| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Ann Thorac Surg 2001;71:386-393
© 2001 The Society of Thoracic Surgeons
a Department of Anaesthesia, The Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
b Department of Radiology, The Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
c Departments of Laboratory Medicine and Pathobiology, The Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
Address reprint requests to Dr Keshavjee, Division of Thoracic Surgery, The Toronto General Hospital, 200 Elizabeth St, EN 10-224, Toronto, ON, Canada M5G 2C4
e-mail: shaf.keshavjee{at}uhn.on.ca
 |
Abstract |
|---|
 TopFootnotes Abstract IntroductionCase reportCommentAcknowledgmentsReferences |
|---|
Methods. We describe the multidisciplinary management of a 34-year-old female patient with a massive actively secreting bronchial carcinoid tumor of the right lung. Furthermore, we provide a review of the literature regarding the operative treatment and the perioperative management of pulmonary carcinoid tumors with respect to surgical, anesthetic, radiologic, and pathologic considerations.
Results. In the reported case, the first symptoms were chronic watery diarrhea, skin flushing, progressive shortness of breath, and increasing right shoulder pain. When the patient initially presented at our institution, the tumor had already reached an enormous size and it involved the right and left atrium as well as the atrial septum. Using an evidence-based, multidisciplinary approach the patient was treated successfully with extended surgical resection.
Conclusions. Carcinoid tumors are potentially curable even if they reach a significant size and thus an aggressive strategy is warranted. The management of such cases requires careful investigation, planning, and treatment with collaborative expertise provided by a multidisciplinary team. We demonstrated that this approach can lead to a favorable outcome in what first appeared to be a formidable and unresectable tumor.
|
Introduction |
|---|
|
TopFootnotesAbstractIntroductionCase reportCommentAcknowledgmentsReferences |
|---|
|
Case report |
|---|
|
TopFootnotesAbstractIntroductionCase reportCommentAcknowledgmentsReferences |
|---|
Computed tomography and magnetic resonance imaging revealed a large lobulated right mediastinal mass (Figs 1A and 1B). The superior border extended into the right anterior mediastinum at the level of the aortic arch. Anteriorly it extended into the retrocaval, pretracheal, precarinal, subcarinal, and right hilar locations. It encased the right main bronchus and displaced the superior vena cava medially against the ascending aorta. Dynamic magnetic-resonance imaging reconstruction demonstrated retrograde flow in the azygos system and near occlusion of the right pulmonary artery. Tumor infiltration of the right atrium and the atrial septum was demonstrated on the magnetic resonance imaging scan (Fig 1C). Despite the size of the tumor, there was no evidence of tracheal compression. Transesophageal echocardiography excluded significant carcinoid related valvular abnormality or direct valvular involvement and confirmed good left and right ventricular function. Tumor compression of the right atrium and superior vena cava (SVC) was evident with turbulent flow in the SVC. Careful questioning of the patient revealed no tendency to cardiovascular symptoms or respiratory compromise when assuming a supine position. Quantitative pulmonary ventilation and perfusion scanning confirmed that the right lung received only 5% perfusion and 47% ventilation. Two separate determinations of urine 5-hydroxy-indole-acetic-acid (5-HIAA) were negative, but serum serotonin levels were elevated. Bronchoscopy confirmed the presence of endobronchial tumor in the right bronchus intermedius but not in the main bronchus or the tracheal wall. A previously obtained fine needle aspiration biopsy had demonstrated this to be a carcinoid tumor with positive immunohistochemical staining for chromogranins, synaptophysin, CD-57 (leu-7), and CD-56. Biopsied cells stained negatively for serotonin. Mitotic activity was not very prominent suggesting typical carcinoid. In addition, a bone scan showed increased activity in this mass, but no evidence of metastatic disease. Computed tomographic scanning of the abdomen showed no intraabdominal metastases.
|
A multidisciplinary approach was planned involving the surgical, medical, endocrinology, and anesthesia teams, incorporating biochemical suppression of tumor secretion, careful review of multimodal imaging of the extent of the tumor with the radiologist, and a precise operative plan. Overriding concerns were the prevention of carcinoid crisis during tumor manipulation and minimization of injury to the left lung, especially during CPB.
