Benign and malignant neoplasms of the lung are the most common type of intrathoracic neoplasms and are among the most common solid tumours in males and females in North America and the United Kingdom. Over 150 000 patients were diagnosed with pulmonary neoplasms in the United States in 1991. Malignant lesions, of varying metastatic potential, account for over 95 per cent of these tumours. Lung cancers are the product of our modern society; their incidence and mortality have risen in an epidemic pattern during the 20th century—in part due to increased life expectancy, but primarily due to increased environmental exposure to carcinogenic agents (e.g. tobacco products).

These tumours are the most common indication for pulmonary resection. For benign lesions, surgical resection provides the potential for cure in nearly all cases. For malignant lung tumours, the majority of which have metastasized at the time of initial presentation, surgery can provide important staging information and offers the greatest likelihood of cure for neoplasms that are localized to the pulmonary parenchyma.

The complexity of the process of neoplastic transformation has been increasingly appreciated within the last decade with the advance of molecular biological techniques and, in particular, molecular genetics. The importance of genetic factors in the host response to carcinogenic stimuli, the role of tumour suppressor genes, and the spectrum of neoplastic behaviour related to specific oncogene expression have been incorporated into the proposed scheme of transformation.

Exposure to an environmental agent culminates in an internal dose of the agent, which may have a direct effect, as in the case of ionizing radiation, or, more commonly, may undergo activation to a carcinogen. The net effective biological dose, determined by the internal dose offset by the rate of activation or excretion of active agent, may then elicit early intracellular events, including inactivation of recessive oncogenes (i.e. tumour suppressor genes) or expression of dominant oncogenes, which ultimately lead to alterations in cellular structure and function. The active carcinogen, or other agents, may have additional, additive effects during the succession of events leading to expression of the neoplastic phenotype (Fig. 1) 1949.

Environmental agents associated with malignant lung neoplasms include tobacco, radon, asbestos, arsenic, chloromethyl ethers, and nickel. In developed countries, exposure to tobacco products is the most common environmental agent linked to lung cancer. Conclusive evidence of the association of cigarette smoking with an increased risk of lung cancer in men has been available from case-control studies dating from the 1950s and 1960s. Newer evidence continues to support a causal relationship between smoking and lung cancer, extending to female smokers and those involuntarily exposed to cigarette smoke.

Radon, an inert gas formed from radium during the natural decay of uranium, is the second most important cause of lung cancer. Radon is invariably present in indoor air. It diffuses from the soil into enclosed spaces and decomposes into short-lived products that emit &agr;-particles. Radon exposure is causally associated with lung cancer in both uranium miners and in those who smoke cigarettes. Radon is commonplace in houses, with some houses having levels close to that of uranium mines, with an attendant lung cancer risk. Most houses, however, have levels acceptable by current guidelines. The lung cancer risk for non-smokers in these environments is unknown.

Occupational exposure to asbestos, arsenic, chloromethyl ethers, and nickel all cause lung cancer in non-smokers, and likely have an additive risk for people who smoke. Finally, ambient air pollution, containing polycyclic hydrocarbons from fossil fuel combustion and other industrial activities, also appears to pose a independent risk for lung cancer, accounting for 1 to 2 per cent of lung cancer cases.

Genetic predisposition to lung cancer has been suggested by the identification of a four-fold increased risk for lung cancer among the non-smoking relatives of people who smoke and have lung cancer, compared with non-smokers without lung-cancer relatives. Other studies, based on genetic models and the chronological causal relationship of lung cancer to tobacco imply that virtually all lung cancers occur among susceptible gene carriers. Phenotypic differences in carcinogen metabolism (e.g. aryl hydrocarbon hydroxylase, debrisoquine hydroxylase) among patients with lung cancer compared with those among matched controls suggests one potential mechanism for a genetic predisposition to the lung cancer. Identification of other such factors would have a profound impact on detection and prevention of lung cancer.

Multiple diverse genetic abnormalities characterize malignant lung neoplasms. Complex karyotypic changes are seen, with a characteristic deletion of the short arm of chromosome 3 (3p) occurring in 90 to 100 per cent of small cell lung cancers (SCLC) and in 25 to 50 per cent of non-small cell lung cancers (NSCLC). Other recessive oncogenes either deleted or mutated include the retinoblastoma gene (95 per cent small cell lung cancer, 20 per cent non-small cell lung cancer) and p&sub5;&sub3; (100 per cent small cell lung cancer, 40–50 per cent non-small cell lung cancer). Dominant oncogenes, either mutated or over-expressed include K- ras (non-small cell lung cancer), myc (small cell lung cancer), and erb B1 (non-small cell lung cancer). Mutations in K- ras and over-expression of myc are associated with a decreased survival rate for their respective histological subtypes.

All the epithelial cells of the lung derive from the endoderm, with subsequent differentiation adapted to different levels of the respiratory tract. After initial growth, the reserve cells of the epithelium are only able to replace dead cells and are looped in a terminal differentiation sequence adapted to local needs. The bronchial epithelial cells have a limited range of initial response to a variety of agents, carcinogenic or not, including basal cell hyperplasia with differentiation toward squamous or goblet (mucus) cells, or proliferation of Kulchitzky (neuroendocrine or K-type) cells of Type II pneumocytes. In the absence of carcinogenesis, most of these changes are reversible. During carcinogenesis, differentiation is switched on again and is executed aberrantly by the process of neoplastic transformation described previously. Heterogeneity of the tumour cell population and clonal selection are important aspects of growth for malignant lung tumours.

For bronchogenic carcinomas, both small cell lung cancer and non-small cell lung cancer, the cell of origin seems to be the same, although the direction of differentiation is different for the various types. To a certain extent, end-stage malignant tumours of these types come to resemble each other histologically (Fig. 2) 1950. For less malignant lung neoplasms, such as carcinoid tumours and bronchial gland tumours, the cell of origin probably derives from the epithelium or the lining of tracheal or bronchial glands, respectively. The precise cell of origin for pulmonary hamartoma, the most common benign lung tumour, is unknown.

Tumours of the lung may be divided into malignant epithelial tumours including both small cell lung cancer and non-small cell lung cancer, carcinoid and bronchial gland carcinomas, benign mesenchymal tumours, including pulmonary hamartomas, carcinosarcomas, primary sarcomas, and lymphoproliferative lesions (Table 1) 529. The malignant epithelial group comprises 98 per cent of lung neoplasms and account for the majority of surgical interventions for these neoplasms.

The most rapidly progressive form of malignant epithelial tumour is small cell lung cancer, also termed oat cell carcinoma, which accounts for 20 to 25 per cent of all lung cancers. Biologically, small cell lung cancer has unique neuroendocrine properties and produces a wide variety of peptide hormones, including both those involved in control of cellular growth (e.g. bombesin-like peptide) and those involved in paraneoplastic syndromes (e.g. ACTH, ADH, serotonin, calcitonin). Small cell carcinoma is composed of small, uniform cells with scanty cytoplasm and nuclei containing finely stippled chromatin and inconspicuous nucleoli (Fig. 3) 1951. Foci of squamous or glandular differentiation may be seen within the larger tumour mass. Although attempts to subdivide the small cell carcinomas on the basis of nuclear morphology have been made, they are of no practical value. Ultrastructurally, membrane bound cytoplasmic granules are found in one of every six cells. These granules, along with amine precursor uptake and decarboxylation (APUD) capabilities, identify the neuroendocrine differentiation of small cell lung cancer.

Small cell lung cancer occurs most commonly in middle-aged and elderly people. Although the number of patients less than 40 years old with lung cancer is small, small cell lung cancer accounts for the majority of patients in this group. Small cell lung cancer usually presents symptoms at an earlier stage than other malignant epithelial tumours because of its rapid growth (mean doubling time = 33 days), propensity for early metastasis and ectopic hormone production. Cough, weight loss, chest pain, and haemoptysis are the most common symptoms of these lesions, which manifest themselves as large, non-cavitating hilar masses with extensive nodal or mediastinal metastases in 65 per cent of cases (Fig. 4) 1952. An endobronchial lesion is found in 80 per cent of patients at the time of initial symptoms. Dysphagia, due to oesophageal compression (10 per cent), hoarseness due to recurrent laryngeal nerve invasion (15 per cent), or superior vena cava syndrome (10 per cent) are more common with small cell lung cancer than with non-small cell lung cancer. Initial symptoms produced by a metastasis to a distant organ, most commonly the central nervous system, are seen in 10 per cent of patients. Although small cell lung cancer produces a variety of hormones at a cellular level, clinical paraneoplastic syndromes are seen in a minority of patients, although more frequently than with non-small cell lung cancer patients. The most common syndromes in small cell lung cancer are Cushing's syndrome due to ectopic ACTH production, inappropriate secretion of ADH, carcinoid syndrome or Eaton–Lambert syndrome. Hypercalcaemia or hypertrophic pulmonary osteoarthropathy are uncommon in small cell lung cancer.

