99 - Screening for Lung Cancer: Challenges for Thoracic Surgery
Editors: Shields, Thomas W.; LoCicero, Joseph; Ponn, Ronald B.; Rusch, Valerie W.
Title: General Thoracic Surgery, 6th Edition
Copyright 2005 Lippincott Williams & Wilkins
> Table of Contents > Volume II > Section XVII - Other Tumors of the Lung > Chapter 116 - Carcinoid Tumors
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Chapter 116
Carcinoid Tumors
Gail Darling
Robert J. Ginsberg
Carcinoid tumors are the second most common tumor type arising in the tracheobronchial tree and historically have accounted for 0.5% to 1.0% of all tumors of bronchial origin. Two recent studies by Fink (2001) and Levi (2000) and their associates have reported an incidence of 2.8 to 4.8 per 100,000 people per year, which represents a significant increase compared with historical data of 0.5 per 100,000 per year. These tumors are an interesting group of malignant growths originally described in 1882 by M ller and coined Karzinoid in 1907 by Oberndorfer because of their resemblance to lung cancer. Until recently, these tumors were grouped with cylindromas (adenoid cystic carcinoma) and mucoepidermoid tumors as bronchial adenomas because of their relatively benign course. It has since become apparent that they represent a spectrum of neuroendocrine tumors of varying malignant potential, depending on their differentiation (typical vs. atypical) and stage at presentation. Although reports have proffered other descriptive nomenclatures, including Kultchitsky cell tumor or neuroendocrine carcinoma, the original term, carcinoid tumor, remains commonly accepted and serves to differentiate them from lung cancers with neuroendocrine features, which have a much more ominous prognosis, as recorded by Dresler and associates (1997).
CLINICAL FEATURES
Carcinoid tumors generally present between the ages of 45 and 55, with typical carcinoids presenting about a decade earlier than atypical carcinoids. They have been reported across all ages with a range from 11 to 81 years of age. There is generally equal distribution between men and women.
Signs and Symptoms
The symptoms and physical findings associated with these tumors depend on their location (central or peripheral). The peripheral tumors are most often asymptomatic, presenting as solitary pulmonary nodules on radiographic studies of the chest (Fig. 116-1). The proximally located tumors grow partially or wholly within a bronchus. Partial or complete endobronchial obstruction and its sequelae, as well as the vascularity of the tumor, account for the symptoms. Cough, hemoptysis, and recurrent infection constitute the classic triad of symptoms (Table 116-1). Smoking history reflects the population norm but appears increased in those with atypical carcinoid, as noted by Fink and colleagues (2001), although a link such as exists for small cell lung cancer and smoking has not been clearly demonstrated.
Because of the small size and slow growth of these tumors, symptoms may persist for many years before the underlying cause is discovered. A history of wheezing or recurrent infection dating back many years is common (Fig. 116-2). One patient in the Memorial Sloan-Kettering series had recurrent hemoptysis for 40 years before diagnosis and treatment of a carcinoid tumor of the bronchus. These tumors frequently masquerade clinically as bronchial asthma, chronic bronchitis, or bronchiectasis, particularly if the tumor produces incomplete obstruction and is located in the trachea or proximal portions of the bronchial tree.
Incomplete obstruction leads to cough, wheezing, or recurrent distal infection with its sequelae. On occasion, a unilateral hyperlucent segment, lobe, or lung is identified on the chest radiograph because of a ball-valve mechanism. Complete obstruction may result in obstructive pneumonitis with pain, fever, and dyspnea. Bronchiectasis or chronic lung abscesses are found in patients with long-standing undiagnosed tumors, eventually resulting in total destruction of lung tissue distal to the obstruction (Fig. 116-3).
Stridor can be the presenting symptom in tracheal or main-stem bronchial tumors. Occasionally, this high airway obstruction becomes life threatening. Recurrent hemoptysis, another frequent symptom, results from ulceration of the mucosa overlying the tumor or simply from chronic inflammation distally. Occasionally, a patient with atypical carcinoid presents initially with metastatic disease.
The carcinoid syndrome is rarely present at diagnosis (a 1% 2% incidence) and exclusively in patients with large
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primary tumors or extensive hepatic metastases. However, according to Ricci and coinvestigators (1973), 2% to 7% of of these patients will develop carcinoid syndrome over time, of which 86% will have hepatic metastases.
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Fig. 116-1. Radiograph of an asymptomatic peripheral carcinoid tumor. |
Carcinoid Syndrome
Carcinoid syndrome is a clinical entity consisting of well-described cutaneous, cardiovascular, gastrointestinal, and respiratory manifestations. It was first described in, and most commonly occurs with, metastatic carcinoid tumors of the gastrointestinal tract, but this syndrome occasionally occurs in association with bronchial carcinoids and was the presenting symptom in one patient in McCaughan and colleagues' (1985) series. Harpole and associates (1992) reported an unusually high incidence of the syndrome of 12%. The carcinoid syndrome occurs in bronchial tumors only when the primary tumor is large, as in a case recorded by Fischer and associates (2001), or when liver metastases have occurred, in the latter instance, often many years after removal of the primary tumor. An interesting phenomenon is the left-sided cardiac valvular abnormalities reported in the carcinoid syndrome associated with large primary carcinoid tumors of the lung, unlike the right-sided valvular lesions found with hepatic metastases.