In preparation for the operation, the somatostatin octapeptide analogue octreotide acetate (Novartis, Montreal, Canada) (50 µg BID) was given subcutaneously for 24 hours preoperatively [7]. The patient reported prompt abatement of diarrheal symptoms for the first time in 6 months. One hour before the operation, a bolus of 100 µg octreotide was administered subcutaneously, followed by a continuous infusion at 50 µg/h in order to prevent the occurrence of refractory hypotension due to the release of vasoactive peptides during surgical manipulation [8, 9]. In order to reduce anxiety and stress to the patient, both of which can induce a carcinoid crisis, further premedication included oral cyproheptadine (4 mg), which has both antihistaminic and antiserotonergic effects, and sublingual lorazepam (2 mg) 90 minutes before the operation.
Monitoring in the operating room included continuous electrocardiogram, pulse oximetry and exhaled gas analysis. A pulmonary artery catheter sheath was placed in the right internal jugular vein. Arterial blood pressures were measured from a radial and femoral arterial line. Central arterial access was sought as carcinoid crisis may have presented with central hypertension accompanied by peripheral vasoconstriction. Lower limb intravenous access was also established in anticipation of a possible SVC resection. Induction of anesthesia was performed by the injection of fentanyl (1 mg), midazolam (5 mg), and vecuronium (8 mg). The patient was intubated with a 37-gauge left-sided double lumen endotracheal tube. Anesthesia was maintained with isoflurane in an oxygen/air mixture titrated to a peripheral arterial blood saturation of more than 97%. Methylprednisolone (250 mg) and aprotinin (500,000 IU) were administered. A CPB perfusion circuit with ultrafiltration capability was prepared.
The operation was performed through an anterior bilateral transverse thoracosternotomy incision through the fourth intercostal space. Multiple dense adhesions to the chest wall were present, which were inflammatory in nature. After mobilization of the right lung, the pericardium was opened and the tumor was confirmed to have invaded through the pericardium (Fig 2). The left and right innominate veins were dissected starting superiorly, working down to their confluence to the SVC. The tumor encased the SVC and right side of the heart almost to the diaphragm. Posterior dissection along the esophagus and in the subcarinal area confirmed that the tumor was indeed resectable. The right pulmonary artery was then mobilized and transected using a vascular stapler. The patient was heparinized, aortic and separate caval cannulas were inserted and CPB was initiated. The area of the sinoatrial node was found to be grossly involved with tumor. After snaring the SVC and inferior vena cava (IVC) to isolate the right atrium, the right atrium was entered and tumor infiltration through the atrial wall was grossly evident. A wide resection margin of the right atrium was taken. Both main pulmonary veins and the lateral wall of the left atrium appeared to be involved with the tumor. The aorta was cross-clamped and the heart was arrested with cardioplegia. The left atrial wall and a portion of the atrial septum were resected en-bloc with the tumor mass. The SVC was transected 1 cm below its venous confluence and 1 cm more above the right atrial appendage; therefore, resection of the sinoatrial node was unavoidable. Both atria were reconstructed primarily. The SVC was repaired using a 4 cm length of 15 mm diameter Gore-Tex graft (W.L. Gore & Associates, Inc, Flagstaff, AZ), which was interposed between the proximal SVC and right atrial appendage. Finally, the right pneumonectomy was completed. The carina and proximal bronchus were free of tumor.
|
The patient was transferred to the surgical intensive care unit intubated and ventilated. A total of fentanyl (2 mg) and midazolam (15 mg) had been administered to the patient during the 11-hour operation. The patient responded to commands within 30 minutes of intensive care unit admission. The patient was placed on pressure support ventilation (10 cm H2O) overnight and was extubated the next morning. The postoperative period was notable for prolonged somnolence disproportionate to administered analgesic and sedative medication. This somnolence may have contributed to the occurrence of respiratory failure requiring reintubation 12 hours later, despite good gas exchange; copious pulmonary secretions resulted in tachypnea and fatigue. The patient was finally extubated again 96 hours after the operation. Octreotide infusion (100 µg/h) was maintained for 24 hours. Phenylephrine infusion (up to 67 µg/min) was required for 36 hours to maintain a mean systemic blood pressure of 60 mm Hg. Atrial pacing was maintained through temporary percutaneous leads until a permanent pacemaker was inserted on postoperative day 8 for persistent slow junctional rhythm. The patient recovered well and returned to her full time job as a computer analyst. One year after the operation the patient continues to remain well without any signs of recurrent disease in follow-up computed tomographic studies.
