointestinal and pancreatic endocrine tumors that are characterized by their capacity to produce and secrete homones.[1] The WHO developed a classification in 2000 that organized pathologies by their site of origin and categorized them according to their complexity of differentiation, whether they are functional or nonfunctional, their cell biology, as measured by mitotic index and proliferative index (Ki67), their size and evidence of vascular or neural invasion.[2] Carcinoid tumors have the capacity to secrete 5-hydroxytryptamine (5-HT, also termed serotonin), together with tachykinins and other mediators that are thought to be responsible for the collection of symptoms, which includes diarrhea, flushing and wheezing, known as carcinoid syndrome.[3]

Carcinoid tumors can originate from any part of the intestine and were historically divided into three groups, according to their origin: foregut (including bronchial and thymic carcinoids), midgut and hindgut. This classification, however, has been superseded by a new one.[2] The most recent European guidelines have been developed for the so-called midgut tumors, and included a new staging system.[4] Midgut tumors are frequently diagnosed incidentally, but can also be diagnosed on the basis of the symptoms of carcinoid syndrome, or following presentation with intestinal obstruction. Tumors of midgut origin frequently give rise to obstruction, which is more often caused by local fibrosis than by direct effects of the tumor mass.

The occurrence of fibrosis, at sites both local to and distant from the primary tumor, is one of the hallmarks of carcinoid tumors that originate in the midgut. The fibrotic process can occur in the mesentery, as a so-called desmoplastic response, or at distant sites. Thus, a product or products secreted by the tumor into the circulation are likely to have a role in this process. Fibrosis is an important clinical complication that occurs in this condition, and the key to therapy will be an improved understanding of its etiology.[5]
Organ Fibrosis and Carcinoid Syndrome
Intestinal Fibrosis

In a series of 37 patients with jejunoileal carcinoid tumors, 8 of 12 patients with bowel obstructions had evidence of fibrosis or kinking of the bowel.[6] Among 36 patients with carcinoid syndrome who were seen at Yale university, 15 either had fibrosis at the time of surgery, or developed it subsequently.[7] In a surgical series of 121 patients with midgut carcinoid tumors, 75 required laparo tomy, due to abdominal pain; of these patients, 59 were noted to have marked mesenteric fibrosis at the time of surgery.[8] Spread of the primary tumor into the mesentery and peritoneum can result in a marked fibrotic reaction (Figure 1). This fibrosis can mat together multiple loops of bowel and result in kinking, ischemia, volvulus and obstruction.[9]

Figure 1. Axial CT image of a calcified mesenteric mass (arrow) with indrawing of the mesentery.

Retroperitoneal Fibrosis

True retroperitoneal fibrosis is a rare clinical entity, in which inflammation results in fibrosis throughout the retro peritoneum. In two-thirds of patients this condition is idiopathic. The majority of cases that are not idiopathic are associated with drugs, such as antihypertensive agents and methysergide.[10] Although retroperitoneal fibrosis is not commonly seen in the context of carcinoid syndrome and has not been reported in any recent, major review, several cases have been reported in the literature (Figure 2).[11-15]

Figure 2. Axial CT image of a patient with a metastatic carcinoid tumor that demonstrates retroperitoneal thickening and fibrosis (arrow).

Pleural and Pulmonary Fibrosis

In a review of 50 patients with carcinoid tumors who presented to a single unit over 9 years and were examined using CT, 14 patients had pleural thickening, and in 9 of these cases no other attributable cause was established. All 14 patients had developed this pleural thickening within 2 years of being diagnosed as having carcinoid syndrome, and 7 of the 9 patients also had fibrosis elsewhere, for example, in the heart valves, skin or mesentery.[16] Carcinoid syndrome has rarely been described as a cause of alveolar fibrosis,[17,18] but fibrosis elsewhere in the lung occurs more frequently. In a series of 25 patients known to have peripheral carcinoid tumors of the lung, 19 displayed hyperplasia of neuroendocrine cells elsewhere in the lung, and 8 patients (25%) had lesions of obliterative bronchiolitis, including 2 with asympto matic obstruction of airflow. These data suggest that bronchiolar fibrosis is not uncommon, although it is usually subclinical.[19]
Skin Fibrosis