The rarity of this syndrome in carcinoids of pulmonary origin may be because they reportedly contain less serotonin per gram of tissue than do intestinal carcinoids. It is possible that this level is reduced because of the lung's high content of monoamine oxidase that can detoxify serotonin.
Other Endocrinopathies
Like small cell carcinoma, bronchial carcinoids have also been associated with various other endocrine disorders (including Cushing's syndrome) as the result of increased adrenocorticotropic hormone (ACTH) production, excessive pigmentation from melanophore-stimulating hormone, and acromegaly. In addition, the multiple endocrine neoplasia syndrome (MEN-1) has been reported in association with these tumors.
Cushing's Syndrome
Limper and co-workers (1992) reviewed 15 cases of a bronchial carcinoid tumor associated with Cushing's syndrome. The latter condition was the presenting clinical feature in each patient. Such a presentation is rare and was not reported in any of the patients in the series included in Table 116-1. The bronchial carcinoids were of the typical type in 10 patients, 3 patients had atypical carcinoids, and metastatic disease was present in 3. Almost all of the tumors were nodules located in the periphery of the lungs. Ten of the 15 tumors were radiographically occult initially; of these, 5 subsequently were discovered radiographically over long periods of observation, and 5 (after 1980) were discovered by computed tomographic (CT) scans. Resection resulted in 10 complete and 2 partial remissions. The three patients with metastatic disease continued to have hypersecretion of ACTH and remained symptomatic. The experience of Pass and co-workers (1990) at the National Cancer Institute with 13 patients who had bronchial carcinoids associated with Cushing's syndrome is not dissimilar. Although 12 of the tumors in this series were typical carcinoids and only one was atypical, lymph node metastases were present in 50% of the patients in this series. An additional seven patients with bronchial carcinoid tumors associated with Cushing's syndrome were reported by Shrager and associates (1997) from the Massachusetts General Hospital. Five of the tumors were histologically of the typical type, but two of these showed local invasion and two were associated with lymph node metastases (43%). Both of the atypical carcinoid tumors had involved lymph nodes. The overall incidence of lymph node invasion was 57%. In these two aforementioned series, the high incidence of lymph node involvement is in contrast to only a 20% incidence of metastases in Limper and colleagues' (1992) collected series and a 24% incidence of lymph node metastases in 72 patients collected by Pass and co-workers (1990) from the literature (1957 1989). Deb and associates (2003) from the Mayo Clinic in Rochester, Minnesota, reported 23 patients, 10 men and 13 women, with Cushing's disease associated with carcinoid tumors of the lung. Lymph node involvement was present in 23% of the patients who underwent lymphoadenectomies (N1 disease was present in two thirds and N2 disease was found in one third of these patients). Long-term survival was the rule; only one patient died of disseminated tumor 18 years after the initial resection. From their experience, the aforementioned authors concluded that carcinoid tumors associated with Cushing's disease do not appear to be more aggressive than carcinoids without this disease.
Although Cushing's disease occurs in no more than 1% of patients with bronchial carcinoid, it is the second most
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commonly observed paraneoplastic syndrome associated with these tumors. Any patient who presents with Cushing's disease, particularly with prominent hypokalemic alkalosis, and who has no evidence of either adrenal or pituitary disease, should undergo a search for an occult bronchial carcinoid. The other two thoracic diseases that must also be considered are small cell cancer of the lung and carcinoid tumor of the thymus.
Table 116-1. Clinical Presentation | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Fig. 116-2. Serial radiographs of a retrocardiac bronchial carcinoid demonstrating slow growth over a 4-year period. |
DIAGNOSIS
No single investigative method is sufficient to diagnose the presence of a bronchial carcinoid in all patients, but by various radiographic techniques and bronchoscopy, most tumors can be located and correctly identified. Fine-needle aspiration biopsy of peripheral lesions can be accurate, but they may be mistaken for a small cell carcinoma. Cytologic examination of bronchial washings or brushings are generally not helpful. Histologic examination of tumor tissue is the only completely reliable means of diagnosis.
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Fig. 116-3. Gross specimen of a typical polypoid bronchial carcinoid (arrows) resected by superior segmentectomy of the right lower lobe, wedge resection of the bronchus intermedius, and bronchoplasty. Note the bronchiectasis and abscesses distally. |
Radiographic Studies
Standard radiographs of the chest may reveal a tumor mass or changes in pulmonary parenchyma caused by tracheobronchial obstruction. A standard radiograph may detect no abnormality in just a little less than half of the patients according to Deb and colleagues (2003) (Fig. 116-4A). Oblique views may detect an otherwise undetectable central lesion and may delineate an endobronchial component of the tumor not readily apparent on routine studies. CT scan has superceded other standard radiographic views and will delineate the endobronchial and parenchymal component of the tumor in most of the patients so examined (Fig. 116-4B). In the past, hilar tomography and bronchography were used frequently to outline the endobronchial obstruction and to demonstrate irreversible bronchiectasis in the bronchial tree distally. These examinations are now rarely, if ever, indicated.