Pathology
The tumor measured 13 cm x 15 cm x 9 cm; all resection margins and the paraaortic, paratracheal, and subcarinal lymph nodes were free of malignancy. The tumor occupied the medial aspects of all three lobes of the right lung (Fig 3A). Pathologic examination revealed a typical bronchial carcinoid tumor that originated from the mucosa of the right lower lobe bronchus (Fig 3B). The tumor invaded the parietal pericardium with focal ulceration of its mesothelial lining, and infiltrated the wall of the SVC as well as the right and left atrial myocardium (Fig 3C). Microscopic lymphangitic spread to the lower lobe parenchyma and focal vascular invasion was also seen. The uniform and polygonal appearing tumor cells showed eosinophilic cytoplasm, coarsely granular chromatin, and occasional small nuclei. Mitotic figures and necrosis were distinctly rare or absent, but focal calcification was noted. Tumor cells showed diffuse and strong cytoplasmic immunoreactivity for chromogranins A and CD57 (Leu-7), and strong membranous staining with CD56 neural cell adhesion molecule (NCAM), all of which have been shown to be useful markers for neuroendocrine differentiation [10]. In addition, tumor cells showed focal positive staining for serotonin (Fig 3D) and secretin. There was also focal weak staining for corticotropin-releasing hormone, glucagon, and glucagon-like peptide 1. Tumor cells stained negatively for adreno-corticotropin, bombesin, calcitonin, calcitonin gene-related peptide, somatostatin, gastrins, human pancreatic polypeptide, vasoactive intestinal polypeptide, cholecystokinin, insulin, and growth hormone-releasing hormone.
|
|
Comment |
|---|
|
TopFootnotesAbstractIntroductionCase reportCommentAcknowledgmentsReferences |
|---|
Bronchial carcinoids are considered true malignancies belonging to the neuroendocrine tumor family, from which small cell lung cancer is the most malignant variant [6, 14], because their general potential to metastasize has been recognized. Bronchial carcinoid tumors are neuroendocrine neoplasms arising from enterochromaffin cells of the bronchial epithelium (Kulchitsky cells). Their cell of origin belongs to the amino precursor uptake and decarboxylation system and has the potential to secrete neuroendocrine peptides [17]. Beside the ability to synthesize more than thirty different peptides, vasoactive amines, kinins, endorphins, enkephalins and other substances [18], the ability to synthesize 5-hydroxytryptamine (serotonin) from dietary tryptophan has been suggested to be pathognomonic of carcinoids [13].
Histopathologically, carcinoids have been classified as typical carcinoids (TCs) and atypical carcinoids (ACs) [10, 17]. This histomorphologic classification has been widely accepted and serves as a relevant predictor of biological and clinical behavior of these tumors and their prognosis with ACs possessing more malignant histologic and clinical features [1]. Typical carcinoids have a favorable prognosis with a 10-year survival of up to 80% to 90% [19], compared to 40% to 60% in patients with ACs [1]. Of all pulmonary carcinoid tumors, ACs appear in 11% to 24% [10]. The most important histopathological findings between both subtypes are, that mitoses are absent or rare in TCs and necrosis is uncharacteristic, whereas in ACs, mitoses are increased (up to 10 per 10 high-power fields) and necrosis is characteristic as focal or punctuate [10]. Nuclear pleomorphism, as well as hyperchromatinism, is usually absent in TCs, but very often present in ACs. Regional lymph node metastases are present in 5% to 15% of patients with TCs at their presentation and in 40% to 48% of patients with ACs [10]. Of the various histopathologic techniques avoidable, such as electron microscopy, light microscopy, cytology (sputum), flow cytometry, DNA analysis, and immunohistochemistry, the latter is widely accepted as the most sensitive and accurate in distinguishing TCs and ACs. Of the various types of pulmonary neuroendocrine tumors, TCs have the highest percentage, distribution and intensity of immunohistochemical markers, which are less for ACs. Chromogranins are the most useful marker of neuroendocrine differentiation, followed by synaptophysin and Leu-7 (CD-57) [10]. Between 10% and 25% of bronchial carcinoids contain bone, which seem to be confined to bronchial tumors because it is almost never seen in other types of foregut carcinoids [17]. The mechanism of bone formation is still unknown, but local calcitonin synthesis has been considered to be involved in this phenomenon [20]. The carcinoid tumor in our patient did not show bone formation, but did demonstrate a large area of calcification with negative staining for calcitonin.