The two most important prognostic factors for small cell lung cancer are the stage of the disease and the performance status at the time of diagnosis. Staging of small cell lung cancer has been commonly based on a two-stage system, with patients being classified as having either limited disease (tumour confined to a hemithorax, with or without pleural effusion and with or without ipsilateral or contralateral supraclavicular or mediastinal lymph nodes) or extensive disease. An important survival difference following treatment can be identified between these two groups. However, recent data suggests that staging small cell lung cancer using the TNM system employed for non-small cell lung cancer (see below) may be useful. Although 85 per cent of small cell lung cancer are Stage III or IV at initial presentation, for patients with Stage I disease surgical resection and postoperative adjuvant chemotherapy provides a better prognosis than non-surgical therapy. For this reason, patients with small cell lung cancer should undergo staging procedures identical to non-small cell lung cancer patients at the time of diagnosis.

The median survival time of untreated small cell lung cancer is 3 months. For the majority of patients with nodal metastases or extensive disease at diagnosis, combination chemotherapy is the mainstay of treatment. Multiple drugs and more aggressive regimens produce better response rates and longer duration of response (see Section 42.4 276). Therapy is typically for 12 months or less; if complete remission is achieved, further therapy has little impact on remission duration and survival. Alternating non-cross-resistant combination chemotherapy and the use of autologous bone marrow transplantation does not improve median survival. Complete response rates range from 20 to 50 per cent, with total response rates (complete and partial response) of 80 per cent. Median survival times range from 7 months to 14 months, with 15 per cent of patients achieving disease-free survival beyond 2 years—primarily patients with limited stage disease.

Radiation therapy as a primary modality, although demonstrating a better mean survival than for surgical therapy alone, does not improve median survival as compared with the use of combination chemotherapy, or when used in conjunction with combination chemotherapy. Radiation therapy does, however, provide excellent palliation of metastatic symptoms, particularly for brain metastases. The benefit of prophylactic cranial irradiation for small cell lung cancer appears to be small and is limited only to patients demonstrating a complete remission with chemotherapy.

Surgical therapy as a primary modality should be reserved for patients with Stage I small cell lung cancer, i.e. with no nodal metastases. Selection of such patients requires maximal use of invasive staging modalities preoperatively. With the addition of postoperative adjuvant combination chemotherapy, survival for this selected group of patients is 55 per cent at 5 years. Adjuvant surgery, i.e. resection of residual pulmonary disease after combination chemotherapy, does not improve median survival.

The most common histological type of malignant epithelial lung tumour is squamous cell carcinoma, a non-small cell lung cancer that accounts for 35 to 40 per cent of all lung cancers. By light microscopy, these tumours demonstrate at least one of three characteristics of differentiation: individual cell keratinization, pearl formation (the formation of small groups of concentrically oriented cells), and/or extensive intercellular bridges, similar to those noted in the prickle cell layers of the epidermis (Fig. 5) 1953. The nuclei are characteristically hyperchromatic with a jagged border. There is often a striking host reaction including both desmoplasia and acute and chronic inflammation.

Squamous cell cancers arise in the bronchial epithelium, and progress through an in-situ phase to a preclinical phase, extending from the time the carcinoma becomes morphologically developed until it produces symptoms or is radiographically detectable, at which time it enters a clinical phase. The preclinical phase may range from 10 to 24 months, during which time it may be detected fortuitously by cytological evaluation or directed biopsy of the airway.

Although not possessing APUD capabilities, squamous cell cancers produce PTH and ACTH, as based on immunohistochemical studies, more frequently than do other types of non-small cell lung cancer (e.g. adenocarcinomas). They also produce carcinoembryonic antigen (CEA) in 50 per cent of cases, which may be useful for postoperative surveillance.

Typically, squamous cell lung cancer arises in older patients (peak incidence, 70–79 years for men, 60–69 years for women), with 75 per cent found in larger bronchi. The remainder present as peripheral nodules. Cavitation of the lesion is a common finding (Fig. 4) 1952. Because of their central location, 50 per cent of cases may be detected by sputum cytology and endoscopic biopsy. Squamous cell cancers have a mean doubling time of 136 days, but have a lower likelihood for distant metastasis than do other malignant epithelial tumours of the lung. As a result, the frequency of squamous cell cancer in surgical resections is higher (45–70 per cent) than in other types of lung cancer, although a relative decrease in the incidence of squamous histology, particularly in women, has been noted over the past decade.

The majority of patients present themselves with cough, haemoptysis, obstructive pneumonitis, or positive sputum cytology. Paraneoplastic hypercalcaemia, due to excessive prostaglandin production, or, less frequently to excessive PTH production, is associated with squamous cell cancers more commonly than with other types of either small cell or non-small cell lung cancer.

The primary treatment of squamous cell carcinoma of the lung is surgical. The prognosis of squamous cancer of the lung is highly dependent upon its biological stage (i.e. preclinical versus clinical), its degree of differentiation (poorly, moderately, or well differentiated) and its pathological stage (TNM classification). For patients undergoing resection in the preclinical phase, the survival rate exceeds 80 per cent. The survival rate correlates directly with histological differentiation—longer survival with more differentiated tumours. Finally, the survival rate following surgical resection for squamous cell cancers is 5 to 10 per cent longer within each pathological TNM stage than for other similarly staged non-small cell lung cancer and small cell lung cancer.

The excellent survival rate is the primary reason for a higher incidence of second primary lung cancers in these patients. Approximately 10 per cent of patients surviving beyond 5 years develop a second primary lung cancer, not necessarily a squamous type. Autopsy studies show that areas of in-situ carcinoma distant from the primary lesion may be found in 25 to 40 per cent of patients. In addition, 15 to 20 per cent of patients develop second primary carcinomas in other foregut sites (head and neck, oesophagus), supporting the concept of a ‘field defect’ of carcinogenesis induced by environmental exposure, most commonly tobacco. Chemoprevention, using &bgr;-carotene derivatives, which reverse preinvasive epithelial changes, may serve to lessen the incidence of these secondary and associated epithelial malignancies.

Extrathoracic metastases occur, in order of frequency, to liver, adrenal, bone, and brain. For symptomatic metastases, radiotherapy is used most commonly, although there are data to support the use of combination resection and radiation for localized cerebral metastases. Although cis-platinum-containing combination chemotherapy regimens are effective against other squamous cell cancers of foregut origin (e.g. oral cavity, oesophagus), those regimens do not offer similar response rates for squamous carcinoma of the lung. Chemotherapy is limited to protocol studies of patients with disseminated metastatic disease or in adjuvant therapy studies of patients with marginally resectable disease.

The second most common type of malignant epithelial tumour of the lung and the second most common type of non-small cell lung cancer is adenocarcinoma. This is a heterogeneous group of tumours, demonstrating various aspects of glandular differentiation, with or without mucus formation, that accounts for 30 to 35 per cent of all lung cancers. Adenocarcinomas range from well differentiated subtypes, with formation of acini or papillary structures, to poorly differentiated subtypes, with only occasional intracellular mucus. Typically, these lesions arise from the epithelium of distal bronchi or bronchioles. No in-situ component, as noted for squamous cell cancers, has been identified. Frequently, there is a prominent desmoplastic reaction associated with these tumours.

A particular subtype of adenocarcinoma is bronchoalveolar carcinoma, characterized by growth of cytologically bland cells, resembling mucus-secreting cells, Clara cells, or Type II pneumocytes, into the alveoli. Unlike other forms of adenocarcinoma, a desmoplastic reaction is rare. Bronchoalveolar carcinomas account for 10 per cent of adenocarcinomas and may be found isolated (40 per cent) or multifocal (60 per cent), although the question of whether spread is multifocal or whether it is aerogenous metastasis through the airways. An ovine neoplasm known as jaagsiekte (Montana progressive pneumonia), which is associated with a transmissible agent, is histologically indistinguishable from bronchoalveolar carcinoma. There is no evidence, however, of a transmissible agent in the aetiology of the disease in humans.