CT scan of centrally located lesions reveals the presence of a well-defined mass that narrows, deforms, or obstructs an adjacent airway. Diffuse or punctate calcifications can be identified in approximately 30% of lesions. According to Magid and associates (1989), this finding should suggest that the tumor is a carcinoid. In rare cases, the tumor may ossify, as recorded by Okike and colleagues (1976). High-resolution CT scan, as reported by Sutedja and co-workers (1996), may be used effectively to demonstrate bronchial wall irregularities, bronchial wall thickening, and peribronchial tumor invasion in patients with central endobronchial lesions. When such findings are absent, it may be surmised that no bronchial wall infiltration by the tumor is present. High-resolution CT is also of value in revealing the presence of enlarged hilar and peribronchial lymph nodes. Peripheral parenchymal changes such as atelectasis or bronchiectatic changes of the distal airways may be demonstrated. Peripheral lesions usually lie adjacent to an airway. Last, using CT scan, homogeneous contrast enhancement of a typical carcinoid is observed after intravenous administration of a bolus of contrast media. Atypical carcinoids show less contrast enhancement and frequently have irregular contours. Regional adenopathy is more often seen in association with the atypical lesions.
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Fig. 116-4. A. A chest radiograph called normal. An endobronchial carcinoid is in the distal left main-stem bronchus. B. An endobronchial carcinoid of the left main-stem bronchus demonstrated by computed tomography. Note the minimal involvement of the bronchial wall. |
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None of these radiologic techniques accurately differentiates these tumors from other benign and malignant neoplasms, although one may suspect their nature by the radiographic appearance of an obstructive lesion or peripheral tumor in a young, nonsmoking person.
Nuclear Scanning
Reubi and co-workers (1990) have shown that 54 of 62 (87%) carcinoid tumors could be labeled by the autoradiographic technique of somatostatin analogue binding. This has led to the use of anatomic localization by somatostatin receptor scintigraphy (octreotide scanning) in patients with Cushing's syndrome caused by an occult ectopic corticotropin-producing tumor by de Herder (1994) and Dewey (1996) and their associates, among others. Raderer and associates (2000) reported the value of octreotide scanning in all sites of carcinoid tumors with a sensitivity of 91% for primary sites and 95% for metastatic sites. In their series, 100% of metastatic sites of bronchial origin were detected by octreotide imaging.
Positron Emission Tomography
The role of positron emission tomography (PET) scanning is as yet undetermined. Initial experience in PET imaging of carcinoid tumors presented by Erasmus and collaborators (1997) indicates that carcinoid tumors are not hypermetabolic and have a low standardized uptake ratio, with a range of 1.6 to 2.4. Because of this, central carcinoids are not easily distinguishable on PET from the background activity of the normal mediastinum, but peripheral carcinoids may be easily distinguished from normal lung. The role of fluorine 18 fluorodeoxyglucose PET in imaging metastatic disease is under evaluation, but early studies, such as that by Le Rest and colleagues (2001), suggest it may be useful. Preliminary results reported by Hofmann and associates (2001) using gallium 68 labeled octreotide PET imaging shows further promise.
The role of technetium 99m labeled peptide depreotide single-photon emission computed tomography (depreotide is a synthetic analogue of somatostatin) in the identification of carcinoid tumors is as yet undetermined. However, Goldsmith and Kostakoglu (2000) reported at least one case of a malignant carcinoid identified by this examination.
Bronchoscopy
Bronchoscopy should be successful in identifying all tumors situated within and proximal to the segmental orifices. Approximately 75% of all carcinoid tumors are visible bronchoscopically (Table 116-1).
Accurate identification of the tumors requires bronchial biopsy. Wilkins (1963) and Donahue (1968) and their associates, among others, reported massive bleeding after biopsies of carcinoid tumors. Indeed, these highly vascular tumors do tend to bleed, but almost all severe postbronchoscopic hemorrhages result from endoscopic attempts at partial or complete removal of the tumor. These tumors present submucosally and require deeper biopsies than are necessary for other malignant bronchial neoplasms. Care must be taken in performing such biopsies. As suggested by Rozenman and colleagues (1987), we perform bronchoscopic
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biopsies of these tumors using a dilute epinephrine solution for vasoconstriction before and after biopsy. Some investigators recommend general anesthesia and rigid bronchoscopy for airway control in case uncontrollable hemorrhage occurs during fiberoptic bronchoscopic examination. We have not found this necessary.
Table 116-2. Stage-Related 5-Year Survival Rates | ||||||||||||||||||||||||||||||||||||||||
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Transbronchoscopic fine-needle aspiration biopsy of the submucosal tumor for cytologic examination may help in diagnosing carcinoid tumors but may be misleading, just as in percutaneous transthoracic biopsy. Because of their similarity to small cell carcinomas, carcinoid tumors have occasionally been misdiagnosed as this more aggressive tumor.