Dermal fibrosis may be primary or secondary to peripheral vasospasm, which occurs in response to vasoconstrictor substances that are secreted by the tumor.[20] Carcinoid syndrome associated with scleroderma has been reported: in one series, its prevalence was 2 cases in 25 individuals.[21] This complication of carcinoid syndrome is usually a late feature and may be attenuated by the use of cyproheptadine hydrochloride, parachlor phenylalanine and prednisolone, which suggests a causative role for tryptophan metabolism and 5-HT.[22]
Cardiac Fibrosis

Carcinoid heart disease was first reported in 1954.[23] The carcinoid plaque, which is composed of smooth muscle cells, myofibroblasts and connective tissue, is deposited on the endocardial surface, and leaves the morphology of the underlying valve intact.[24] Such plaques are a well-recognized feature of carcinoid syndrome that predominantly affect the right side of the heart and are associated with characteristic pathological changes to the tricuspid and pulmonary valves, which leads to functional impairment and cardiac failure. Cardiac fibrosis is a serious sequel of carcinoid syndrome: one-third of all carcinoid-syndrome-related deaths are attributed to rightsided heart failure.[25] Estimates of the incidence of valve patho logy vary from around 65% of patients who have some evidence of cardiac fibrosis[26] to around 20%.[27]

Today, following the introduction of somatostatin analogs, the frequency of heart disease has markedly diminished, and in many series of patients is now less than 4%. Several researchers have suggested that its severity is also reduced. The development of cardiac fibrosis is thought to relate to vasoactive substances that are secreted by carcinoid metastases in the liver, which reach the right side of the heart. In the absence of a rightto- left shunt, such substances are inactivated in the lung, thus, left-sided heart damage is uncommon (when it does occur, it may be related to the presence of a persistently patent foramen ovale). Occasionally, a similar process is seen in carcinoid disease without liver metastases. In this case, vasoactive substances might be secreted from other organs, such as the ovary, from which 5-HT is thought to reach the circulation directly and bypass the portal system and liver.[28]
Diagnosis of Fibrosis

The clinical method used to diagnose fibrosis is dependent on the affected organ. Cardiac fibrosis is most frequently diagnosed on the basis of clinical symptoms of right-sided heart failure or by echocardiography. Visible fibrosis on echocardiography is well described,[29] and is pathognomonic in the absence of exposure to drugs that could cause valvulopathy.[30] Mesenteric fibrosis may be diagnosed during laparotomy; however, imaging studies may be also helpful. On CT imaging, visible features characteristic of fibrosis may include the presence of a soft tissue mass with mesenteric involvement. Secondary mesenteric masses of less than 1.5 cm in diameter have been reported in 50–75% of patients with midgut carcinoid tumors.[31,32] Mesenteric masses and soft tissue seem to be of a similar density on CT scans; they commonly have a ‘spoke-wheel’ appearance with radiating strands of soft tissue (Figure 3). The extent of these radiating strands typically increases as the fibrosis progresses. Calcification is seen in 40–70% of patients with mesenteric fibrosis and may be small and stippled, or bulky and conglomerate (Figure 4).[33] Calcifications may draw the radiologist’s eye to a small, mesenteric mass. The appearance of these masses shares some features with those of sclerosing mesenteritis, in which the mesentery has a characteristic ‘misty’ appearance (Figure 3). Some specific features, such as the ‘fat ring sign’ of preserved fat and vessels, are pathognomonic of carcinoid fibrosis and aid diagnosis if they are present.[34] The appearance of fibrosis on MRI scans reflects the relative abundance of collagen and myxoid stroma: fibrosis with low to intermediate signal density on T1-weighted MRI scans and variable enhancement with contrast might be evident (Figure 5).[35] In a retrospective review of seven cases, in which multi detector CT and histological examinations were performed, the arterial phase of enhancement detected small tumors and areas of encasement or obstruction of small vessels, and was helpful to identify fibrosis.[36]

Figure 3. Axial CT image that shows calcified mesenteric mass (arrow) with indrawing of the mesentery and appearance of misty mesentery.

Figure 4. Axial CT image of a patient with a metastatic carcinoid tumor and marked calcification within the mesenteric mass (arrow).