Adenocarcinomas of all subtypes tend to occur with a higher frequency in women than other forms of lung cancer. In addition, adenocarcinomas are the most frequent type of peripheral carcinoma, accounting for 40 to 50 per cent of such lesions, and for 70 per cent of such lesions in women. Scar formation is found in association with adenocarcinoma in 50 per cent of cases—at times as a pre-existing lesion and at times as a manifestation of the desmoplastic response. Various explanations for this association, including interruption of local lymphatics with focal concentration of carcinogenic substances and chronic stimulation of epithelial regeneration, have been proposed; none has been proved (Fig. 4) 1952.

Cough and haemoptysis are presenting symptoms in less than one-third of patients, the majority being identified as solitary, non-cavitating nodules on chest radiograph in asymptomatic patients. Bronchoalveolar carcinomas, with their bronchiolar origin, typically manifest themselves as bronchopneumonia, which progresses to a lobar consolidation by extension to surrounding airspaces, not by bronchial obstruction. In such patients, cough may be a more prominent symptom, and sputum cytology may demonstrate characteristic cells or psammoma bodies. Intractable bronchorrhoea is an unusual but characteristic presentation for multifocal bronchoalveolar carcinoma (also termed ‘adenomatosis’). Hypertrophic pulmonary osteoarthropathy occurs most frequently with adenocarcinomas of the lung, as compared with other histological types and may be seen in 10 per cent of patients.

Grossly, adenocarcinomas are firm; they frequently involve or distort the overlying visceral pleura from their peripheral location. Cavitation is uncommon, although larger tumours may have regions of necrosis. Histologically, the cells are large, with abundant cytoplasm, and may demonstrate apical microvilli and intracytoplasmic secretory granules by electron microscopy. Cytokeratin and CEA expression are common. At the periphery, the tumour may invade along normal lung architecture, in a bronchoalveolar pattern, which nonetheless does not imply classification into the bronchoalveolar carcinoma subtype (Fig. 6) 1954. Bronchoalveolar subtypes typically have a pneumonic appearance grossly, or demonstrate confluence of multiple bronchiolocentric nodules. Growth of cytologically bland cells along the normal lung framework, without desmoplasia, is characteristic (Fig. 7) 1955.

The only curative therapy for adenocarcinomas is surgical resection. The overall prognosis for adenocarcinoma is not as favourable as for squamous cell carcinoma. Although adenocarcinomas have the longest doubling time among lung cancers (189 days) they have an increased propensity for metastasis to the liver, adrenal gland, bone, and brain. Among resectable non-small cell cancers of the lung, adenocarcinomas have the highest incidence of asymptomatic brain metastasis (25–30 per cent). Prognosis for adenocarcinomas is more dependent on pathological staging (i.e. TNM classification) than on the degree of differentiation. Expression of K- ras by adenocarcinomas is an independent risk factor for a decreased survival time after surgical excision. Survival from a solitary bronchoalveolar carcinoma is higher than is that for other subtypes of adenocarcinoma because of a higher resectability rate. Patients with solitary bronchoalveolar cancer, however, seem to be at a higher risk for metachronous primary bronchoalveolar carcinomas, perhaps reflecting the multicentric origin of this subtype. Conversely, survival for diffuse (i.e. multicentric) bronchoalveolar cancer is much lower than is that for other adenocarcinomas, with no long-term survivals reported for any form of therapy.

Finally, distinction between a peripheral primary lung adenocarcinoma and an adenocarcinoma metastatic from an extrathoracic primary can be very difficult. No reliable histological distinction is possible. The association of the lesion with a scar, especially one with anthracotic pigment, or the presence of hilar or mediastinal nodal metastasis favours a lung primary. However, among patients with prior resected extrathoracic adenocarcinomas, 90 per cent of new solitary lung nodules will be primary lung adenocarcinomas. Thus, unless a characteristic histological pattern is identified, all solitary lung adenocarcinomas should be considered primary pulmonary lesions for the purposes of staging and therapy.

A third type of non-small cell lung cancer is large cell carcinoma, an amorphous group of lung tumours accounting for 5 to 10 per cent of all lung cancers. These tumours are composed of undifferentiated cells, without evidence of squamous cell characteristics or of acini or mucus formation. The cells are larger than are those of small cell lung cancer and they lack neuroendocrine characteristics. Although the majority of poorly differentiated non-small cell lung cancer are composed of undifferentiated carcinoma cells with foci of squamous or glandular differentiation, only neoplasms composed entirely of undifferentiated cells are included in this category.

Histologically, the tumour cells grow in sheets, without organization or pattern. Desmoplastic reaction is rare. The cells are large, having pale cytoplasm and varied nuclear configuration. Rarely, a large number of pleomorphic multinucleated giant tumour cells or a majority of cells with clear cytoplasm may be seen, identifying the giant cell and clear cell histological subtypes, respectively.

Large cell cancers tend to be bulky, with frequent areas of necrosis; cavitation is unusual. Subsegmental or larger bronchi are involved in 50 per cent of cases; however, lobar or main bronchial involvement tends to be secondary to growth of a tumour originating in a more distal region of the bronchial epithelium (Fig. 4) 1952. No in-situ component is seen. Clinical presentation is evenly divided between those patients in whom the lesion is asymptomatic and those in whom symptoms of cough or distant metastasis to liver, adrenal gland, bone, or brain are identified.

Treatment of large cell carcinomas is primarily surgical, with results of treatment being dependent upon the pathological stage of the tumour. Seventy per cent of lesions are large, (greater than 3 cm in diameter), and lymph node metastases are present in one-half of patients at the time of diagnosis, with a concordant decrement in survival rate following resection. Even among smaller lesions, without nodal metastases, 5-year survival rates following surgical resection of 40 to 45 per cent are materially lower than are the survival rates following resection of other non-small cell lung cancer. The survival rate for the giant cell and clear cell subtypes is even lower than is that for the typical large cell lung cancer.

Fewer than 1 per cent of lung cancers consist of lesions with predominantly large cell undifferentiated carcinoma histology and an equal frequency of foci of squamous cell and adenocarcinoma differentiation. Such adenosquamous carcinomas are diagnosed on the basis of histological appearance, not ultrastructural findings. Typically, these lesions arise as peripheral asymptomatic lung nodules. Their clinical behaviour is similar to that of large cell undifferentiated carcinomas, with an increased propensity for metastasis compared with that of other non-small cell lung cancers. Treatment is primarily surgical, with the prognosis being stage-dependent and similar to that of large cell undifferentiated lung carcinomas.

Carcinoid tumours are uncommon, low grade malignant tumours with biochemical and structural features of tumours of the APUD system. Non-neoplastic cells with APUD characteristics are found in normal bronchial submucosal glands and the epithelium of major bronchi and peripheral bronchioles. Although the concept of a spectrum of biological behaviour for lung neoplasms demonstrating evidence of neuroendocrine differentiation (Kulchitzky cell carcinomas), ranging from carcinoid tumours to small cell lung cancer has been advanced, there is no conclusive evidence for a common cell of origin or for the progression from one type of Kulchitzky cell carcinoma to another. Carcinoid tumours and small cell lung cancer should be considered as separate types of malignant epithelial lung neoplasms demonstrating similar characteristics of neuroendocrine differentiation.

Carcinoid tumours demonstrate two patterns of histology. A typical carcinoid demonstrates uniform cells with abundant clear cytoplasm and regular centrally placed nuclei admixed with cells containing eosinophilic cytoplasm and smaller hyperchromatic nuclei. Occasionally, an intermingling of spindle cells is noted. Mitoses are absent or very rare. The cells are arranged in an ‘endocrinoid’ pattern, consisting of a combination of cords, nests, trabeculae, and ribbons (Fig. 8) 1956. Although vascular invasion may be present, it is not an indicator of metastasis. Metaplastic bone formation may occur, but is uncommon. Argyrophilic stains demonstrate numerous positive cells, while argentaffin stains demonstrate only rare foci of positive cells. Small foci of mucus production may be seen. The cells will stain for neuroendocrine substances, including chromogranin, serotonin, ACTH, catecholamines, and kinins. Ultrastructurally, abundant neurosecretory granules are seen. Typical histology is seen in 90 per cent of carcinoid tumours. An atypical carcinoid tumour does not show the same uniform histological features. These neoplasms demonstrate increased nuclear and cytological pleomorphism with frequent mitotic figures with microscopic evidence of necrosis and/or haemorrhage. The atypical carcinoid cells may be distinguished from small cell lung cancer cells by a larger amounts of cytoplasm and by less marked nuclear abnormality.

Typical and atypical carcinoid tumours are indistinguishable on a clinical basis. Carcinoid tumours occur in equal frequency in both sexes and have been reported from the first to the tenth decade of life, although the mean age is in the fifth decade. These tumours are not related to smoking and have no known environmental risk factors.