Staging
Because of the adverse prognostic effect of lymph node metastases in this disease, researchers reporting results of treatment have used the American Joint Committee on Cancer/International Union Against Cancer Lung Cancer Staging criteria for carcinoid tumors as well. Stage-related survival is shown in Table 116-2. Most (78% 90%) typical carcinoid tumors present as stage I lesions as compared with 25% to 63% of atypical carcinoids. The majority of atypical carcinoids present as stage II or III, with bronchopulmonary or mediastinal lymph node involvement (Table 116-3).
Since the optimum treatment of carcinoid tumors is surgery with resection of the primary tumor and lymph node dissection if nodal disease is present, preoperative nodal staging by mediastinoscopy has little value unless preoperative imaging suggests that the primary tumor or lymph node metastases are unresectable.
Biochemical Studies
Unless the carcinoid syndrome is suspected, screening patients with suspected bronchial carcinoids for serotonin and its breakdown product (5-hydroxyindoleacetic acid) in blood or urine has no diagnostic value, although Harpole and co-workers (1992) found elevated levels to be an adverse prognostic variable on univariate analysis.
PATHOLOGY
Experimental evidence reported by Churg (1988) suggested that these tumors arise from stem cells of the bronchial epithelium rather than from amine precursor uptake and decarboxylation (APUD) cells that migrated from the neural crest as was previously proposed. A review by Gould and associates (1983) of the histogenesis and differentiation of bronchial carcinoids and their proposed relationship with other pulmonary tumors with neuroendocrine features is provocative. Gould and colleagues (1988) and Flieder (2002) as well as others have suggested, based on structural and functional similarities, that pulmonary neuroendocrine tumors exist in a spectrum from typical carcinoid to small cell carcinoma. Neurosecretory granules on electron microscopy are common to all, as are the light microscopy findings of organoid nesting, palisading, and rosettes. These latter findings are more common in typical and atypical carcinoids. Immunohistochemical studies demonstrate the expression of cytokeratins and desmoplakin across the spectrum of all pulmonary neuroendocrine tumors, confirming their epithelial origin according to Gould and co-workers (1988). Pulmonary neuroendocrine tumors, including carcinoids,
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demonstrate reactivity for thyroid transcription factor-1 as noted by Oliveira and collaborators (2001), a feature that is useful in determining the pulmonary origin of a tumor.
Table 116-3. Stage of Typical and Atypical Carcinoid Tumors at Presentation (%) | |||||||||||||||||||||||||||||||||||
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Immunoreactivity for a variety of peptides is also seen across the spectrum of neuroendocrine tumors, including serotonin, bombesin, calcitonin, leu-enkephalin, growth hormone releasing hormone, gastrin, melanin-stimulating hormone, vasoactive intestinal peptide, ACTH, chromogranin, and synaptophysin. Cells may stain for more than one peptide, and the intensity of immunostaining may be variable within a given tumor.
Recent genetic studies reported by Onuki and associates (1999) have also demonstrated similar genetic abnormalities across the spectrum of pulmonary neuroendocrine tumors with loss of heterozygosity at 3p, 5q, 9p, 11q, 13q, and 17p, the severity of which increases in high-grade tumors.
The current World Health Organization classification of neuroendocrine tumors is typical carcinoid (low grade), atypical carcinoid (intermediate grade), and large cell and small cell neuroendocrine carcinoma (high grade) (World Health Organization, 1999).
Typical Carcinoids (Low-Grade Neuroendocrine Tumors)
Most of these tumors are situated centrally; 20% are located in the main-stem bronchi, approximately 60% in the lobar and segmental bronchi, and another 20% are located peripherally. Carcinoid tumors infrequently involve the main carina or trachea (Fig. 116-5). Multiple or multicentric tumors may occur but are rare.
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Fig. 116-5. An unusual carcinoid tumor presenting in the left main-stem bronchus and extending to the carina. This lesion required carinal resection for management. |
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Fig. 116-6. Bronchoscopic view of a carcinoid adenoma. |
Bronchoscopically, typical carcinoids appear as highly vascularized pink to purplish soft tumors, covered by intact epithelium (Fig. 116-6). Large areas of ulceration are rare. A few tumors are polypoid with a definite stalk, but most are sessile. Because the bulk of the tumor is usually extraluminal, they have been called iceberg tumors. They penetrate the bronchial wall and may directly extend into the pulmonary parenchyma and peribronchial lymph nodes.
Microscopically, the tumor consists of uniform round to polygonal cells with small oval nuclei containing finely granular chromatin, but cells may be spindle shaped, particularly in peripherally located tumors. The cytoplasm is abundant and eosinophilic. Travis and coinvestigators (1998) report that mitoses are infrequent, with less than 2 per 10 high-power fields (HPF). Necrosis is absent. The cells are arranged in small nests, rosettes, or interlacing cords, or both, separated by highly vascular connective tissue (Fig. 116-7). The stroma may show osseous metaplasia, which may be secondary to necrosis within the tumor or necrosis of compressed bronchial cartilage with secondary ossification (Fig. 116-8). As previously noted, this may be seen as calcification within the tumor on CT scans. The overlying bronchial epithelium can undergo squamous metaplasia, but frank ulceration or invasion by tumor is rare. Bertelsen and co-workers (1985) reported that only 10% to 15% of patients with typical carcinoid tumors present with lymph node metastases. Vascular invasion is rare, as are distant metastases.
