management leads to complete resection, and the operative risk is comparable with that of standard

pulmonary resection. Importantly, combined-modality treatment requires close collaboration among

medical oncologists, radiation oncologists, surgeons and pulmonologists, preferably in a

multidisciplinary tumor board setting, as well as anesthesiologists at the time of operation. In the

future, three key areas warrant further investigation: (a) The optimal combination and sequence of

newer, less toxic chemotherapeutic agents and a variety of new radiation techniques; (b) whether

concurrent chemoradiation is superior to chemotherapy alone as preoperative induction therapy; and (c)

the identification of the molecular features that dictate tumor response to different chemotherapeutic

agents allowing a more individualized selection of induction treatment regimens which may lead to

improved long-term outcomes.

Superior Sulcus Tumors

Tumors of the superior sulcus (Fig. 79-2), described in detail by H. K. Pancoast in 1932,147 represent an

uncommon (3%) and challenging subset of NSCLC. Tumors frequently involve the brachial plexus,

subclavian vessels, or spine and typically fall into two categories; T3N0–1 (stage IIB or IIIA) or T4N0–1

(stage IIIB).148 Until the 1950s these tumors were felt to be almost universally fatal, with no benefit

provided by resection. In 1961, Shaw and Paulson demonstrated that preoperative thoracic radiation

followed by resection was potentially curative.149 For the subsequent 30 to 35 years, reports

demonstrated 5-year survival of approximately 25% to 30%. In a single-institutional experience,

spanning 24 years, during which 225 patients underwent thoracotomy at MSKCC, 5-year survival for

patients undergoing resection for Stage IIB, IIIA and IIIB superior sulcus tumors was 46%, 0% and 13%,

respectively.150 In this retrospective study, the mode of preoperative therapy, with radiation and/or

chemotherapy, or adjuvant therapy did not appear to affect survival, which was influenced only by the

completeness of resection and tumor (T) and nodal (N) status in a multivariate analysis. As in other

retrospective series, locoregional recurrence was the most common form of relapse, occurring in 40% of

patients.151

Figure 79-2. Gross figure of a squamous cell carcinoma showing a superior sulcus tumor (Pancoast tumor) arising from apex of the

right lung. From Cagle PT. Color Atlas and Text of Pulmonary Pathology. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.

Spurred by reports of the apparent success of neoadjuvant chemotherapy and thoracic radiation in

achieving improved local control and survival for patients with locoregionally advanced NSCLC, the

Southwestern Oncology Group coordinated a phase II trial, the first prospective, multicenter trial

(SWOG 9416/Intergroup 0160) for superior sulcus tumors.152 Of 110 patients eligible, including 32

patients with T4 disease, 104 completed induction chemoradiation and 95 were eligible for operation.

Patients with mediastinal lymph node metastases (N2) were excluded from this trial. Of the 88 patients

who underwent thoracotomy, 83 had a complete resection, with 61 patients demonstrating complete

pathologic response (R0) or minimal residual disease (R1). There were three treatment-related deaths

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and two perioperative deaths. Of note, intracranial and other distant metastases were more common

(22% each) than locally recurrent disease only (11%). Overall 2- and 5-year survival was 55% and 41%

for all patients enrolled, and 70% and 53% for patients with a complete response.

NEUROENDOCRINE TUMORS

Neuroendocrine tumors of the lung include a varied group of lesions ranging from tumors with lowgrade malignant potential (typical carcinoid) to SCLC, which is among the most rapidly growing and

aggressive of human tumors. Between those two extremes, atypical carcinoid and large cell

neuroendocrine carcinoma have been defined.153

Figure 79-3. Typical carcinoid tumor of the lung. A microscopic view shows ribbons of tumor cells embedded in a vascular

stroma. From Rubin E, Farber JL. Pathology. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 1999.

Typical and Atypical Carcinoid Tumors

Carcinoid tumors, which are neoplasms with a low-grade malignant potential, account for about 2% of

lung tumors in the United States. They arise from neuroendocrine stem cells of the bronchial epithelium

and are classified as either typical or atypical. Histologically, typical carcinoids consist of uniform

polygonal cells with round nuclei and fine granular chromatin (Fig. 79-3). Mitotic figures are rare.

Atypical carcinoids show increased mitotic activity, nuclear pleomorphism, and areas of disorganized

architecture and tumor necrosis (Fig. 79-4).154

Carcinoid tumors occur equally in both sexes and at a median age of 55 years. Half of patients present

with pulmonary symptoms, including hemoptysis, dyspnea, and recurrent or persistent pneumonitis

because 40% of lesions are centrally located in the main or lobar bronchi (Figs. 79-5 and 79-6). The

lesions may be diagnosed by bronchoscopy, appearing as pink or purple friable endobronchial masses

covered by intact epithelium. In the other half of patients, carcinoid tumors are diagnosed when

radiologic abnormalities are detected on a chest roentgenogram as part of a routine examination.155

Figure 79-4. Atypical carcinoid tumor of the lung. A cellular tumor shows central necrosis and a disorganized architecture. From

Rubin E, Farber JL. Pathology. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 1999.

