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Primary Carcinoid Tumors of the Lung: A Role for RadiotherapyPublished on Physicians Practice (http://www.physicianspractice.com)

Primary Carcinoid Tumors of the Lung: A Role for RadiotherapyReview Article [1] | November 01, 2006By Heath B. Mackley, MD [2] and Gregory M. M. Videtic, MD, CM, FRCPC [3]

Primary neuroendocrine neoplasms of the lung represent a clinical spectrum of tumors ranging fromthe relatively benign and slow-growing typical carcinoid to the highly aggressive small-cell lungcarcinoma. The rarity of carcinoids has made the role of radiation therapy in their managementcontroversial. This review considers the results of published studies to generate treatmentrecommendations and identify areas for future research. Surgery remains the standard of care formedically operable disease. Histology plays the most important role in determining the role ofadjuvant radiation. Resected typical carcinoids likely do not require adjuvant therapy irrespective ofnodal status. Resected atypical carcinoids and large-cell neuroendocrine carcinomas have asignificant risk of local failure, for which adjuvant radiation likely improves local control. Definitiveradiation is warranted in unresectable disease. Palliative radiation for symptomatic lesions hasdemonstrated efficacy for all histologies. Collaborative group trials are warranted.

The term carcinoid was first used by Oberndorfer in 1907 to describe tumors more indolent thanadenocarcinomas,[1] but earlier reports of bronchial carcinoids[2] described some of theircharacteristics. Pulmonary carcinoids were originally grouped with adenoid cystic carcinomas underthe more general term bronchial adenoma, but this classification was subsequently abandoned.[3]Within the category of carcinoids, a more aggressive atypical carcinoid was first described byEngelbreth-Holm in 1944,[4] but it was not until 1972 that Arrigoni formally separated typical andatypical carcinoids[5] as separate clinicopathologic entities.

Within non-small-cell lung cancer (NSCLC), the large-cell undifferentiated carcinoma withneuroendocrine features was proposed to be a clinically separate entity in 1985, and in 1991 Travisproposed criteria for the large-cell neuroendocrine carcinoma.[5] The current World HealthOrganization classification of neuroendocrine lung neoplasms recognizes four distinct pathologicentities: the typical carcinoid (TC), atypical carcinoid (AC), large-cell neuroendocrine carcinoma(LCNEC), and small-cell lung cancer (SCLC).[6]IncidenceThe true incidence of pulmonary carcinoids is difficult to estimate. The number of all-site carcinoidcases in the United States has been estimated to be about 4,500 cases per year.[7] Of these,bronchial sites account for 23% to 37%.[7,8] This would imply that the annual number of pulmonarytypical and atypical carcinoids is about 1,000 to 1,500. However, lung cancer series estimatecarcinoids as 2% of all cases,[9] which would place the number at around 3,400.By contrast, there were an estimated 35,000 small-cell lung cancers in 2004, indicating thathigh-grade neuroendocrine neoplasms outnumber carcinoids at the minimum by a factor of 10:1.The incidence of LCNEC is also difficult to estimate, in large part due to its recent definition. In ahistologic review of 572 lung cancer patients, 87 were found to be LCNECs, accounting for 9% ofNSCLCs and 44% of SCLCs reviewed.[10] It would be inappropriate to try to extrapolate the annualincidence from these data, but they do seem to indicate that the number of LCNECs may besignificant.Patient CharacteristicsThe median age at diagnosis of neuroendocrine lung neoplasms is about 50 years, with TCs tendingto occur in younger patients, and ACs and LCNECs occurring in older patients.[11] For patientsyounger than age 50, women outnumber men in a ratio of 1.6:1.[12] Cigarette smoking appears tobe a risk factor for the development of ACs[12] but not TCs.[13] Smoking is almost certainlyassociated with LCNECs, with 98% of patients having a history of habitual smoking in one series.[10]PathophysiologyThe cell of origin is the Kulchitsky cell,[14] a bronchial mucosa cell that can synthesize bioactiveamines. Pulmonary carcinoids have stained positive for serotonin, adrenocorticotropic hormone(ACTH), vasoactive intestinal peptide (VIP), bombesin, and leucine enkephalin.Various genetic mutations have been described, with different lesions associated with differenthistologies. Both 11q deletions and MEN1 mutations are found in TCs and ACs, but not in LCNECs or