Ultrastructurally, Bensch and associates (1965) were the first to describe that these tumors consist of closely packed cells with small but well-formed desmosomes and numerous neurosecretory granules. The neurosecretory granules (Fig. 116-9) are large, heterogeneous, and numerous.
Genetic changes include deletions at 3p in 40% of cases and 11q in 44%. Abnormalities of the MEN-1 gene have been reported by Onuki (1999) and Ullmann (2002) and their colleagues, as well as by berg (2002), but revisions in the criteria for typical versus atypical carcinoid suggest that these abnormalities are more common in atypical tumors. Abnormalities of p53 are uncommon in typical carcinoids,
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occurring in only 10% of cases according to Onuki and associates (1999).
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Fig. 116-7. A. Low-power photomicrograph of a typical carcinoid with intact overlying bronchial epithelium. B. High-power photomicrograph of a typical carcinoid tumor composed of nests of regular polygonal cells separated by a network of capillary vessels reflecting the vascularity of the tumor. |
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Fig. 116-8. Gross (A) and microscopic (B) appearance of a carcinoid adenoma with osseous metaplasia. Note the large, extrabronchial component of this tumor. |
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Fig. 116-9. High-power electron photomicrograph (original magnification 32,300) of a carcinoid adenoma reviewing secretion granules, typical of neurosecretory cells. From Toker C: Observations on the ultrastructure of a bronchial adenoma (carcinoid-type). Cancer 19:1943, 1966. With permission. |
Atypical Carcinoids (Intermediate-Grade Neuroendocrine Tumors)
Atypical carcinoids, which display both malignant histologic features and aggressive behavior, were described by Englebreth-Holm (1944 1945) and Von Albertini (1951), but most accurately by Arrigoni and associates (1972). The average age of patients with atypical carcinoids is 55 years, compared with 45 years for patients with typical carcinoids. Warren and colleagues (1985) referred to these tumors as well-differentiated neuroendocrine carcinomas. They have also been referred to as a Kultchitsky cell II tumor; Kultchitsky I is a typical carcinoid and Kultchitsky III is a small cell carcinoma. In contrast to typical carcinoids, more than 50% of these tumors are located peripherally, the age of onset is later, and 35% to 75% of patients present with lymph node or distant metastases. In some instances, it is difficult to differentiate an atypical carcinoid from a small cell undifferentiated carcinoma. Despite the pathologic similarities, it is interesting to note the lack of correlation of smoking with carcinoid tumors and the invariable smoking history in patients with small cell carcinomas, as well as the relatively poor response of atypical carcinoids to chemotherapy.
The original criteria for the diagnosis of atypical carcinoid described by Arrigoni has been modified by Travis and colleagues (1998) to include tumors with 2 to 10 mitoses per 10 HPF or the finding of necrosis. By including tumors with 2 to 5 mitoses per 10 HPF in the atypical category rather than as typical carcinoids as originally described by Arrigoni, differences in prognosis were more consistently predicted. Atypical carcinoids retain a carcinoid-like pattern, but display pleomorphism with mitotic activity, nuclear abnormalities, prominent nucleoli, peripheral palisading, and necrosis (Fig. 116-10). Neurosecretory granules are present but are of small size; that is, typical carcinoid. In older series, about 10% of carcinoids are atypical, but subsequent to the revision in the criteria for diagnosis, many typical carcinoids have been reclassified as atypical such that in recent publications, as those of Thomas (2001) and Beasley (2000) and their associates, atypical carcinoids represent 25% of pulmonary carcinoids.
Genetic abnormalities noted in atypical carcinoid include 3p deletions in 73% of tumors, 22% with loss of heterozygosity at the RB gene, 50% at 11q13 (MEN-1 gene), and
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45% with p53 abnormalities. Such genetic changes, as noted by Onuki and colleagues (1999) are similar but more frequent in large and small cell neuroendocrine carcinomas.
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Fig. 116-10. High-power photomicrograph of an atypical carcinoid tumor consisting of ribbons of polygonal cells that show greater pleomorphism and mitotic activity than those seen in a typical carcinoid tumor. |
The differences between typical and atypical carcinoids versus small cell lung cancer are summarized in Table 116-4.
Pathologists have identified a group of large cell tumors with neuroendocrine features. These tumors are indeed lung cancers, have prognoses similar to those seen with small cell lung cancer, and must be differentiated from atypical carcinoids. The criteria of differentiating large cell neuroendocrine tumors from atypical carcinoids, as suggested by Travis and co-workers (1998), are presented in detail in Chapter 101. According to Przygodzki and co-workers (1996), these large cell neuroendocrine tumors are more akin genetically and immunohistochemically to small cell cancers and also behave like them as demonstrated by Dresler and coinvestigators (1997).
Melanocytic Carcinoid
The rare pigmented carcinoid has been reported by Cebelin (1980) and by Grazer (1982) and Gal (1993) and their colleagues. Its differentiation from a pulmonary melanoma is discussed in Chapter 119.