Figure 5. MRI scans of a patient with metastatic carcinoid tumor. a) A T1-weighted image that shows low signal density (arrow), which contrasts with the T2-weighted image of the same tumor. [b]) T2-weighted image that exhibits high signal density (arrow).

Physiological Effects of 5-hydroxytryptamine

Serotonin is a monoamine neurotransmitter, of which the brain synthesizes 10% and the gastrointestinal tract synthesizes 90%; 5% of gastrointestinally produced serotonin originates from 5-HT neurons and 95% from enterochromaffin-like cells. Serotonin is synthesized from the amino-acid, tryptophan, via a short metabolic pathway that involves two enzymes—tryptophan hydroxy lase and amino acid decarboxy lase (Figure 6). Almost all (95%) of the 5-HT that is released into the plasma is taken up and stored within platelets.[37]

Figure 6. Serotonin synthesis pathway.

After 5-HT is released, it is taken up by cells through the 5-HT transporter and degraded using monoamine oxidase. Seven main types of 5-HT receptors have been described, several of which have numerous subtypes: 5-HT1 (sub types a, B, D, E, F and P), 5-HT2 (subtypes a, B and C), 5-HT3, 5-HT4, 5-HT5, 5-HT6 and 5-HT7.[38] The receptors have different tissue distributions, and each receptor subtype mediates a different spectrum of function.

Strong evidence supports the involvement of 5-HT in the symptoms of carcinoid syndrome. Serotonin increases secretion of fluid from the gut and the speed of its transit within the gut, which contribute to the diarrhea that is characteristic of this syndrome. The apparent efficacy of measures that lower or antagonize 5-HT to control diarrhea supports this observation. For example, p-chlorphenylalanine reduces the synthesis of 5-HT, whereas cyproheptadine hydrochloride and ketanserin block the 5-HT receptor. Both types of agents can help to control the symptoms of carcinoid syndrome;[39] however, 5-HT may also be involved in the long-term complications of carcinoid syndrome, such as fibrosis. Several studies have demonstrated that 5-HT can be involved in fibrosis in multiple ways and organ systems. In cell culture, 5-HT is associated with fibroblast mitosis, but only after the cells have been made susceptible to it.[40,41]
Serotonin and Noncarcinoid Cardiac Fibrosis

Several apparently unrelated drugs, including the antimigraine ergot alkaloids, ergotamine tartrate and methy sergide,[42] The anorectic agent, fenfluramine,[43] and 3,4-methylenedioxy-methamphetamine (also known as MDMA or ‘ecstasy’[44]), cause similar types of cardiac fibrosis. These drugs all exert 5-HT-like effects on human tissue[45] and have a particular affinity for 5-HT2B receptors on heart valves. In animal models, 5-HT injections, deficiency of the 5-HT transporter gene and transplantation of carcinoid cells have morphological and echo cardiographic characteristics similar to those seen in human carcinoid valvulopathy.[46-48] The downstream pathways may involve src kinase, extracellular-regulated kinases and tyrosine kinases, with a final, common pathway that might include phosphorylation of retinoblastoma protein, which leads to excessive cell division and overgrowth valvulopathy.[49]
Serotonin and Noncarcinoid Hepatic Fibrosis

Increased concentrations of platelet 5-HT and reduced urinary levels of 5-hydroxyindoleacetic acid (5-HIAA) are seen in cirrhosis, which suggests an impairment of 5-HT metabolism.[37] The hepatic stellate cell, which expresses 5-HT1B, 5-HT1F, 5-HT2A, 5-HT2B and 5-HT7 receptors, is the key mediator of cirrhosis and liver fibrosis,[50] although the downstream pathways that are involved in these processes are not well understood.
Serotonin and Carcinoid Fibrosis

Carcinoid syndrome is associated with fibrosis of several organs and the production of numerous hormonal mediators. 5-HT is an important mediator, but other amines, including epinephrine, dopamine, norepinephrine and histamine, may also be secreted. Polypeptides, including bradykinin, kallikrein, chromogranin A, glucagon, motilin, neurokinin B, neurokinin K, substance P, vasoactive intestinal peptide and prostaglandins might also be produced.[51,52] In theory, one or more of these products may be responsible for carcinoid fibrosis in place of 5-HT, but they are probably present in addition to it.