The clinical presentation of carcinoid tumours depends on the site of origin of the lesion within the tracheobronchial tree (Fig. 4) 1952. Central carcinoid tumours, accounting for 90 per cent of lesions, arise from bronchial submucosal glands in the wall of a subsegmental or larger bronchus. Patients frequently show cough, haemoptysis, or wheezing of long duration (months to years). The chest radiograph may be normal or may demonstrate atelectasis or pneumonitis if bronchial obstruction has occurred. A smooth polypoid mass, ranging from 2 to 4 cm in size and covered by intact mucosa, is seen at bronchoscopy. Biopsy examinations of the lesion may lead to haemorrhage due to its vascularity, although this event is rare. Peripheral carcinoid tumours (10 per cent of lesions) originate in the bronchiolar epithelium and superficially infiltrate the surrounding lung. These neoplasms present themselves as circumscribed pulmonary nodules on a chest radiograph, indistinguishable from other solitary pulmonary nodules. Typically these are, asymptomatic. Peripheral carcinoids may have a more frequent spindle cell component and more nuclear variation than do central lesions. At times, multiple peripheral carcinoid tumours may be seen.

The therapy for carcinoid tumours is complete surgical resection. These tumours arise within the bronchial or bronchiolar wall, extending transmurally to involve surrounding lung parenchyma. Therefore, excision requires techniques to encompass the region of involvement, not merely the visible and/or obstructive endobronchial component. For central carcinoids, excision typically requires anatomical lobectomy or lobectomy combined with removal of the involved portion of airway and pulmonary parenchyma, reanastomosing the portions of the airway proximal and distal to the site of the lesion (‘sleeve lobectomy’). For peripheral lesions, non-anatomical parenchymal excision or anatomical lobectomy to obtain tumour-free margins, depending on the size and location of the lesion, are used for resection.

Metastases occur in 10 per cent of carcinoid tumours, most commonly to regional peribronchial lymph nodes. The incidence of metastasis correlates directly with histology. Approximately 5 per cent of typical carcinoids and 70 per cent of atypical carcinoids will have evidence of metastatic disease. Distant metastases may occur to the liver (which may be associated with a clinical carcinoid syndrome) or to bone (resulting in osteoblastic lesions).

The overall 5-year survival rate following surgical resection or carcinoid tumours is greater than 90 per cent. Survival is related primarily to histology, with a 95 to 98 per cent survival for typical carcinoids and a 70 per cent survival for atypical carcinoids. Survival is also stage dependent within respective histological categories. However, the indolent growth of typical carcinoid tumours, the potential for endobronchial obstruction and the lack of responsiveness to non-surgical therapies all support the concept of resection even for advanced stages, including those presenting with a pleural effusion or nodal metastases.

Throughout the tracheobronchial tree, submucosal serous and mucus glands identical to those found in the upper airway and salivary glands are present. Neoplasms arising from these glands are morphologically and biologically analogous to salivary gland tumours. Previously, these various tumours, accounting for 1 to 2 per cent of all lung tumours, were classified as ‘bronchial adenomas’ in conjunction with carcinoid tumours. The term has been discarded, however, because it ignores the biological heterogeneity of these neoplasms and implies that they are benign, whereas the majority are, in fact, low-grade malignant tumours. Bronchial gland carcinomas are now differentiated from carcinoid tumours.

Adenoid cystic carcinoma is the most common bronchial gland carcinoma. This tumour is characterized by infiltrative growth, especially along neural structures, a propensity for local recurrence and a prolonged clinical course. Adenoid cystic tumours arise most commonly in the trachea and are the second most common type of primary tracheal tumour, after squamous cell cancers. Grossly, these lesions are polypoid or annular, arising within the airway wall and extending transmurally into the surrounding tissues. The mucosa is typically intact over the tumour, with a characteristic prominence of submucosal vessels. Histologically, regular glands are seen, some containing mucus, others containing a hyaline material (Fig. 9) 1957. Characteristic infiltration at the margins of the gross lesion can occur in submucosal, extramural, and perineural patterns.

These tumours occur in men and women equally, the average age being 45 years. Presenting symptoms are those of tracheobronchial irritation and obstruction: stridor, positional wheezing, cough, dyspnoea, and haemoptysis. Duration of symptoms is usually 18 months or longer. Diagnosis is made by laminar tomography of the airways or by bronchoscopy with biopsy. Chest radiograph, CT scanning, or sputum cytology are not useful.

Treatment consists of local excision of the involved airway, if technically possible. Segmental tracheal or carinal resection and reconstruction is generally required. Intraoperative pathological examination of the margins of resection is mandatory to determine the limits of resection. However, presence of microscopic residual tumour at the margins after maximal airway excision may be satisfactorily managed by postoperative external beam radiation therapy. Primary external beam radiation therapy, augmented by endobronchial high dose-rate brachytherapy, is useful for inoperable lesions.

Overall survival for adenoid cystic carcinoma is 85 per cent at 5 years and 55 per cent at 10 years. Survival following surgical resection with postoperative adjuvant radiation therapy is 85 per cent at 10 years. Adenoid cystic tumours frequently recur after a long time interval. A routine chest radiograph and bronchoscopy are required for at least 20 years following resection. Metastases, most commonly to the lung parenchyma or bones, are usually asymptomatic and slow growing.

Mucoepidermoid carcinoma is the second most frequent bronchial gland carcinoma. The lesion has been subclassified into a low-grade and a high-grade subtype. Both present themselves as firm polypoid masses arising within a major bronchus, with both intraluminal and extramural extension. Histologically, low-grade mucoepidermoid cancers show an admixture of glandular elements and sheets of large cells with little or no squamous differentation (i.e. keratinization) (Fig. 10) 1958. High-grade mucoepidermoid cancers, which are extremely rare, resemble low-grade mucoepidermoid lesions, except that mucus-filled cystic spaces are more common and more cellular atypia, mitoses, and foci of necrosis are seen. Differentiation of high-grade tumours from the much more common adenosquamous carcinoma may be difficult.

Mucoepidermoid carcinomas occur in men and women with equal frequency, and at a mean age of 40 years. Symptoms of bronchial irritation or obstruction, often of several years duration, are typical. Chest radiographs to identify signs of bronchial or lobar obstruction, laminar tomograms of the airway, and bronchoscopy with biopsy examination are useful for diagnosis.

Treatment consists of excision of the involved airway, typically including the distal portion of affected lung. Intraoperative evaluation of resection margins is critical to obtain complete excision. For low-grade mucoepidermoid cancers, the prognosis is excellent. No distant metastases have been reported with these tumours. In high-grade mucoepidermoid cancers, distant metastases occur. However, long-term survival has been reported following complete excision of these lesions.

Mucus gland adenoma and pleomorphic adenoma are two rare, benign tumours of well differentiated elements of the bronchial glands. Both are very slow growing and may be identified by bronchoscopy while asymptomatic, or they may present themselves with bronchial obstruction. These cancers are best treated by local excision of the involved airway. Intraoperative pathological evaluation of resection margins is crucial to obtain a complete excision and eliminate the possibility of local recurrence. No distant metastases have been reported; complete surgical excision is curative.

Carcinosarcoma is a malignant tumour in which both epithelial and mesenchymal elements are present and both demonstrate metastatic potential. Presumably, these lesions represent the manifestation of the multipotentiality of the tissue of origin. In the lung, these cancers account for less than 1 per cent of malignant tumours and arise in two forms, pulmonary carcinosarcoma and pulmonary blastoma.

Pulmonary carcinosarcomas are bulky, vascular neoplasms, arising in major bronchi in 50 per cent of cases. Admixture of squamous carcinoma and fibrosarcoma account for half of these lesions histologically. Other malignant epithelial components include adenocarcinoma and large cell carcinoma; a small cell lung cancer component has not been reported. Chondrosarcoma is the second most common mesenchymal differentiation. In most cases, the mesenchymal component predominates, creating difficulty in differentiating these cancers from mixed malignant mesothelioma. Mesothelioma can be identified, however, by its hyaluronic acid production. The mean attack age is 45 years; the tumour occurs twice as frequently in men as in women.

Pulmonary blastoma is a tumour that differentiates to produce a histological appearance reminiscent of the lung during its pseudoglandular period of development at about 3 months' gestation. These lesions are typically large, peripheral tumours, compressing major bronchi. Histologically, the epithelial elements have a primitive appearance and may condense about a small lumen or demonstrate subnuclear vacuolization that causes a resemblance to embryonic cells containing glycogen. Ultrastructural evidence supports the concept that the epithelial component is a form of poorly differentiated adenocarcinoma. The mesenchymal component has large hyperchromatic nuclei, with little differentiation in most regions. The majority of patients are men; the tumour has been reported in patients from 11 to 77 years of age.