Oncocytic Carcinoid
Oncocytic carcinoid is a rare subtype of the typical carcinoid tumor. It is composed of a variable admixture of large eosinophilic oncocytes and cells characteristic of the typical carcinoid tumor. Ghadially and Block (1985), among others, have described this tumor and its differentiation as a true oncocytic tumor.
Clear Cell Carcinoid Tumors
According to Leong and Meredith (1997), a carcinoid tumor infrequently may exhibit extensive clear cell change and thus require differentiation from other clear cell tumors of the lung. Differentiation requires immunohistochemical stains and ultrastructural examination. Clear cell tumors are discussed in Chapters 118 and 119.
Tumorlets and Multiple Peripheral Carcinoids
Whitwell (1955) coined the term pulmonary tumorlet to describe isolated foci of atypical hyperplastic bronchial epithelium. Tumorlets were initially regarded as forms of early invasive or in situ small cell carcinoma. They are usually an incidental finding at autopsy or in a lung resected for infection or tumor. Miller and co-workers (1978) described them particularly in patients with restrictive pulmonary disease.
Immunohistochemical staining has demonstrated differences in secretory products between tumorlets and typical carcinoids. Because of the similarity in staining patterns between tumorlets and normal bronchial epithelium, Cutz and associates (1982) suggested that tumorlets are hyperplastic proliferations of neuroendocrine cells rather than neoplasms, although D'Agati and Perzin (1985) described one case with peribronchial lymph node metastases. Aguayo and associates (1992)
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implicated a diffuse form as an etiologic mechanism in small airway obliterative disease. A similar patient described by Sheerin and colleagues (1995) was successfully treated by lung transplantation. Histology of the explanted lung demonstrated multiple periarteriolar nodules consisting of nests of cells with fibrosis, with obliteration of adjacent bronchioles by connective tissue deposition.
Table 116-4. Selected Histopathologic and Molecular Features of Pulmonary Neuroendocrine Tumors | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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TREATMENT
Unless distant metastatic disease is evident, the principles of treatment of carcinoid tumors include complete removal of the primary lesion with preservation of as much normal lung tissue as possible. Because most of these tumors are only locally invasive, the most conservative resection that allows complete removal of the tumor is indicated when possible. Surgical lymph node staging is mandatory, and regional lymphadenectomy is advised in all patients with positive nodes or atypical carcinoids.
Endoscopic Resection
Endoscopic removal of carcinoid tumors was a frequent mode of treatment before the advent of modern techniques in surgery, anesthesia, and postoperative care, which has permitted removal of pulmonary tissue with low morbidity and mortality. Because most of these tumors are also extraluminal, and frequently only a small part of the tumor is visible and accessible to the rigid bronchoscope, incomplete removal with recurrence was common. The highly vascular connective tissue within the tumor made this mode of therapy dangerous, including the risk for exsanguinating hemorrhage. Personne (1986) and Diaz-Jimenez (1990) and their co-workers reported that the advent of the neodymium: yttrium-aluminum-garnet (Nd:YAG) laser has reduced the risk for hemorrhage in endoscopic removal of these tumors by photocoagulation. This technique is not recommended as the primary form of treatment of carcinoids, however, because local recurrence is inevitable, except for the rare occasion when a polypoid tumor, easily accessible, is on a narrow, uninvolved stalk (Fig. 116-11).
Sutedja and associates (1995) described 11 patients with endobronchial carcinoids treated endoscopically by Nd:YAG laser plus photodynamic therapy or mechanical removal. In six patients, subsequent resection demonstrated no residual tumor, and in five patients, not surgically treated, follow-up between 27 and 246 months demonstrated no sign of recurrence. Van Boxem and colleagues (1998) of Sutedja's group have attempted to better define the role of endoscopic treatment of intraluminal typical carcinoid tumors by a prospective
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study. Only patients who met the criteria of accessibility of the tumor by fiberoptic bronchoscopy and, more important, the absence of any signs of bronchial wall infiltration on high-resolution CT scan and the absence of any enlarged lymph nodes were included in the study. Endoscopic resection was performed via Nd:YAG laser or bronchoscopic electrocautery. Complete response was obtained in 14 of 19 patients. In the five patients who did not respond completely, the distal margin of the tumor could not be determined because of its location in a segmental bronchus. Thus, they now believe that patients in whom the distal margin cannot be adequately visualized are not candidates for this type of therapy. Furthermore, they suggested that when subsequent resection was required in such patients, a less extensive procedure could be performed after preoperative bronchoscopic treatment. Although additional experience must be reported before this therapeutic approach is fully accepted, it appears that in a highly selected subset of patients, definitive endoscopic therapy is possible.