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Figure 79-5. Gross figure of a carcinoid tumor protruding into the bronchial lumen. From Cagle PT. Color Atlas and Text of

Pulmonary Pathology. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.

Lymph node metastases occur in approximately 10% to 15% of patients at diagnosis but are more

frequent in atypical carcinoids. Carcinoid syndrome is associated with bronchial carcinoids in only 2% of

cases, usually in patients with metastatic disease, particularly to the liver. The most common sites of

metastases are lung, bone, liver, adrenals, and brain.155

The standard treatment for bronchial carcinoids is complete resection, regardless of the presence of

nodal involvement, with mediastinal lymph node sampling or dissection. Lobectomy can be

accomplished in the majority of patients with resectable disease, although parenchymal-sparing

segmentectomy or nonanatomic wedge resection can be considered particularly for patients with a

typical carcinoid tumor.156 For patients who have centrally located tumors and for which

pneumonectomy might be performed, bronchoplastic techniques (i.e., sleeve lobectomy) should be

considered instead.157 Endoscopic resection is invariably associated with local recurrence and should be

used only as a palliative maneuver in patients whose general medical condition precludes thoracotomy

and pulmonary resection.155

Figure 79-6. Gross figure of a resected carcinoid tumor cut in cross section to show invasion through the bronchial cartilage. From

Cagle PT. Color Atlas and Text of Pulmonary Pathology. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.

The long-term survival rate after resection exceeds 90% in patients with typical carcinoids, even when

hilar or mediastinal nodal metastases are present. In contrast, patients with atypical carcinoids have a 5-

year survival rate of 60% after complete resection. The outcome is more closely linked to histology than

to tumor size, location, or nodal involvement. Recurrence is more frequent with tumors larger than 3

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cm and in patients who present with lymph node metastases.157,158

Large Cell Neuroendocrine Carcinomas

Large cell neuroendocrine carcinoma is characterized by the microscopic features of neuroendocrine

tumors, but the tumor cells are large, have a high mitotic rate, and frequently show necrosis (Fig. 79-

7).153,154 According to Travis et al.159,160 large cell neuroendocrine carcinomas are related to smoking,

as is SCLC, and are high-grade tumors with 5- and 10-year survival rates of 27% and 9%, respectively,

despite complete resection. Few data are available concerning adjuvant therapy. For the time being, the

management of large cell neuroendocrine carcinoma is identical to that of NSCLC.161

Small Cell Lung Cancer

Small cell carcinoma of the lung has the most aggressive clinical course of any type of pulmonary tumor

and is often widely disseminated by the time of diagnosis. The proportion of patients with SCLC has

been decreasing from 17% in the 1980s to 13% of lung cancer cases in 2002.162 In contrast to non–small

cell tumors, these lesions are notably responsive to chemotherapy and are rarely within the domain of

the surgeon. The staging system for SCLC was developed by the Veterans Administration Lung Cancer

Staging Group and divides patients into those with limited-stage (LS) and those with extensive-stage

(ES) disease. This distinction was first based on what could be encompassed by a tolerable radiation

portal. After clarification by the International Association for the Study of Lung Cancer, LS disease

includes patients with tumors confined to one hemithorax and regional lymph nodes (hilar, ipsilateral,

and contralateral mediastinal nodes, and ipsilateral and contralateral supraclavicular nodes) as well as

patients with ipsilateral pleural effusion, regardless of whether the cytology is positive or negative.163

On the other hand, both pericardial and bilateral pulmonary involvement are considered ES disease.164

Figure 79-7. Large cell neuroendocrine carcinoma of the lung shows positive immunostaining with synaptophysin antibody. From

Cagle PT. Color Atlas and Text of Pulmonary Pathology. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.

Common sites of distant metastases are bone, liver, bone marrow, and the central nervous system,

and therefore the metastatic evaluation includes a bone scan, CT of the chest and abdomen, and brain

MRI. Some oncologists also perform bone marrow biopsies, but because the marrow is the sole site of

extensive disease in fewer than 5% of patients, biopsies are usually judged unnecessary. After the

staging process, approximately 30% to 40% of patients are found to have LS disease.

For patients with LS SCLC, response rates of 85% to 90% and complete response rates of 50% to 60%

can be expected with the combination of etoposide and cisplatin and radiation therapy.165 The median

survival is 18 to 24 months, and the 2-year survival rates are 40% to 50%. The addition of definitivedose thoracic radiation therapy, particularly when administered concurrently or within several weeks of

completing chemotherapy confers a 5% 2- to 3-year overall survival benefit.166–168 In ES SCLC treated

with chemotherapy, response rates reach 75% to 85%, although complete response is seen in only 15%

to 25% of patients. The median survival is between 7 and 11 months, with a 2-year survival less than

5%.162 Although the prognosis in SCLC depends primarily on the anatomic extent of disease, after a

review of prognostic variables in its 2,580-patient SCLC database, the Southwest Oncology Group

determined that the two-stage system should be extended into a four-stage system, with serum lactate

dehydrogenase level, age, and pleural effusion used as additional staging criteria.169

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