Carcinosarcomas of both types behave as high-grade malignant tumours, although some cases of pulmonary blastoma may have a slow rate of growth. One-half of both types of carcinosarcoma present with extrapulmonary metastases. Surgical resection, if possible, is the only therapy that is curative. Radiotherapy has been used for palliation.

Hamartoma is the most common benign tumour of the lung. It is a benign mesenchymal neoplasm composed of a loose fibrous or myxoid mesenchyme, which undergoes alteration to cartilage, mature fibrous tissue and fat in varying amounts. The term fibrochondrolipoma has also been used for these lesions. With growth, the tumour entraps bronchial and alveolar epithelium. Most hamartomas arise as isolated lesions in the periphery of the lung, although 15 per cent are endobronchial. In the parenchyma, these neoplasms are well circumscribed and irregularly lobulated with an apparent capsule. Histologically, there are wide variations in the appearance of the mesenchymal component, although cartilage in varying stages of maturation is a consistent finding. The cartilage is invariably benign, and calcification and ossification may occur. At the margin, chronic inflammation and fibrosis may be seen. A true capsule is not present. Endobronchial hamartomas demonstrate proliferation of the overlying epithelium as secondary change, not a primary neoplastic process. Rarely, multiple hamartomas occur; they tend to be more cystic and lipomatous, having a paucity of cartilage.

Hamartomas are found in 1 of 400 autopsies. Men are affected two to three times more frequently than women. They do not occur in infants or children. The median age at presentation is 35 years. Typically, parenchymal tumours are asymptomatic and detected on routine chest radiograph. Endobronchial lesions may result in symptoms of bronchial obstruction. A very slow rate of growth is characteristic, as is the determination of cartilage within the lesion by chest CT scanning or by percutaneous needle biopsy.

Treatment consists of localized parenchymal or endobronchial excision to prevent the complications of continued growth of the lesion. Malignant change is extremely rare. Recurrence results only from incomplete parenchymal excision. At times, with supporting histological evidence of benign cartilage from needle biopsy, serial observation of these lesions may be indicated in the asymptomatic patient.

A special circumstance is that of multiple pulmonary leiomyomatous hamartomas. These occur in asymptomatic, middle-aged women with a prior history of myomectomy or hysterectomy for uterine leiomyoma. Such lesions are actually metastases from a uterine or other leiomyosarcoma with a low grade growth potential. Histologically, the pulmonary lesions are more bland than are the uterine primary lesion. A few leiomyomatous hamartomas may be treated by multiple limited pulmonary parenchymal resections. In unresectable cases, hormonal therapy should be used for control of the growth.

Bronchial chondroma is an unusual neoplasm that arises within pre-existing cartilage in the bronchus. These tumours are small, bosselated masses 1 to 2 cm in diameter, found incidentally at bronchoscopy. Histologically, there is enlargement of bronchial rings within the lesion. Cartilage is mature, and ossification may be seen. Unlike hamartomas, chondromas cannot be separated from the bronchial wall; they have a propensity for malignant degeneration to a chondrosarcoma. Treatment consists of resection of the involved bronchus and associated lung tissue if necessary. Intraoperative pathological evaluation of the margins is mandatory to ascertain the likelihood of complete removal. When a bronchial chondroma is incompletely removed, recurrence is frequent.

Believed to be of Schwann cell origin, granular cell tumours occur rarely in the lower trachea and major bronchi. Histologically, large cells with abundant granular cytoplasm grow in an infiltrative pattern. Frequently, squamous metaplasia of the overlying bronchial mucosa is seen. Multiple tumours may occur and 15 per cent of patients have similar tumours of the tongue or skin. Treatment consists of local excision, with appropriate considerations to assure complete removal. Although local recurrence has been reported, no reports of malignant degeneration or metastases have been made.

Lipomas, fibromas, neuromas, and leiomyomas have all been reported as isolated benign tumours of the lower respiratory tract. Presentation occurs either as asymptomatic isolated parenchymal lesions or endobronchial lesions, with a greater likelihood for symptoms related to bronchial obstruction. The incidence of these lesions is low and their histology is characteristic of the specific type. Treatment consists of localized surgical excision of the involved airway or parenchyma, with curative results.

Primary malignant mesenchymal tumours arise in the lung and show the same variety of types seen in sarcomas in other parts of the body. Leiomyosarcoma and fibrosarcoma are the most common histological types. They arise in the parenchyma and invade surrounding parenchymal and extrapulmonary structures. An endobronchial origin is rare. Presenting symptoms include cough, haemoptysis, or chest pain. Men and women are equally represented. On chest radiography primary sarcomas present themselves as large, circumscribed parenchymal mass lesions; diagnosis may be made by percutaneous needle biopsy. Therapy consists of surgical excision of the lesion when technically possible. Radiation therapy may be used as adjuvant therapy for an incompletely excised lesion or as primary palliative treatment for unresectable tumours. The prognosis is better for patients having the rare endobronchial sarcoma and for the uncommon lesion occurring in a paediatric patient.

A unique form of sarcoma found in the lung is primary sarcoma of the pulmonary artery. It arises in the intima of the major branches of the pulmonary artery. The sarcoma extends peripherally through the arterial tree and then invades the lung in an interstitial and intra-alveolar pattern. The sarcoma may also spread proximally to the right ventricular outflow tract. The tumour occurs in men and women equally, commonly in the sixth decade. Presentation consists of unexplained intractable right heart failure. Diagnosis is made by right heart catheterization with pulmonary arteriography and biopsy. Distant metastases are present in one-half of the cases at diagnosis. The neoplasm is uniformly fatal, with death most commonly occurring from progressive obstruction of the pulmonary arterial tree.

Pseudolymphoma, or localized pulmonary lymphoma, is a clonal lymphoid proliferation within lung tissue that resembles benign reactive lymphoid tissue. Typically, these lesions present as subpleural parenchymal masses with ill-defined margins. Histologically well differentiated lymphoid cells are seen extending in an interstitial fashion and infiltrating vessels and small airways. In the centre of the lesion, normal pulmonary architecture is obliterated. Plasma cells are inconspicuous, but germinal centres are present. Men and women are affected with equal frequency, typically in the sixth decade. Most are asymptomatic, but some have local symptoms of cough or chest pain, while others have systemic symptoms of fever, chills, and fatigue. Radiographs demonstrate one or more parenchymal lesions without calcification or cavitation. Diagnosis is by excisional biopsy or by excision of the lesion in toto if it may be encompassed by a limited parenchymal excision. Percutaneous needle aspiration reveals only non-specific lymphoid aggregates. After conservative excision, fresh tissues should be prepared for immunohistochemical studies. The presence of a polyclonal cell population or of paraproteinaemia, particularly of IgM, is associated with an increased likelihood of development of disseminated lymphoma. Overall, prognosis is good, with a 70 per cent survival rate at 10 years.

Primary pulmonary lymphocytic lymphoma is a malignant neoplasm composed of well to poorly differentiated lymphoid cells, with or without regional node involvement, without evidence of lymphoma elsewhere. These lesions may present themselves as pulmonary nodules, but frequently invade and destroy the overlying pleura; they may be associated with a pleural effusion containing characteristic lymphoma cells. Clinical presentation is similar to that of pseudolymphoma. Gross and histological findings are also similar to those of pseudolymphoma, although plasma cells and true germinal centres are absent, and cellular pleomorphism is greater. Excision, for diagnosis and as therapy for localized lesions, should be accompanied by regional lymph node sampling and evaluation for presence of disseminated disease (e.g. bone marrow aspiration). Final classification is based on immunohistochemical studies of freshly excised tissue and determines the type of adjuvant postoperative therapy required. Overall, the prognosis is poorer than for pseudolymphoma, with a 20 per cent survival rate at 10 years. Absence of regional lymph node involvement is a favourable prognostic sign.

The essential elements for the diagnosis of lung neoplasms include symptoms, physical examination, and chest radiography. Benign or low-grade malignant neoplasms are more likely to present in an asymptomatic state. Most malignant neoplasms present themselves with symptoms leading to radiographic evaluation. For malignant tumours (i.e. lung cancers), the degree of manifest symptoms roughly correlates with the amount of disease. A symptomatic lung cancer is less likely to be a curable lesion.