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SCLCs, while 10q and 13q deletions are found in ACs, LCNECs, and SCLCs.[12]Pathologic CriteriaClassically, the gross description of a carcinoid is a vascular-appearing mass with a smooth surfaceand pink or yellow color, but this is seen more often with TCs than ACs.[15] Under a lightmicroscope, carcinoids have small nuclei, few nucleoli, and ample cytoplasm. They classically stainwith silver,[16] although chromogranin, synaptophysin, and neuron-specific enolase are commonlyused today to identify neuroendocrine tumors. Using an electron microscope, neurosecretorygranules, which contain biogenic amines, are diagnostic.TCs and ACs are differentiated from one another by the presence of necrosis and the amount ofmitoses per high-power field (Table 1).[6] LCNECs and SCLCs both have high mitotic rates and largeamounts of necrosis, but can be differentiated based on light microscopy, with LCNECs havingcytologic features similar to NSCLCs. LCNECs can be differentiated from NSCLC either by thepresence of neurosecretory granules on electron microscopy, or by positive staining ofneuroendocrine markers.

Clinical PresentationUp to 24% of TCs and 7% of ACs are asymptomatic, with their detection only coming at autopsy.[17]Among the rest of neuroendocrine tumors, local symptoms are the common presenting symptoms,including dyspnea, chest discomfort, unilateral wheezing, bronchial obstruction, hemoptysis, cough,or recurrent pulmonary infections.[12]Pulmonary carcinoids commonly arise from the lobar bronchi (55%) or segmental bronchi (32%), andless commonly, the mainstem bronchi (13%).[18] The right lung is involved in 60% of cases, and themiddle and lower lobes may be involved more often than the upper lobe.[19]Symptomatic clinical syndromes from the production of functional hormones are rare with primarybronchial neuroendocrine tumors, even in those staining positive for bioactive amines.[20] Carcinoidsyndrome is found in 1% of patients[18] and is associated with the presence of liver metastases. It ismost often caused by the secretion of serotonin, and the classic clinical manifestations includediarrhea, flushing, and palpitations. Less common sequelae include heart dysfunction[12] andcoronary valve fibrosis. Rarely, surgical manipulation can cause pulmonary edema or vasomotorcollapse, the so-called carcinoid crisis. ACTH production is found in 1% of cases, resulting inCushing's syndrome, which is clinically manifested by weakness, hypertension, glucose intolerance,hypokalemia, alkalosis, weight loss, anemia, and hyperpigmentation. Growth hormone-releasingfactor causing acromegaly has also been rarely described in cases of pulmonary carcinoid tumor.DiagnosisThe diagnosis of pulmonary carcinoid is commonly made via either bronchoscopy or computedtomography (CT)-guided biopsy. Although significant bleeding at biopsy is relatively rare, it can bedifficult to control with a flexible bronchoscope. When a carcinoid is suspected because of its grossappearance, some centers use prophylactic dilute epinephrine solution and only perform a biopsy inan environment where a rigid bronchoscope or Nd:YAG laser is on hand.[21]Imaging often includes chest x-ray and chest computed tomography. Immunoscintigraphy withsomatostatin analogs such as octreotide is increasingly helpful in staging pulmonary carcinoids.[14]In assessing the primary, octreotide scanning has a sensitivity of 97% and specificity of 95%, and forevaluation of metastatic disease, a sensitivity of 93% and specificity of 90%.[14] Nodal disease is