The clinical diagnosis of carcinoid tumors is controversial and symptoms are highly variable. Beside general symptoms such as watery diarrhea, headache, skin flushing, and sleep disorders, specific symptoms that accompany bronchial carcinoids are important for diagnosis [3, 21, 22]. The most common pulmonary manifestations are hemoptysis (18%), postobstructive pneumonitis (17%), and dyspnea in 2% of patients [10, 13, 18]. Additional symptoms may be chest pain, pleural effusion, cough, wheeze, hoarse voice, or atelectasis [22, 23]. The symptoms are dependent on the location of the tumor (central or peripheral). Central tumors are more commonly located in the right lung and present with hemoptysis or recurrent bronchial obstruction [17]. Endocrine manifestations occur in 1% to 7% of cases [24] including the carcinoid syndrome, which occurs in 86% of patients with liver metastases resulting in the failure of metabolism of vasoactive agents by the monoamine oxidase enzyme system in the liver [10, 19]. It is important to note that carcinoid syndrome can be seen in large (> 5 cm) bronchial carcinoid tumors that have not metastasized, as was the case in our patient [6]. In a retrospective study of 69 patients with bronchial carcinoid tumors at our institution, 3% developed carcinoid syndrome [23]. Patients with carcinoid syndrome that developed symptomatic carcinoid heart disease have a dismal prognosis and most commonly die of progressive right heart failure due to tricuspid or pulmonary regurgitation, or both, within 1 year after the onset of symptoms [25]. Although the perioperative mortality after valvular operations (tricuspid or pulmonary valve replacement, or both) in these patients is high (35%), marked symptomatic improvement was seen in survivors of a cohort of 26 patients with carcinoid heart disease after valvular replacement as reported by Connolly and colleagues [26]. Other paraneoplastic syndromes that rarely occur with bronchial carcinoid tumors include Cushing’s syndrome [27], acromegaly [28], paraneoplastic encephalomyelitis [29], subacute dysautonomia [29], and multiple neuroendocrine neoplasia, Type I [30]. The symptom complexes in patients with bronchial carcinoid tumor will vary with the peptides that are released by the tumor.
One important step in the diagnosis of bronchial carcinoid tumors is the measurement of actively secreted peptides by the tumor, but this is often unverifiable due to limitations in the sensitivity of blood assays and histochemical techniques to identify the full complement of the synthesized peptides in many cases. Additionally, peptide release may be impaired in some tumors, particularly in bronchial carcinoids, resulting in a lack of complete concordance between immunohistological findings and clinical presentation (personal communication, Dr Shereen Z Ezzat, Department of Endocrinology, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada). The diagnosis is suggested by finding neurosecretory granules on conventional light microscopy or electron microscopy [19] and may be confirmed by detection of the hormonal content of these granules by immunohistochemistry [13]. In comparison to the more commonly found midgut carcinoids (eg, ileal carcinoids), bronchial carcinoids are of foregut origin and usually do not secrete serotonin. Urinary 5-hydroxy-indole-acetic-acid (5-HIAA), a very specific marker for carcinoid syndrome, is often absent in this group, as was the case in our patient. Definitive diagnosis by transbronchial biopsies may be difficult because the tumor is often covered by normal mucosa [18]. Other authors favor the rigid bronchoscope to obtain larger tissue samples [3, 5]. However, rigid bronchoscopy can cause severe hemorrhage. Out of a cohort of 223 patients with bronchial carcinoid tumors, 15 patients developed severe hemorrhage after rigid bronchoscopy, and 4 patients required emergency thoracotomy [31].
There is great variability in the detection rate of the primary carcinoid tumor [13]. Both computed tomographic scanning and magnetic resonance imaging can detect bronchial carcinoid tumors more than 1 to 2 cm in diameter [32]. The expression of several neuroendocrine peptides by carcinoid tumors has been used for scintigraphic imaging with labeled somatostatin or its synthetic analogue octreotide [14, 33], and labeled meta-iodobenzyl guanidine [34]. Somatostatin-receptor scintigraphy has been shown to be more sensitive than scanning with meta-iodebenzyl guanidine alone to detect either primary or metastatic carcinoid tumors [35]. Angiography may be used for the localization of carcinoid tumors by showing a tumor blush, but it is invasive and may not significantly further contribute to noninvasive diagnostics [36, 37]. It could potentially provide information for planning selective intravascular embolization in patients with nonresectable tumors, but there is little in the literature regarding experience with this approach.