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Fig. 116-11. A. A polypoid carcinoid tumor arising in the apical segment of the right upper lobe. Note that on exhaling (right), the tumor protrudes out of the orifice. This lesion was found to have a definite uninvolved stalk. B. The polypoid tumor in A was smeared (left) and removed with the base coagulated using an Nd:YAG laser (right). The stalk was uninvolved with tumor. Two-year follow-up has failed to reveal any local recurrence. Courtesy of M. Burt. |
Bronchoscopic management is useful before definitive thoracotomy in relieving distal obstructive symptoms and controlling infection. When thoracotomy is contraindicated for other reasons, transbronchoscopic removal of the tumor may be warranted to alleviate bronchial obstruction and perhaps to provide long-term asymptomatic management. The use of Nd:YAG laser, photodynamic laser therapy, or electrocautery may well augment this approach.
Surgical Resectional Therapy
Keeping in mind the locally invasive nature of this tumor, complete removal with preservation of as much normal lung as possible is the goal of treatment. Destroyed, functionless lung tissue distal to the lesion should also be removed. The types of procedures performed in the Memorial Sloan-Kettering Cancer Center series are listed in Table 116-5. The high incidence of pneumonectomy reflects earlier management efforts in patients who now would commonly be treated by sleeve resection, when possible.
Surgical staging is a necessary adjunct to any thoracotomy. Biopsies of the lymph nodes located in the bronchopulmonary segment, lobar areas, and hilum should be performed. Frozen section analysis is required. In those patients who have nodal metastases, a more extensive cancer operation (with complete lymph node dissection, including all accessible mediastinal lymph nodes) is required.
Table 116-5. Treatment of Carcinoid Tumors at Memorial Sloan-Kettering Cancer Center (101 Operations) | ||||||||||||
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Bronchotomy
Bronchotomy and simple wedge excision of the affected bronchial wall can be used on occasion. Polypoid tumors accessible by bronchotomy thus can be removed with the attached bronchial wall, ensuring a complete resection, in comparison with endoscopic removal. However, this simple bronchotomy approach is rarely applicable.
Sleeve Resection
Main-stem bronchial tumors or, occasionally, tumors located in the bronchus intermedius, as Frist and co-workers (1987) described, can be removed by sleeve resection of the bronchus, preserving all pulmonary tissue. This technique is preferable to pneumonectomy or bilobectomy. On occasion, carinal resection is required, as reported by Stamatis and co-workers (1990).
Wedge Resection
Wedge resection is appropriate only in dealing with the occasional small peripheral, typical carcinoid tumor and should be accompanied by lymph node sampling and frozen section analysis of proximal (segmental and hilar) lymph nodes as well as the primary tumor to confirm that it is truly a typical carcinoid.
Segmental Resection
Segmental resection is the procedure of choice for selected tumors arising distal to the origin of the tertiary bronchi. For example, tumors originating in the orifice of the superior segment of the lower lobes can be treated by segmental resection combined with sleeve resection of the lower lobe bronchus, preserving all basal segments, assuming frozen section analysis reveals regional lymph nodes are uninvolved and bronchial resection margins are clear.
Lobectomy
Lobectomy, with or without a bronchoplastic procedure, is the most common operation because most tumors occur in or near the origins of the lobar bronchi. A concomitant sleeve resection of the main-stem bronchus is required if the orifice of the lobar bronchus or the adjacent main-stem bronchus is involved by tumor. Addition of the bronchoplastic procedure permits preservation of distal normal lung tissue that otherwise would have to be sacrificed and is preferable to pneumonectomy. In this regard, preoperative endoscopic removal of tumor can allow time for recovery of concomitant pneumonia and assessment of the reversibility of the damage to the distal lung parenchyma before definitive therapy.
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Pneumonectomy
Since the advent of bronchoplastic procedures, pneumonectomy is rarely required in the treatment of this tumor. Only in the unusual instances of destruction of all lobes by a proximal tumor, or an unusually positioned tumor not permitting a sleeve resection, should pneumonectomy be considered.
When resecting these endobronchial lesions, the margin of the bronchial resection must be examined by frozen section at the time of operation. If microscopic tumor is found at the margin of resection, a more proximal resection is required. With typical carcinoids, a negative resection margin, only millimeters away from the tumor, is sufficient. Although some surgeons, such as Smith (1969), McCaughan and associates (1985), and others, advocate a complete mediastinal node dissection in all patients because of the possibility of occult microscopic involvement, nodal staging by frozen section at the time of surgery is an acceptable alternative. If an atypical carcinoid is present or nodal involvement is identified at frozen section analysis, then a complete mediastinal node dissection is required.
Radiation Therapy
Bronchial carcinoids are resistant to irradiation, so this type of therapy should not be considered the primary treatment when surgical resection can be performed. However, Baldwin and Grimes (1967) and others have reported cases of an inoperable lesion that responded to such treatment. Postoperative irradiation has been recommended for patients with atypical carcinoids and lymph node metastases when a complete surgical resection has not been accomplished or mediastinal lymph nodes are involved. The benefit of this treatment has not been documented, although as reported by Martini and colleagues (1994), only one local recurrence was seen in such a group of patients treated with postoperative radiation therapy.