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less sensitive (60%) and specific (85%), suggesting that pathologic staging remains standard.Although the use of positron-emission tomography (PET) to stage carcinoids is currentlyinvestigational, individual cases of 18F-fluorodeoxyglucose (FDG)-avid TCs and ACs have beenreported.[22]The most common sites of distant metastatic disease are the liver, bone, brain, adrenal glands, andovary,[23] but imaging of these organs is generally deferred unless clinical symptoms are present. InLCNECs, it is reasonable to routinely order a PET/CT of the abdomen and brain imaging to rule outmetastatic disease because these studies are commonly used in the work-up of SCLC and NSCLC. Forserotonin-secreting tumors, urine 5-hydroxyindoleacetic acid (5-HIAA) can be useful in monitoringthe response to treatment and/or screening for a recurrence.SurgerySurgery is the treatment of choice for primary pulmonary carcinoid tumors. TCs are most oftenmanaged with a lobectomy, but some surgeons advocate lung-sparing procedures such as asegmentectomy or wedge resection because of the relatively benign nature of the disease.[24] Onthe other hand, ACs and LCNECs are generally treated with an oncologic resection, and a lobectomyis the smallest acceptable procedure.[11] Mediastinal lymph node sampling should also beperformed in these patients, but the role of this procedure in TCs is somewhat controversial. Forobstructive lesions, an endobronchial laser resection can provide palliation, although this should notbe used definitively,[25] as most lesions spread extraluminally and adequate margins would not beattainable using this approach.Prognostic FactorsLong-term results from numerous surgical series suggest that the histologic subtype of a bronchialcarcinoid is the most important prognostic factor. Tumor-node-metastasis (TNM) stage appears lesscritical since there seems to be a strong correlation between histology and stage.[26] In a Japaneseseries of 366 surgically resected neuroendocrine tumors, 3.6% of TCs had nodal disease, comparedwith 50% of higher-grade lesions.[27] In Fink's series, 10% of TCs were node-positive and 3% hadmetastatic disease, whereas 57% of ACs were node-positive and 21% had metastatic disease.[18]Tables 2 and 3 summarize survival rates in patients with carcinoid tumors by histology and stage.

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Other prognostic factors include completeness of resection, the presence of paraneoplastic

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symptoms, and age.[27] One carcinoid series also shows an association between tobacco use andadvanced stage.[19] Gender has been inconsistently reported as a prognostic factor, with two seriesshowing worse outcomes in males,[19,27] and one series of ACs suggesting that women had a worsesurvival.[23]Patterns of FailureTCs with regional metastatic lymph node involvement appear to have similar outcomes compared tothose without nodal disease. Thomas et al reported the Mayo experience of 36 patients with regionallymph node disease treated with surgery alone.[4] Of 23 TC patients treated with surgery alone(median follow-up: 84 months), 83% had no evidence of disease recurrence and 9% failed distantly.Schreurs et al reported excellent results in a series of TCs following surgery, including 10% withnode-positive disease and 2.1 % with positive resection margins. The disease-specific survival rate inthis group was 100% through 15 years.[25] In Kaplan's series of 206 patients, stage I TCs that werecompletely resected had an 8% local failure rate and 7% distant failure rate.[26]Failure rates appear to be worse with more aggressive histologies. Kaplan and colleagues reportedthat for completely resected stage I ACs, 23% failed locally and 23% failed distantly.