Heart valves of patients with carcinoid fibrosis express increased amounts of TGF-β and TGF latent binding protein. Serotonin has been shown to upregulate TGF-β and to stimulate collagen synthesis by heart-valve interstitial cells.[53] Furthermore, in carcinoid heart disease, a high peak urinary 5-HIAA level is associated with progression of valvulopathy.[54] In a study of patients with carcinoid heart disease, the presence of cardiac abnormalities detected by ultrasonography was correlated with levels of both 5-HT and tachykinin.[26]

In a series of 52 patients with midgut carcinoid tumors, CT scans of the abdomen and pelvis showed soft-tissue stranding in 26 patients and discrete mesenteric masses in 25 patients. A logistic regression model showed that levels of serum 5-HT, platelet 5-HT and urinary 5-HIAA were correlated with the presence of liver metastases. In addition, the presence of a mesenteric mass, which is suggestive of fibrosis, was related to the level of platelet 5-HT, although not to the urinary level of 5-HIAA.[32] Overall, both duration of exposure to and absolute peak level of 5-HT are probably important in the etiology of fibrosis associated with carcinoid syndrome, but these factors are difficult to separate in the clinical setting, as the disease process may be subclinical for a prolonged period of time.
Other Mediators in Carcinoid Fibrosis

Fibrosis in carcinoid syndrome has been linked with substances other than 5-HT. Tachykinins stimulate DNA synthesis in fibroblasts,[55] and neurokinin A and substance P have been linked to cardiac fibrosis.[26] In a series of 30 patients with midgut carcinoid tumors and pancreatic neuroendocrine tumors, increased expression of platelet-derived growth factor, its receptor and fibroblast growth factor were reported. Over 80% of tumors expressed all three isoforms of TGF-β, which may have a role in stromal proliferation and fibrosis.[56]

TGF-β stimulates fibroblasts in the extracellular matrix. Immunohistochemistry of nine samples of heart valves that displayed carcinoid plaques obtained at surgery showed a variable increase in expression of TGF-β1, an insignificant difference in expression of TGF-β2, and a substantial increase in expression of TGF-β3 compared with levels found in normal tissue.[57] Quantitative, reverse transcriptase polymerase chain reaction of rna from small intestinal enterochromaffin-like tumors demonstrated greater increases in connective tissue growth factor (CTGF) and TGF-β1[58] than were observed in gastric, enterochromaffin-like tumors (which are not prone to fibrosis) and normal mucosa.

Immunohistochemistry studies also showed increased levels of CTGF and TGF-β1 in the cytoplasm of smallintestinal carcinoid cells, and activated myofibroblasts in the fibrotic areas were positive for CTGF. These observations led to the hypothesis that fibrosis is driven by TGF-β1. Serum levels of CTGF were reported to be highest in patients with small-intestinal carcinoid tumors, although in this cohort, the presence and severity of fibrosis was not recorded.[58] These data are interesting, but do not prove causation or demonstrate a correlation between actual fibrosis and these markers.

Many newly described signaling pathway proteins may be important in the regulation of cell proliferation, and in the production of bioactive products that are responsible for fibrosis, such as Raf-I, insulin-like growth factor I (IGF-I), notch1 and ‘transcription factor HES-1. Mediators that interfere with these pathways may affect the production of bioactive amines, and in turn may influence fibrosis.[59]

The current options for treatment of carcinoid fibrosis are extremely limited. At present, when fibrosis is diagnosed (for example on presentation with small-bowel obstruction or on the basis of cardiac disease), it is treated using conventional approaches, regardless of its etiology. The mainstay of treatment for cardiac fibrosis is symptomatic management of heart failure. In patients who cannot undergo surgery, balloon valvuloplasty may provide short-term, symptomatic benefit.[28] Valve replacement is a widely used treatment, although the choice of replacement valve type remains controversial. Some studies reported degeneration of bioprosthetic valves, but such valves require no anticoagulation, which is helpful if patients require additional interventional therapies.[28] The optimal timing of valve replacement still remains to be clarified. Brain natriuretic propeptide is a promising serum marker for the presence of carcinoid heart disease, but evidence to support monitoring of this molecule as a marker of disease progression has not yet been demonstrated.[60]

The mainstay of treatment for intra-abdominal disease is surgical resection and/or bypass. An important feature of fibrosis is its association with intestinal ishchemia. Surgery is often challenging from a technical standpoint and may include complex peritoneal resection, but it has proved valuable in the attainment of symptomatic relief for large series of patients.[61] Therapies to prevent the development of fibrosis, or pharmacological measures to reduce it, would be welcome.