Studies of screening examinations for lung cancer in asymptomatic patients have shown that more early stage, peripheral non-small cell lung cancers are identified by routine chest radiography (which is more sensitive than routine sputum cytology). However, despite the inherent resectability of such tumours, the death rate of the population as a whole is not decreased by routine screening examinations.

Symptoms from pulmonary neoplasms can be classified according to their aetiology. Bronchopulmonary symptoms are those caused by direct tumour effects within the airway or parenchyma, including cough, haemoptysis, wheezing, dyspnoea, or pneumonia. Recurrent pneumonia suggests partial bronchial obstruction. Alternatively, pneumonia characterized as a persistent infiltrate indicates complete bronchial obstruction or neoplastic consolidation (e.g. by bronchoalveolar cancer). Intrathoracic symptoms are those created by tumour extension outside the parenchyma. In most cases, these are signs of extensive disease and relative unresectability. Typical intrathoracic symptoms include:

1.Hoarseness due to recurrent laryngeal nerve invasion, either directly or by metastasis to mediastinal lymph nodes,

2.Phrenic nerve invasion with hemidiaphragmatic paralysis,

3.Chest pain or pressure, due to parietal pleural or chest wall invasion,

4.Superior vena cava syndrome, due to extrinsic compression by a large hilar mass or bulky mediastinal lymph node metastases,

5.Cardiac dysrhythmias, resulting from atrial or pericardial invasion,

6.Dysphagia, due to compression or invasion of the oesophagus in the posteroinferior mediastinum,

7.Vascular pain, typically central, severe and unremitting, due to invasion of the aortic wall.

Extrathoracic symptoms are due, in most cases, to metastatic extension of the tumour to distant sites, with direct local effects. However, in 5 to 10 per cent of lung cancers, paraneoplastic syndromes may be identified. These remote tumour effects are not caused by metastatic deposits, but are due to polypeptide hormone production, interference with immune function, inappropriate initiation of physiological mechanisms, or competitive receptor blockade. They are more common with malignant lung tumours and are most frequently seen with small cell lung cancer. A notable exception is the syndrome of hypertrophic pulmonary osteoarthropathy, consisting of digital clubbing and symptomatic long bone periosteal reaction, which is seen in 10 per cent of non-small cell lung cancer, especially adenocarcinomas.

Chest radiography is the basic diagnostic modality for neoplasms of the lung, with a high sensitivity at a low cost and minimal risk to the patient. Standardized techniques employ a high kilovoltage source and inspiratory posteroanterior and lateral views. Indications for chest radiography include persistent or recurrent pulmonary symptoms, a past medical history or family history of lung cancer, or as an annual study in patients over 50 years of age who have a history of tobacco use. Chest radiographs should always be examined in concert with prior chest films, if they are available. If a nodule or mass is identified, the pertinent diagnostic features are its duration and the presence of calcification. Nodules present for longer than 2 years without documented change in size are considered benign in nature—either benign neoplasms or granulomas. Calcification, if present in a solitary central or a lamellar distribution, signifies a granuloma. ‘Popcorn’ calcification is characteristic of hamartoma. All other types of calcification are non-diagnostic. Lung cancers demonstrate calcification in 7 per cent of cases due to dystrophic deposition or to neoplastic growth about a pre-existing calcified focus in the parenchyma.

In general, asymptomatic pulmonary nodules are inflammatory or infectious in 30 per cent of cases, benign tumours in 25 per cent of cases, and malignant tumours in 45 per cent of cases. However, the proportion of malignant tumours rises to 60 per cent in patients greater than 50 years of age. Any non-calcified asymptomatic nodule in a patient over 40 years of age should be considered a lung cancer until histological evidence to the contrary is obtained.

Conventional laminar tomography of the chest has limited application in the diagnosis of parenchymal pulmonary neoplasms, as computerized tomographic scanning provides a more sensitive and precise examination. However, for neoplasms involving the central airways (trachea and main and lobar bronchi), laminar tomography provides an unparalleled image. Laminar tomograms precisely define the tumour within the central airways and are essential before surgery.

CT scanning has greatly enhanced the imaging of intrathoracic structures. The indications for chest CT scanning include all patients with a suspected pulmonary neoplasm or with a questionable hilar abnormality. A CT scan provides contour and density characteristics of a nodule, which can differentiate inflammatory from neoplastic lesions and occasionally identify specific histological subtypes. Additional parenchymal lesions, beyond the sensitivity of chest radiographs, may be identified. The mediastinum and mediastinal lymph nodes are well delineated. Nodes larger than 1 cm (short axis) are considered abnormal; they should be sampled for biopsy examinations of potential metastatic spread. Nodes smaller than 1 cm are considered normal unless they arise in the context of a known malignant neoplasm of the lung or in an undiagnosed nodule greater than 3 cm in diameter. In such cases, biopsy of these ‘normal’ nodes is indicated, as the incidence of nodal metastasis ranges from 15 to 25 per cent. Finally, the CT scan provides visualization of two common sites of extrathoracic metastasis, the adrenal glands and liver (the latter to a limited extent). Metastasis from lung cancer to the adrenal gland is a frequent event, usually occurring coincident with mediastinal lymph node metastasis. However, two-thirds of enlarged adrenal glands identified on chest CT scans in lung cancer patients are benign adenomas. Indicators of a benign adrenal nodule include a size of less than 3 cm, a low density, and normal mediastinal lymph nodes. Biopsy data are reserved for adrenal nodules in lung cancer patients that do not meet these criteria.

MRI scanning has limited application for patients with pulmonary neoplasms. It is the imaging modality of choice for the region of the thoracic inlet because of the spatial and histological resolution obtained by MRI for the pulmonary, neural, and vascular structures in this region. MRI studies are useful for any neoplasm arising in this area. Identifying invasion of the thoracic aorta by a malignant neoplasm in a symptomatic patient is another frequent indication for MRI.

Positron emission tomographic (PET) scanning is an experimental technique for biochemical characterization of tumours and their metastatic deposits. Substrates modified to emit positron radiation are injected intravenously and localize to neoplastic cells, whereupon a tomographic image can be obtained, reconstructed, and compared with a conventional CT scan. Positron emission tomography scanning appears to be extremely sensitive and specific, and may provide a new benchmark for non-invasive diagnosis of extrapulmonary metastasis.

Cytological evaluation of sputum for neoplastic cells can diagnose malignant lung neoplasms in 60 per cent of cases, particularly when the tumour arises endobronchially and invades transmucosally. Usually these will be squamous or small cell lung cancers, or occasionally adenocarcinomas with bronchial invasion. A lower yield is found for peripheral tumours, submucosal lesions, or when bronchial obstruction is present. Cell type can be specified in 80 per cent of cases, with a false positive rate of less than 1 per cent. Sputum cytology should be obtained on any patient with a suspected lung neoplasm who has a productive cough or haemoptysis. Specimens should be collected in the early morning, on three consecutive days.

Bronchoscopy is the endoscopic evaluation of the bronchial tree using rigid or flexible instruments. Rigid bronchoscopes, which allow visualization to the third order (segmental) bronchi, are ideal for interventional procedures, including endobronchial tumour excision for relief of obstruction (‘coring-out’), dilatation of tracheal or bronchial stenoses, and management of massive haemoptysis. Precise measurements of relative lengths of airway involved are also possible to provide an estimate of resectability. Flexible bronchoscopes allow visualization to fifth or sixth order bronchi and permit a wide range of diagnostic procedures, including directed bronchial washings, cytological brushings, transmucosal or transbronchial biopsy, and selective transmural aspiration of paratracheal nodes. For lesions greater than 2 cm in size, located in the inner one-third of the pulmonary parenchyma, these procedures accurately diagnose neoplasms in 87 per cent of patients. Accuracy falls to 23 per cent for smaller lesions in the outer one-third of the lung.

Indications for bronchoscopy include any clinical context in which a lung neoplasm is suspected (Table 3) 531. Rigid bronchoscopy usually requires general anaesthesia, while flexible bronchoscopy can be performed with either topical or general anaesthesia. Complications include hypoxia, requiring supplemental oxygen administration in all patients, laryngospasm, cardiac dysrhythmia, lidocaine toxicity, pneumothorax, or bleeding (particularly if the platelet count is less than 50 000/mm³). The incidence of serious complications is less than 5 per cent, comparing favourably with that of the diagnostic accuracy of the procedure.