[26] In the MayoClinic series reported by Thomas et al, systemic failure was the dominant site of relapse for 64% ofACs and 100% (2 of 2 patients) of LCNECs. In Gould's series of 87 patients, atypical histology was theonly factor associated with an increase in local recurrence-local failure occurred in 17% of ACs and6% of TCs.[28]Perkins reported a series of 79 patients from M.D. Anderson with pulmonary carcinoid and nometastatic disease[29]; 49 were TCs and 14 were ACs. A total of 24 had aggressive features, definedas involving regional lymph nodes, carina or vessel invasion, or inoperable disease. The group withaggressive features had a significantly worse 5-year overall survival (51% vs 77%, P = .01). Of theeight patients who died of disease with aggressive features, one died of local disease, four died oflocal and distant disease, and three died of distant disease only. Two patients who died from diseasewith nonaggressive features had local recurrence and distant disease. Takei reported on failurepatterns for a LCNEC series; first recurrences were local in 34% of patients, distant in 57%, and bothin 9%.[10]In summary, bronchial carcinoid patients with aggressive histologies (AC, LCNEC), and possiblyhigh-risk tumor features (positive lymph nodes, invasion of local structures, gross residual disease),have higher rates of failure, both local and systemic.Radiation TherapyIn the management of neoplasms, the role of radiation therapy (RT) is conventionally defined by itscurative (definitive, primary, adjuvant) or palliative intent. With respect to primary neuroendocrinetumors of the lung, the utility of RT has been explored in the postoperative setting—that is, as anadjuvant to surgical interventions.Adjuvant RTPathologic features including lymph node positivity and positive resection margin status haveprompted clinicians to consider the use of adjuvant radiotherapy for resected bronchial carcinoids,based on patterns of failure following surgical resection and then modeling treatment approachesafter the paradigms employed for resected NSCLC. This approach remains controversial.For example, Cooper et al[30] reported a surgical series of 77 patients including 50 with TCs, 5 withACs, 9 with LCNECs, 4 with mixed large-small-cell neuroendocrine carcinoma (LSNEC), and 9 withSCLCs. The authors recommended that adjuvant radiotherapy was warranted for lymph nodeinvolvement regardless of histology but did not provide supporting postoperative results for thisconclusion. Due to the relative rarity of the primary bronchial carcinoids, no randomized studies haveaddressed the benefits of adjuvant radiotherapy, and therefore, clinical practice has been guidedmainly by single-institution retrospective reports.Carretta described a series of 44 pulmonary neuroendocrine tumors treated initially with resectionand lymphadenectomy.[31] One patient received neoadjuvant chemotherapy. A total of 36 were TCs,3 were ACs, and 5 were LCNECs. Approximately 11% of TCs were node-positive, compared with 25%of ACs/LCNECs. All node-positive patients were treated with adjuvant radiation to a median dose of56 Gy (range: 45-58 Gy). No local recurrences occurred after RT. Recurrence rates were 8% for TCsand 25% for ACs/LCNECs. The 5-year overall survival rates were 93% for patients with TCs and 70%for those with ACs/LCNECs.An Italian series described 42 patients with pulmonary carcinoids treated initially with surgicalresection[14]; 26 had TCs and 16 had ACs. All patients with stage III disease received radiationand/or systemic therapy. One patient treated with radiation failed in the same lung, but whether thiswas an in-field recurrence was not recorded. Among the four patients who failed without radiation,