From the anesthesiology point of view, it is important to note that the severity of symptoms reported by patients does not predict the degree of intraoperative hemodynamic effects [38]. As in our patient, specific vasoactive peptides frequently are not identified preoperatively. A strategy of inhibition of tumor secretion is advised. The somatostatin analogue, octreotide, is more potent than somatostatin and also has a longer half-life (90 minutes vs 30 minutes). Octreotide (50 to 100 µg) BID intravenously for 24 hours before the operation is recommended [7]. Intravenous boluses of 50 to 250 µg and an infusion of 250 µg/h have been lifesaving in the treatment of refractory hypotension during manipulation of both intestinal and bronchial carcinoid tumors [8, 9]. No significant side effects were seen with doses approaching 6,000 µg/d [39]. The use of specific mediator antagonists as adjuncts to octreotide has been recommended; these include aprotinin (protease inhibitor), cyproheptadine, and ketanserin (serotonin receptor antagonists), as well as antihistamines (H1 and H2 inhibitors) and glucocorticoids [8, 38]. Both methylprednisolone [40] and aprotinin [41] have anti-inflammatory actions, which have the potential to diminish lung injury on CPB. Aprotinin inhibits a variety of proteases including kallikrein and plasmin and is a potent antifibrinolytic, shown to reduce perioperative bleeding and requirement for blood transfusion in cardiovascular operations [42]. The removal of inflammatory mediators by continuous hemofiltration while on CPB has been suggested to be helpful to reduce the systemic inflammatory response and improve hemodynamic stability and postoperative gas exchange [43]. In the case described, all these measures were taken to optimize protection of the remaining left lung after right pneumonectomy on CPB. Anxiety, hypothermia, hypercapnia, hypotension, and hypertension can provoke a carcinoid crisis and should be avoided. The anesthetic regimen should preclude histamine-releasing drugs such as morphine, atracurium, curare, succinylcholine, and catecholamines, which are all known to mediate the release of peptides from carcinoids. Hypotensive episodes should not be treated with ß-agonists as these may provoke a crisis and lead to circulatory arrest. Somatostatin bolus is recommended for the management of hypotension during carcinoid crisis [9]. Phenylephrine, calcium chloride, angiotensin, and vasopressin have also been used with success [8, 38]. If positive inotropic agents are required, phosphodiesterase inhibitors are the agents of choice [2]. Hypertension can be treated with increasing depth of anesthesia [38] and serotonin antagonism with ketanserin (10 mg), cyproheptadine (1 mg), or methotrimeprazine (2.5 mg) [44, 45]. Delayed awakening has been previously described in patients who suffered carcinoid crisis [8]. Both serotonin and its precursor 5-hydroxytryptophan are implicated as neurotransmitters involved in sleep, but no precise mechanism of action has been identified. This effect is likely related to the prolonged somnolence that was seen in our patient.
Carcinoid tumors are potentially curable even when they reach a significant size; thus an aggressive treatment strategy is warranted. The management of such cases requires careful investigation, planning, and treatment with collaborative expertise provided by a multidisciplinary team. We have demonstrated that this approach can lead to a favorable outcome in what at first appeared to be a formidable and unresectable tumor. Advances in imaging modalities, in the understanding of the biology and pharmacology of carcinoid tumors, and in anesthetic and surgical technology and techniques have made this sort of aggressive treatment a viable consideration for patients with large bronchial carcinoid tumors.
|
Acknowledgments |
|---|
|
TopFootnotesAbstractIntroductionCase reportCommentAcknowledgmentsReferences |
|---|
|
Footnotes |
|---|
|
TopFootnotesAbstractIntroductionCase reportCommentAcknowledgmentsReferences |
|---|
|
References |
|---|
|
TopFootnotesAbstractIntroductionCase reportCommentAcknowledgmentsReferences |
|---|
This article has been cited by other articles:
|
|
 |
|
  G. Olgac, F. Peirovi, A. Yilmaz, and C. A. Kutlu Giant Carcinoid Tumor Mimicking Pulmonary Sequestration Ann. Thorac. Surg., October 1, 2007; 84(4): 1375 - 1376. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. de Perrot, S. Fischer, M.-A. Brundler, Y. Sekine, and S. Keshavjee Solitary fibrous tumors of the pleura Ann. Thorac. Surg., July 1, 2002; 74(1): 285 - 293. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| ANN THORAC SURG | ASIAN CARDIOVASC THORAC ANN | EUR J CARDIOTHORAC SURG |
| J THORAC CARDIOVASC SURG | ICVTS | ALL CTSNet JOURNALS |