Percutaneous needle aspiration of pulmonary neoplasms is a safe, accurate method for histological identification, particularly for those tumours located in the outer two-thirds of the pulmonary parenchyma. The technique employs a 19 gauge needle with a stylet that is positioned near the lesion using fluoroscopic or CT scan guidance. Ultrasound localization may be used for very peripheral lesions. The stylet is removed and a second needle is inserted for aspiration or core biopsy of the nodule. Diagnosis for nodular lesions is possible in 85 per cent of cases, with an accuracy of 95 to 98 per cent for malignant lesions and 85 per cent for benign lesions. Indeterminate lesions may be rebiopsied to increase diagnostic yield.

Pneumothorax occurs in 20 to 25 per cent of patients and may be lessened by positioning the patient in a decubitus position on the side of the biopsy. Less than 2 per cent of patients require chest tubes. Although minor haemoptysis is common, massive haemoptysis is rare. Air embolism or tumour implantation occurs only in 1 in 5300 biopsy specimens. Contraindications to needle biopsy include abnormal coagulation studies, pulmonary artery hypertension, and an inability to co-operate with the examination (e.g. inability to hold respirations, uncontrollable cough).

Excisional biopsy of lung lesions may be used as a diagnostic modality. The frequency of such an approach has decreased with the advent of percutaneous needle biopsy and improved staging procedures. In most cases, excision for diagnosis should be performed only after clinical staging is complete and with the availability of accurate intraoperative pathology, so that appropriate operative decisions regarding the extent of resection can be made.

Biopsy examination of the scalene fat pad or of supraclavicular nodes has been employed as a diagnostic procedure for malignant lung neoplasms. Only 15 per cent of non-palpable nodes contain metastatic disease; if nodes are clinically palpable, metastases will be identified in 90 per cent. These procedures are more accurately used as clinical staging methods when nodes are identified on physical examination.

Clinical staging prior to surgical intervention is primarily useful for malignant lung tumours, to allow reproducible classification, prognostication, and comparison of therapeutic modalities. Since 95 per cent of all lung neoplasms are malignant, staging of a lung lesion before resection is a frequent requirement. A modified TNM classification for lung cancers is currently in use.

The T descriptor refers to the primary lesion, in terms of its size and involvement of local tissues.

T1—a tumour 3 cm or less in greatest dimension, contained within the visceral pleura and without invasion proximal to a lobar bronchus at bronchoscopy, or a superficial lesion confined to the bronchial wall (Fig. 11(a)) 1959.

T2—a tumour more than 3 cm in greatest dimension, or a tumour with visceral pleural invasion, or bronchial obstruction extending to the hilar region; at bronchoscopy, the lesion must be 2 cm or more from the tracheal carina (Fig. 11(b)) 1959.

T3—a tumour of any size with direct extension into the chest wall (including superior sulcus tumours), diaphragm or mediastinal pleura or pericardium, without involvement of central mediastinal structures, or a tumour within 2 cm of the carina without direct carinal involvement.

T4—a tumour of any size with invasion of the central mediastinal structures (heart, great vessels, trachea, oesophagus, vertebral bodies) or a cytologically proven malignant pleural effusion.

N0—no demonstrable metastasis to regional nodes

N1—metastasis to peribronchial or ipsilateral hilar nodes, including by direct extension (Fig. 12) 1960

N2—metastasis to ipsilateral mediastinal and/or subcarinal nodes (Fig. 12) 1960

N3—Metastasis to contralateral mediastinal or hilar nodes or to ipsilateral or contralateral scalene or supraclavicular node.

Stage grouping of TNM subsets are demonstrated in Table 4 532. Stage I consists of localized tumours (T, T2) with no evidence of lymph node metastasis. An important subset are T1 N0 tumours, which have an extremely favourable prognosis. Stage II includes patients with localized tumours and metastasis to N1 nodes (Fig. 13) 1961. Stage III is subdivided essentially on the basis of surgical resectability. Stage IIIa includes T3 N0 and N1 tumours, as well as T1–3 tumours with N2 nodal metastasis (Fig. 14) 1962. Although surgically resectable, patients with N2 nodal disease frequently require neoadjuvant or adjuvant therapy. Stage IIIb includes patients with T4 tumours without distant metastasis and any tumour with N3 nodes. Most patients with Stage IIIb lesions are not candidates for surgical resection, with the notable exception of localized carinal tumours; carinal resection and reconstruction may be possible. Stage IV includes any tumour with evidence of M1 disease. These lesions are generally considered unresectable, with the exception of those in patients with isolated cerebral metastasis, in whom combined pulmonary and cerebral resection may lead to prolonged survival.

Staging of lung tumours may be begun by a series of non-invasive studies. Chest CT scans provide important information with regards to tumour size (T descriptor), the size of mediastinal lymph nodes, and the presence of extrathoracic metastatic disease at selected sites (the cephalad one-third to one-half of the liver, the adrenal glands). Involvement of the visceral or parietal pleura or of the chest wall cannot be determined from CT scans or other non-invasive studies without direct evidence of extrapleural extension (e.g. bony destruction, pericardial effusion). A notable exception is the ability of MRI scans to identify the presence of vascular or neural invasion for superior sulcus tumours.

Non-invasive studies that may further elucidate extrathoracic metastases include bone scans and CT scans of the head and abdomen. Typically, these are indicated only for patients with symptomatic complaint or biochemical abnormalities related to these regions (e.g. abnormal alkaline phosphatase). However, for large tumours, poorly differentiated lung cancers, and for adenocarcinomas (which have a propensity for early cerebral metastasis) routine metastatic studies may be indicated. Bone marrow aspiration is indicated for small cell lung cancer because of the frequency of metastasis to this site.

Invasive staging procedures are primarily reserved for patients with intrathoracic lesions who are candidates for surgical resection. Mediastinoscopy, by a cervical incision, allows biopsy examination of common mediastinal sites of lymph node metastasis, including the paratracheal, tracheobronchial, and anterior subcarinal regions (Fig. 15) 1963. The aorticopulmonary window, posterior subcarinal, hilar, and peri-oesophageal nodes are not accessible by this method. Mediastinoscopy should be performed in all patients with suspected or proved malignant epithelial tumours of the lung, except in cases of T1 lesions with normal mediastinal lymph nodes on chest CT scan examination. Sampling of all accessible nodal sites at mediastinoscopy is required. Mediastinoscopy has a documented sensitivity of 93 per cent and diagnostic accuracy of 96 per cent. Its use has decreased the incidence of exploratory thoracotomy from 25 per cent to less than 10 per cent and increased resectability rates to greater than 90 per cent. Major complications occur in 0.3 per cent of cases, usually bleeding from the brachiocephalic artery or azygous vein. Other complications include injury to the left recurrent laryngeal nerve (1 per cent), pneumothorax, mediastinal emphysema, infection, and oesophageal perforation.

Mediastinotomy, allowing surgical access to the prevascular and hilar regions by a right or left parasternal incision, is useful for biopsy of aorticopulmonary or hilar nodes, as well as to assess direct invasion of the central pulmonary artery or thoracic aorta. In general, metastatic extension to aorticopulmonary or hilar nodes does not exclude the patient from potential surgical resection. This approach is most commonly used for left upper lobe lesions, in whom lymphatic drainage proceeds from peribronchial to aorticopulmonary window nodes (Fig. 16) 1964.

Video-assisted thoracoscopy is an evolving technique that allows access to the entire pleural space for inspection of both parenchymal and mediastinal structures as well as for biopsy and surgical intervention. All sites not accessible to mediastinoscopy are potentially accessible to video-assisted thoracoscopy. Further experience with this technique will be required to identify its utility as a routine staging procedure.

The lung provides oxygen and eliminates carbon dioxide from the body. Several factors are involved in normal pulmonary function, each of which can be measured to some extent ( Table 5 533, and see also Section 3.4 6). All surgical interventions, including bronchoscopy or thoracotomy, as well as parenchymal resection, may interfere with one or more of these components. Assessment of these factors, and approximation of the effect of the planned surgical intervention, is critical to the evaluation of patients with lung neoplasms.

Many of the tests listed in Table 5 533 have been used to predict perioperative risk. However, the complexity of pulmonary function means there are no absolute cut-off points. FEV&sub1; and arterial blood gas tests are the most important initial tests. Important information on the physiological status of the patient is also obtained from a chest radiograph and CT scan. Evidence of coronary artery calcification on chest CT scan indicates an increased risk for cardiac dysrhythmias and myocardial ischaemia in the postoperative period.

A clinical assessment of integrated pulmonary function can be made by walking with the patient up two flights of stairs. Completion of this task without extreme dyspnoea signifies sufficient compensatory capability to tolerate at least a thoractomy, which alone may diminish maximal breathing capacity by 50 per cent.