The treatment of carcinoid tumors has traditionally been divided into two approaches. The first aims to remove the tumor or reduce its mass, or at least to stabilize its growth in the presence of progressive disease. The available methods include surgery, chemotherapy and radionuclide therapy with 131I-metaiodobenzylguanidine or radiolabeled octreotide. Responses to intraperitoneal chemotherapy (for example with cisplatin) have also been described for some tumors, such as malignant carcinoid tumors,[62] but data from large series of patients are lacking. The second approach aims to control symptoms, either directly (for example, by the use of bowel bypass surgery to relieve symptoms of fibrosis-related, small-bowel obstruction) or to control the level of bioactive products that are secreted in fibrosis (which can be achieved by cytoreduction, surgery, chemotherapy, physical or chemicalembolization [transcatheter arterial chemoembolization], or radionuclide therapy). Drugs have had an important role in this strategy, as they are used to reduce the release of mediators or to block their peripheral effects.

The most widely used medications are octreotide and lanreotide—somatostatin analogs that reduce the release of peptides and amines from tumor cells. These drugs are available as short-acting (octreotide) or longacting (octreo tide and lanreotide) derivatives. Such analogs significantly reduce flushing and diarrhea, and produce a clear improvement in quality of life for patients. Biochemically, a reduction in urinary levels of 5-HIAA is seen in over 50% of patients.[3] For patients who cannot tolerate somatostatin analogs, drugs that were previously used in carcinoid crisis, such as cyproheptadine hydrochloride, may block the 5-HT-like effects and hence can effectively control symptoms such as flushing and diarrhea.[63] Control of symptoms can be achieved by nonselective blockade of the 5-HT receptor (for example, with ketanserin),[64] selective blockade of the 5-HT1 and 5-HT2 receptors (with ranitidine) to improve flushing,[65] or blockade of the 5-HT3 receptor (with ondansetron) for the amelioration of diarrhea.[66] However, one study reported a case where blockade of the 5-HT3 receptors led to precipitation of other features of carcinoid crisis, which was perhaps related to upregulation of receptors.[67]

The effects of these medications on fibrosis have not been studied. Intuitively, if fibrosis is driven—at least on some level—by 5-HT, then octreotide therapy to reduce 5-HIAA excretion should reduce fibrotic progression. Indeed, some anecdotal evidence suggests that the reduction in frequency of carcinoid valvulopathy seen in recent years may be related to the use of octreotide.[28] For patients who cannot tolerate somatostatin analogs or in whom the consequent reduction in urinary levels of 5HIAA is incomplete or inadequate, receptor-blocking agents may be useful. The effects of these medications on fibrosis, however, have not been formally tested. Studies that examine the effects of cyproheptadine hydrochloride or ketanserin treatment on the development of fibrosis in vivo in animal models or in patients who are being treated for carcinoid syndrome would be useful.