Chemotherapy
Combination chemotherapy similar to that used in small cell carcinoma, especially etoposide (VP-16) and cisplatin, has been effective in managing metastatic carcinoid tumors, although the response rate to this chemotherapy is not as high as that seen in small cell carcinoma, with only 50% or less of patients demonstrating an objective response. berg (2001) and Granberg and associates (2001) noted that agents such as doxorubicin, streptozotocin, and 5-fluorouracil have yielded disappointing responses in carcinoids of bronchial origin despite favorable responses in pancreatic carcinoids. Some researchers advocate adjuvant chemotherapy for atypical carcinoids that have been associated with mediastinal nodal spread at the time of resection, usually in combination with mediastinal radiation therapy. The value of this therapy has never been assessed.
Carcinoid Syndrome
Total removal of large primary tumors associated with the carcinoid syndrome ablates the symptoms of the syndrome. The perioperative management of such tumors is discussed in detail by Fischer and colleagues (2001). However, once hepatic metastases have occurred, the management of the syndrome can become more difficult. Karmy-Jones and Vallieres (1993) describe the successful use of a somatostatin analogue (octreotide) in preventing a carcinoid crisis at the time of resection of an active bronchial carcinoid tumor in a patient that had developed a carcinoid crisis after examining this tumor via biopsy. Somatostatin analogues also have been demonstrated to be effective in treating patients with metastases suffering from the carcinoid syndrome. Octreotide given in doses of 100 to 300 g per day gives symptomatic responses in 60% of patients and tumor response in 5%. Higher doses, as noted by Filosso and colleagues (2002), as well as by berg (2001), may be used with increased tumor response with similar symptom and biochemical response. Long-acting formulations, sandostatin-LAR (20 30 mg once per month) and Lanreotide-PR (30 mg every 2 weeks) provide symptom control in more than 50% of patients according to berg (2001) and significant improvement in quality of life as measured by the QLQ-30.
berg and colleagues first reported their experience in the use of interferon- in 1983. Recombinant interferon- 2b titrated to leukocyte count is reported to produce a biochemical response rate in 50% of patients and a significant tumor response in 15%. berg (2001) recorded stabilization of disease with no further tumor growth in 35% while in 15% the disease progressed.
Other options reported for treatment of carcinoid syndrome due to hepatic metastases include embolization of liver metastases as suggested by Granberg and colleagues (2001) or therapeutic use of radionuclides (iodine 123 metaiodobenzylguanidine, indium 111 octreotide, and yttrium 90 octreotide) as reported by Pathirana (2001) and Chatal (2000) and their co-workers.
PROGNOSIS
Carcinoid tumors grow slowly, and the natural history is prolonged. We have seen one patient with symptoms of 40 years duration without treatment, and a second patient, who refused surgical treatment, alive and well 20 years later.
Five-year survival rates after resection depend on the aggressiveness of the tumor. Almost all typical carcinoid tumors with or without lymph node metastases are cured by adequate surgical treatment. One should expect a 90% or greater 5-year survival rate in this group of patients (Table 116-6). Once lymph node metastases have occurred with
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typical carcinoids, complete excision with lymph node dissection still allows an excellent prognosis. In a series reported by Martini and colleagues (1994) involving 12 typical carcinoids with lymph node metastases (N1 or N2), the 5-year disease-free survival rate was 100%. One patient only had a recurrence after 8 years. However, results reported by other researchers have not been as encouraging.
Table 116-6. Overall Survival for Typical (TC) and Atypical (AC) Carcinoid Tumors | |||||||||||||||||||||||||||||||||||
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Atypical carcinoids, with their frequent incidence of lymph node and distant metastases, are associated with lower 5-year survival rates, ranging from 25% to 69%. Of 13 patients with atypical carcinoids with nodal involvement at Memorial Sloan-Kettering Cancer Center, the 5-year disease-free survival rate was only 57%, but 73% of all patients were still alive with lymph node dissection and postoperative radiation therapy; most patients in whom the carcinoid recurred had distant metastases only, with only one local recurrence identified. In this latter group of tumors, the role of postoperative adjuvant chemotherapy and irradiation has not been adequately assessed, although standard chemotherapy has yet to yield a greater than 50% response rate. More aggressive management (e.g., postoperative chemoradiation) is worthy of this study.
Harpole and associates (1992) reported that stage and histology (atypical) were associated with a worse prognosis on multivariate analysis. In patients with atypical histology reported by Beasley and colleagues (2000), stratified for stage, number of mitoses and tumor size greater than 3.5 cm were associated with a worse prognosis. Whether gender is a prognostic factor has not been clearly defined because being a woman has been reported as having both an adverse and beneficial effect on prognosis.
SUMMARY
Carcinoid tumors of the lung are rare, representing 0.5% to 1% of all lung tumors. Patients typically present with symptoms of cough, hemoptysis, or recurrent infections. Most tumors are central in location, with 75% to 80% being visible by bronchoscopy. Peripheral tumors are usually asymptomatic. Historically, 10% of all carcinoids are found to be atypical, but with the recent revision of the criteria defining atypical carcinoids, a third of all carcinoids were found to be atypical in a more recent series. The primary treatment is complete surgical resection, including lymphadenectomy if lymph nodes are involved or the primary tumor is atypical. Long-term prognosis is excellent, with the 5-year survival rate for typical carcinoids greater than 85%.
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