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all failed distantly.Perkins and colleagues from M.D. Anderson reported on 7 of 73 surgical patients who receivedadjuvant RT and/or chemotherapy based on positive surgical margins, local invasion, and/or lymphnode involvement.[29] They were not classified by histologic subtype. One patient who receivedsurgery followed by RT was alive without evidence of disease 10 years after diagnosis.Martini et al at Memorial Sloan-Kettering reported on a series of 25 patients with lymphnode-positive disease[9]; 12 had TCs and 13 had ACs. Of 15 patients with N2 disease, 9 receivedadjuvant radiation. The 5-year overall survival rate for patients with TCs was 92% and for those withACs, 60%. The authors concluded that most recurrences were distant and correlated with cell type,that no local recurrences were observed in N2 patients, and that the role of adjuvant RT could not beassessed because of the small number of cases treated.Ohta et al reported a case of a patient successfully treated with neoadjuvant chemotherapy andradiation.[32] This patient with a T3, N2, M1 AC of the right superior sulcus and a single brainmetastasis was treated with thoracic RT (45 Gy) and concurrent methotrexate, vinblastine, andcisplatin. The patient was restaged and found to be T3, N0, M0, with complete resolution of both thebrain metastasis and gross nodal disease. He was then treated with a definitive resection andadjuvant high-dose rate brachytherapy to a dose of 21 Gy to the operative bed. The patientultimately developed systemic metastases and died but experienced no local recurrences.We have very little data specific to the treatment of LCNECs in the adjuvant setting. However, asmany LCNECs were previously classified as NSCLC, it is instructive to review the approach for thelatter histology. In NSCLC, the role of adjuvant radiation is controversial for N1 patients based on thepostoperative radiation therapy (PORT) meta-analysis, which suggested a survival decrement inpatients treated with adjuvant radiation.[33] However, adjuvant mediastinal radiation is indicated inpatients with N2 disease, since the modality improves local control in this group with no impact onsurvival.[34]In summary, there appears to be little role for adjuvant RT in resected TCs. However,pattern-of-failure findings and suggestions from reported data for AC and LCNECs indicate thatadjuvant RT may offer a potential benefit with respect to improved local control in cases withhigh-risk findings after surgery.Definitive RT for Unresectable Bronchial CarcinoidThe use of definitive RT for medically inoperable or surgically unresectable nonmetastatic pulmonaryneuroendocrine tumors has been infrequently reported. Chakravarthy and Abrams from JohnsHopkins reviewed the effectiveness of RT for a broad range of bronchial carcinoids.[35] Of 240patients reviewed, they described 5 who were treated with RT to the lung or mediastinum forprimary localized, unresectable disease. Three were exclusively chest primaries without distantdisease. The median RT dose used in treatment to the chest was 51 Gy (range: 39-55.8 Gy). Three ofthe five patients showed clinical improvement, and one did not respond. Two of the five were alivewith in-field disease control at 24 and 48 months. Only one of the five had in-field progression withsymptoms.Wirth et al at the Dana-Farber Cancer Institute reviewed the outcomes of patients with bronchialcarcinoids treated with chemotherapy with or without radiotherapy.[36] They identified 18 suchpatients, with either a TC (n = 8) or an AC (n = 10). Seven of these patients had locallyadvanced/unresectable disease. Stage IB TC was diagnosed in two patients, one of whom wastreated with radiochemotherapy followed by chemotherapy and was alive at 60 months. One patientwith stage IIIA TC was treated with platinum-based chemotherapy alone and had stable disease at 6months. Two ACs in the series were stage IIIA, and two were stage IIIB. Three of these AC patientswere treated with radiochemotherapy; two were alive with stable disease at 8 and 10 months, andthe other had a partial response with a survival of 84 months. The other patient with stage IIIAdisease was alive at 10 months with stable disease after two forms of chemotherapy.Overall, the authors felt that advanced pulmonary carcinoid disease can respond to treatmentmimicking that used for small-cell lung carcinoma (chemotherapy plus radiotherapy), but with farlower response rates. Further study of treatment modalities for unresectable pulmonary carcinoidappears warranted.Palliative RadiationNumerous case reports and write-ups of small series have described the utility of RT in the palliativesetting. Of interest, these often deal with unusual presentations sometimes seen with metastaticbronchial carcinoid. In general, the efficacy of RT in the palliative setting has been well recognized.Ameer et al notes that RT has a defined palliative role in the treatment of bronchial carcinoids.[37]According to these authors, about 80% of treated patients have a partial or complete response to RT.