For any pulmonary resection, the proportion of functional lung tissue that will be removed can be approximated by the use of quantitative radionuclide V/ Q scanning. Postoperative pulmonary function can be estimated by multiplying preoperative FEV&sub1; by the percentage of uninvolved lung obtained from the V/ Q scan.

Resectional surgery should not be carried out in most instances in the presence of the following contraindications.

1.Predicted FEV&sub1; < 0.8 l.

2.Pco&sub2; > 45 mmHg

3.Po&sub2; < 50 mmHg

4.Single breath DLco less than 50 per cent of predicted value

5.Mean pulmonary artery pressure, after balloon occlusion of the artery to the involved lung, ≥ 35 mmHg.

Various approaches have been used to access the pleural space for surgical interventions. Thoracotomy, performed with the patient in a lateral decubitus position, remains the most common incision. The standard posterolateral thoracotomy is an incision beginning midway between the medial border of the scapula and thoracic spine and continuing in a curvilinear fashion, parallel to the ribs, to the anterior axillary line. The maximum exposure of the pulmonary parenchyma and hilar structures is afforded by this incision. Optimal exposure of the tracheal carina is also afforded by this incision when performed on the right side. A disadvantage to this incision is the necessary transection of the latissimus dorsi muscle, an important accessory respiratory muscle (Fig. 17) 1965. An alternative approach is an anterolateral ‘muscle sparing’ thoracotomy, extending from the tip of the scapula to the inframammary crease (Fig. 18) 1966. The operative exposure is somewhat less extensive with this incision, but transection of the chest wall musculature is avoided.

Median sternotomy affords a limited exposure of both pleural spaces and the anterior hilar structures. Surgical manoeuvres involving the lower lobes or bronchi are limited by this incision. Exposure of the supracarinal trachea, however, is excellent. Median sternotomy causes the least compromise of pulmonary function in the early postoperative period of any thoracic incision. Bilateral trans-sternal anterior thoracotomy is occasionally of use when bilateral pulmonary resections involving the lower lobes or main bronchi are necessary. Finally, video-assisted thoracoscopy allows a minimally invasive approach for limited peripheral pulmonary resections. Its long-term efficacy and utility, however, remain to be elucidated.

Upon entering the pleural space a systematic evaluation of the pleural surfaces, mediastinum, and pulmonary parenchyma should be completed. All intrapleural adhesions should be divided, and any fluid aspirated and submitted for cytological evaluation. Systematic palpation and excisional biopsy of mediastinal masses or enlarged lymph nodes should be performed. Palpation of the entire pulmonary parenchyma with the lung in both an inflated and atelectatic state is necessary to identify any potential lesions. In patients with multiple pulmonary nodules, palpation at thoracotomy identifies 20 per cent more lesions than can be identified by preoperative chest CT scan.

The resection of lung neoplasms should adhere to a principle of complete excision of the tumour and appropriate lymphatic drainage. En-bloc resection should be employed whenever possible. Margins of resection, both parenchymal and bronchial, should be free of residual neoplastic disease. Maximal attempts at conservation of uninvolved pulmonary parenchyma should be made, however, in view of the vital function of the lung as well as the incidence of second primary neoplasms (10 per cent at 5 years for patients with non-small cell lung cancer).

Vascular structures are identified and ligated. Bronchial closure is performed with an interrupted suture technique or a mechanical stapling device. In skilled hands, no difference in the rate of bronchial stump fistula is noted between these techniques. Application of a vascularized flap of pleura or pericardial fat to the closed stump diminishes the incidence of postoperative fistula, particularly when adjuvant radiation or chemotherapy is contemplated.

Typically, anatomic resection such as lobectomy or pneumonectomy is performed. Parenchyma sparing resection is performed for localized peripheral lesions only if regional lymph nodes are demonstrated to be free of metastasis by intraoperative pathological examination or when predicted postoperative pulmonary function is marginal. Knowledge of segmental anatomy allows control of the bronchovascular structures for more central lesions requiring parenchyma sparing resections. The margins of such a resection, however, are determined by the limits of the neoplasm, not strictly by the anatomical boundaries of the associated bronchopulmonary segment, to assure complete excision.

Involvement of the lobar or main bronchus does not always require progression to a pneumonectomy. The techniques for bronchial resection and reconstruction (‘sleeve resection’) have been used for both benign and malignant lung neoplasms without adverse effects on postoperative morbidity or prognosis.

Pleural effusion occurring in association with lung neoplasms may indicate a malignant lesion with extension beyond the limits of surgical resection. Aspiration of any pleural effusion occurring with a pulmonary neoplasm for biochemical and cytological study is required. An exudative effusion with more than 100 000 red blood cells/mm³ or a predominance of lymphocytes suggests a malignant effusion. However, cytological confirmation is required. Among patients with lung cancer who present with a pleural effusion, only 40 to 75 per cent will demonstrate a positive cytology; the remainder are candidates for surgical resection.

Chest wall invasion by a pulmonary neoplasm does not preclude potential surgical resection. Typically, these are malignant epithelial neoplasms. Survival and resectability relates to nodal status and the possibility of extrathoracic metastasis in such cases. Resection should include a margin of 5 cm about the region of chest wall invasion. Reconstruction with prosthetic material (e.g. Marlex-methacrylate, PTFE patch) is required for lateral or anterior defects with involvement of two or more ribs and their adjacent intercostal spaces. For the more common posterolateral defects, overlain by the scapula and shoulder girdle, reconstruction is rarely needed. Adjuvant radiation therapy appears beneficial only for compromised margins of resection.

Superior sulcus tumours arise in the apex of the lung cephalad to the clavicle, as seen on an anteroposterior chest radiograph. The narrow anatomical confines of the region makes early diagnosis difficult, invasion of local chest wall and neurovascular structures likely, and complete resection challenging. Many patients present themselves with symptoms of involvement of the stellate ganglion (i.e. Horner's syndrome) and of C8 or T1 nerve roots (Pancoast syndrome). MRI scans optimally visualize the region and determine the extent of invasion. Invasion of the vertebral body or subclavian vessels contraindicates resection. Diagnosis is made by percutaneous needle biopsy. Following extrathoracic and mediastinal staging preoperative radiation therapy (30–35 Gy) is used to optimize the margins of resection. Excision of the parenchymal lesion and associated chest wall involved, as well as the lower trunk of the brachial plexus, if affected, is followed by additional radiation therapy to a total dose of 50 to 55 Gy. Survival following this approach is 35 per cent at 5 years; squamous histology has a more favourable prognosis.

Metastasis to N2 lymph nodes typically indicates microscopic metastatic dissemination of tumour at extrathoracic sites. For this reason, the majority of patients with N2 disease identified at mediastinoscopy undergo preoperative neoadjuvant therapy with chemotherapy or a combination of chemotherapy and mediastinal radiotherapy followed by surgical resection. Survival following this approach ranges from 15 to 30 per cent, depending on the specific regimen. In rare instances, when N2 nodes not identified at mediastinoscopy are found at thoracotomy, when microscopic intranodal N2 metastasis from squamous cell cancers is found at mediastinoscopy, or when carcinoid tumours present with N2 metastasis, concurrent parenchymal resection encompassing all lymphatic drainage and involved nodes may be performed. Survival in these cases ranges from 25 per cent (negative mediastinoscopy) to 10 per cent (positive mediastinoscopy for intranodal disease).

Involvement of the tracheal carina by a pulmonary neoplasm, although classified as a T4 lesion, may be managed by primary resection and reconstruction. The critical factors include the extent of involvement of the distal trachea and proximal bronchi and the possibility of mediastinal or extrathoracic metastases. For benign or low-grade malignant neoplasms (carcinoid, bronchial gland tumours), resection to the limits of the neoplasm or to the limits of reconstruction is curative in 80 to 85 per cent of cases. For non-small cell lung cancer, carinal involvement may be surgically managed by carinal resection and reconstruction alone, or by incorporation of resection of the tracheal carina with an ipsilateral pneumonectomy, depending on the anatomical disposition of the lesion. Survival in this group is 25 to 30 per cent at 5 years.

Isolated cerebral metastasis in lung cancer patients occurs most commonly with adenocarcinoma. When the lung primary is otherwise localized or when the lung primary has been previously resected and no other metastatic disease is evident, the treatment of the cerebral lesion determines survival. Surgical resection of the cerebral metastasis is indicated for isolated superficial lesions, in the presence of a large amount of oedema or mass effect or when there is associated haemorrhage. For concurrent pulmonary and cerebral lesions, mediastinoscopy to complete clinical staging is usually followed by cerebral resection prior to pulmonary resection. Survival rates of 15 to 20 per cent at 5 years have been reported.

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