The etiology of fibrosis implies that blockade of the 5-HT2B receptor could be most useful to treat this condition. Agents that provide selective blockade of this receptor are not available for general clinical use, but numerous nonselective alternatives are. Notably, many of these broad-spectrum agents are likely to have adverse effects. In a rat model in which cardiac fibrosis was induced by peripheral injections of 5-HT, the use of ergoline terguride (transdihydrolisuride, a derivative of lisuride) led to decreased heart weight and a slight difference in the pathology of cardiac valves compared with those of control animals. Terguride is a dopamine agonist and an antagonist of 5-HT2B and 5-HT2C receptors. In this study, 25% of animals that received 5-HT injections developed aortic insufficiency, with or without the use of terguride. However, 2 out of 12 animals that were treated with 5-HT alone developed pulmonary insufficiency, compared with none in the 5-HT plus terguride group.[68] These results are preliminary, but they may be worthy of further investigation, particularly as terguride is clinically available and has been safely administered to healthy human volunteers.[69] Several other agents are being investigated to determine their effects on newly described, carcinoidsyndrome-related, downstream signaling pathways, such as that of valproic acid on Notch1[70] and inhibition of the phosphoinositide 3-kinase–akt pathway, among others.[71] A further exciting possibility is the use of a novel agent, LX1032, which reduces 5-HT synthesis in the gastrointestinal tract by inhibiting the gut-specific isoform of tryphophan hydroxylase.[72] The effects of these agents on fibrosis are also of interest.

Fibrosis in patients with carcinoid syndrome can present a major clinical challenge. The importance of this clinical problem in cardiac disease is well described.[28] The clinical effect of intra-abdominal fibrosis needs further exploration, and further reviews of case series and corroboration of symptoms with imaging or histological findings would be helpful in this regard. Interventional studies that use animal models would be also welcome. The absence of an accurate animal model of carcinoid syndrome is a limiting factor, but injection of 5-HT may provide a sufficient tool with which to investigate the effects of blockade of different receptor subtypes on the development of intra-abdominal fibrosis, as well as on cardiac fibrosis. Such investigations could also provide supportive data on the effects of other possible markers of fibrosis, such as serum CTGF and TGF-β. Randomized, controlled trials of interventions in patients with carcinoid syndrome are hampered by the heterogeneity of this condition, and by the fact that the available data were collected from small series of patients who were treated in geographically distinct areas. However, a prospective study on the effect of aggressive therapy to reduce the level of markers of bioactive substances (such as urinary 5-HIAA) on fibrosis and markers of fibrosis would be helpful. Similarly, the effect of blockade of 5-HT2B receptors on fibrosis is also of interest—particularly in patients who cannot tolerate somatostatin analogs or do not experience adequate reduction in urinary 5-HIAA level, even if they receive the maximum tolerated doses of these agents.

We certainly need novel therapies for this intractable condition. In addition, modern imaging techniques, such as diffusion-weighted MRI and new methods in PET imaging, require further evaluation as potential diagnostic tools and to assess future biomarkers of response to treatment of fibrosis.

This article is part of a CME certified activity. The complete activity is available at:

http://cme.medscape.com/viewprogram/19293

Key Points

* Fibrosis that develops either local to or distant from the primary tumor is a hallmark of carcinoid tumors that originate from the midgut
* Fibrosis is an important clinical complication of carcinoid syndrome and is associated with ischemia and obstruction in the small bowel, and cardiac valvulopathy
* The biology of carcinoid-syndrome-related fibrosis is not fully understood, but evidence suggests that 5-hydroxytryptamine and the 5-hydroxytryptamine 2B receptor both have a role
* Other mediators, including TGF-β and growth factors, may also be important in the development of carcinoid-syndrome-related fibrosis
* Improved understanding of the etiology of carcinoid-tumor-related fibrosis may lead to better treatments for this condition than those we currently have

[ CLOSE WINDOW ]
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Author(s)
Maralyn Druce, MA, MBBS, MRCP, PhD

Clinical Lecturer; Honorary Consultant, Hammersmith Hospital and St Bartholomew’s Hospital, London, United Kingdom

Disclosure: Maralyn Druce, MA, MBBS, MRCP, PhD, has disclosed no relevant financial relationships.
Andrea Rockall, BSc, MBBS, MRCP, FRCR

Consultant Radiologist, Barts and the London NHS Trust; Honorary Reader in Diagnostic Imaging, Queen Mary University of London, United Kingdom

Disclosure: Andrea Rockall, BSc, MBBS, MRCP, FRCR, has disclosed no relevant financial relationships.
Ashley B. Grossman, BA, BSc, MD, FRCP,FMedSci

Professor of Neuroendocrinology; Consultant Physician, Barts and the London School of Medicine, London, United Kingdom

Disclosure: Ashley B. Grossman, BA, BSc, MD, FRCP, FMedSci, has disclosed no relevant financial relationships.

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