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Chakravarthy and Abrams described the use of RT for a range of metastatic pulmonary carcinoidlesions including bone, skin, CNS, liver, and prostate metastases.[35] Overall, 87% of 31 treatedsites showed clinical improvement with RT and 61% of sites were controlled for greater than 3months.Schupak and Wallner analyzed the role of RT for 416 patients treated for metastatic or unresectablecarcinoid at Memorial Sloan-Kettering.[38] Considering only those with primary lung tumors, threepatients with brain metastases showed stable disease without progression after palliative RT, four ofsix patients with spinal cord compression showed complete responses and two had partial responsesfollowing median doses of 30 Gy in 10 fractions, and three of three patients with bone metastaseshad complete responses after 20 to 24 Gy. RT was overall judged effective at symptomatic palliationin most patients with metastatic carcinoid tumors. In that regard, many authors have noted that RTprovides effective pain relief in patients with bone metastases from metastatic carcinoid.[39-41]Many examples in the literature have documented the use of palliative RT in specific clinical cases.Nakamura et al[42] described a case report involving stereotactic radiosurgery for brain metastasesfrom a pulmonary AC. Three brain metastases showed radiographic evidence of necrosis afterradiosurgery, but 1 year later the procedure had to be repeated because of disease progression. Thepatient died of systemic disease. Pulmonary carcinoids may rarely metastasize to the uvea. Harbouret al[43] reported the Wills Eye experience of uveal metastases from carcinoid tumors, seven ofwhich were pulmonary carcinoids. Five patients were treated with external-beam irradiation, andfour experienced regression. The fifth was salvaged with plaque brachytherapy. Two other patientswere treated primarily with plaque brachytherapy, either 125I or 106Ru. All seven patients experienceddurable local control. Gragoudas and Carroll[44] reported a case of bilateral multiple choroidallesions 8 years after removal of a bronchial carcinoid tumor. Biopsy confirmed carcinoid metastases.One eye was treated with conventional RT, which produced adverse effects. The other was treatedwith photocoagulation and proton-beam irradiation without adverse -effects.Shimon et al reported an unusual case of metastatic atypical bronchial carcinoid to the anteriorpituitary gland in a 47-year-old male who presented with bitemporal hemianopsia andhypopituitarism. The primary bronchial carcinoid had been resected 2 years earlier. Partial removalof the suprasellar mass was performed, and metastatic atypical carcinoid was confirmed.Fractionated radiotherapy to the sella, supplemented with octreotide, was administeredpostoperatively. The patient's vision returned to normal and the pituitary mass diminished insize.[45] Palliative RT has also been specifically described for LCNECs. Takei and colleagues reporteda series of 18 patients treated palliatively with radiation, noting a 28% complete response rate.[10]Systemic TherapyThe indications and forms of systemic therapy for neuroendocrine lung tumors are also controversialand beyond the scope of this review. However, in the context of RT, a novel systemic therapy usedto treat metastatic disease involves attaching a radioisotope, such as 90Y or 111In, to a somatostatinanalog.[46,47] Carcinoid tumors express high levels of somatostatin receptor; therefore, linking aradioactive element with a limited range of activity to the analog permits the delivery of high localdoses to tumor while theoretically minimizing normal tissue exposure. Although an interestingconcept, systemic radiation in the treatment of carcinoid continues to be investigational.Treatment RecommendationsSurgical resection remains the standard of care for medically operable localized disease. If grossresidual disease is present after surgery, adjuvant radiation is recommended for all histologies. Forcompletely resected TCs, with or without regional nodal involvement, no adjuvant therapy isrecommended. Evidence suggests that no adjuvant therapy is indicated for TC with positive margins.For completely resected ACs, adjuvant mediastinal irradiation appears indicated for mediastinalnodal disease but its role in N0/1 disease is uncertain. For completely resected LCNECs, adjuvantmediastinal radiation is recommended in N2/N3 disease but not in N0/N1 cases.If a patient has localized unresectable disease, definitive radiation is offered, likely withchemotherapy, but the optimal sequence of modalities is unclear. In the metastatic setting, palliativeradiation should be considered for symptomatic lesions. Specific dose recommendations are difficultto make considering the range of reported doses used, the heterogeneity of treated sites, and theabsence of clear dose-response data. However, common practice has been modeled after theregimens used in similar settings for either non-small-cell or small-cell cancers.Future DirectionsNeuroendocrine neoplasms of the lung continue to offer a challenge to the clinician and investigatoralike. Most patients with completely resected TCs have an excellent outcome, but other clinicalsubsets do not. Improvements in both local and systemic control need to be achieved, and to further

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this goal the roles of radiation and systemic agents need to be systematically studied. The bestmechanism for proper study of these unusual tumors in their various presentations is throughcooperative group trials, which should be encouraged. Disclosures: The authors have no significant financial interest or other relationship with the manufacturers of anyproducts or providers of any service mentioned in this article. References: 1. Oberndorfer S: Karzinoide tumoren des dunndarms. Frankfurt Zschr Pathol 1:425-429, 1907.

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50. Filosso PL, Rena O, Donati G, et al: Bronchial carcinoid tumors: Surgical management andlong-term outcome. J Thor Card Surg 123:303-309, 2002. Source URL: http://www.physicianspractice.com/printpdf/primary-carcinoid-tumors-lung-role-radiotherapy/page/0/2

Links:[1] http://www.physicianspractice.com/review-article[2] http://www.physicianspractice.com/authors/heath-b-mackley-md[3] http://www.physicianspractice.com/authors/gregory-m-m-videtic-md-cm-frcpc

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