Paraneoplastic syndromes occur in approximately 10% of patients with lung cancer (Table 66-1). Such syndromes may be the initial presenting complaint triggering an evaluation but also can develop late in the course of disease. Paraneoplastic syndromes are unrelated to direct invasion or distant spread of tumor and in and of themselves do not preclude curative-intent therapy. Endocrine syndromes associated with lung cancers often are characterized by tumor production of biologically active hormones. Lung cancer is the most common cause of cancer-associated hypercalcemia, hyponatremia, and syndromes involving ectopic production of adrenal corticotropic hormone (ACTH).

Table 66-1 Paraneoplastic Syndromes Associated with Lung Cancer

Endocrine	Syndrome of inappropriate secretion of antidiuretic hormone (SIADH)/hyponatremia; hypercalcemia; ectopic adrenocorticotropic hormone (ACTH) syndrome; Cushing syndrome; hyperglycemia; hypoglycemia; hyperthyroidism; carcinoid syndrome; gynecomastia; elevated growth hormone; elevated follicle-stimulating hormone (FSH); galactorrhea
Musculoskeletal	Hypertrophic osteoarthropathy (HOP); clubbing, myopathy; dermatomyositis; polymyositis
Neurologic	Lambert-Eaton myasthenic syndrome (LEMS); encephalomyelitis/subacute sensory neuropathy; cerebellar degeneration; opsoclonus-myoclonus; autonomic neuropathy; retinopathy; mononeuritis multiplex; peripheral neuropathy; myopathy
Skin	Acanthosis nigricans; pruritus and urticaria, erythema multiforme; erythroderma; exfoliative dermatitis; hyperpigmentation
Hematologic	Anemia, thrombocytosis, leukocytosis, hypercoagulable state

Hypercalcemia of malignancy is the most frequent of these syndromes and is seen most commonly in patients with squamous cell carcinoma. Hypercalcemia in lung cancer patients usually is related to the ectopic production of parathyroid hormone–related peptide (PTHrP), rather than to the osteolytic effects of bone metastases. Early symptoms—thirst, polyuria, fatigue, constipation, nausea—are nonspecific. Mental status changes, lethargy, and even coma may accompany more severe hypercalcemia. The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) most commonly occurs in patients with small cell lung cancer (SCLC). In some SCLC series, hyponatremia related to SIADH is present in up to 10% to 15% of patients. As with hypercalcemia, the symptoms—weakness, nausea, headache—often are nonspecific; more severe hyponatremia may have serious consequences, including confusion, seizures, and coma. Ectopic ACTH syndrome is seen most commonly with SCLC. The classic features of Cushing syndrome—truncal obesity, myopathy and muscle weakness, diabetes, hypertension, hirsutism—often are absent. In most cases, tumor cells express a precursor hormone that is cleaved to ACTH. A minority of patients produce corticotropin-releasing hormone, which stimulates ACTH production in the pituitary. The distinction between these two processes can be determined by a dexamethasone suppression test.

Nonendocrinologic extrapulmonary syndromes include musculoskeletal abnormalities, most commonly asymptomatic digital clubbing, which can be seen in isolation or in the setting of hypertrophic pulmonary osteoarthropathy (HPO). The pathogenesis of HPO is unknown, but the disorder consists of a proliferative periostitis characterized by symmetric, painful arthropathy that typically involves the ankles, shins, knees, wrists, and elbows. The diagnosis usually is confirmed by the identification of new periosteal bone formation on plain radiographs of the long bones, or by demonstration of diffuse long bone uptake of radionuclide on bone scan or positron emission tomography (PET) imaging. HPO is more commonly seen with adenocarcinoma. Hematologic dyscrasias commonly occurring in patients with lung cancer include anemia, which may compound fatigue and dyspnea; thrombocytosis; and leukocytosis. Eosinophilia is seen only rarely. Lung cancer is the most common cause of hypercoagulability associated with malignancy, which usually declares itself as deep venous thrombosis or thromboembolism, or with classic Trousseau syndrome (migratory superficial thrombophlebitis). Lung cancer, and specifically SCLC, also is the most common cause of a clinically diverse group of paraneoplastic neurologic syndromes (see Table 66-1).

The commonality with several of these syndromes is that they appear to be driven by autoimmune mechanisms. The most common of these is the Lambert-Eaton myasthenic syndrome (LEMS), which occurs in approximately 2% to 4% of patients with SCLC. LEMS is characterized by proximal muscle weakness, hyporeflexia, dysarthria, blurred vision, and autonomic dysfunction. In contrast with myasthenia gravis, muscle strength typically does not improve with the administration of anticholinesterases, but some recovery of strength may be obtained with treatment of the underlying malignancy. LEMS is associated with an antibody that inhibits acetylcholine release by binding to calcium channels in peripheral cholinergic nerve terminals. The diagnosis usually is based on electromyography demonstrating small amplitude of the resting muscle action potential, which increases with repeated nerve stimulation or exercise. The syndrome of encephalomyelitis–subacute sensory neuropathy is associated with antineuronal nuclear-antibody types 1 and 2 (ANNA-1 and ANNA-2), also called anti-Hu and anti-Ri antibodies, respectively, which react with SCLC tumor cell surface proteins and with neuronal nuclear antigens. Anti-Hu antibodies also are seen in patients with SCLC and cerebellar degeneration as well as opsoclonus-myoclonus. Other paraneoplastic neuropathic syndromes include encephalomyelitis, autonomic neuropathy, and cancer-associated retinopathy.

Asymptomatic Presentation

Approximately 25% of patients with lung cancer present at an early stage of their disease, so only a minority are asymptomatic at the time of diagnosis. The poor overall 5-year survival for patients with lung cancer reflects the disproportionate number of patients who are diagnosed at an advanced stage. Interest in establishing screening for early disease detection in asymptomatic patients has understandably been the focus of many studies. The reasons to develop a reliable lung cancer screening tool are quite evident. Most lung cancers are discovered because of symptom-driven evaluation; a diagnosis of advanced-stage disease unfortunately portends a limited prognosis. By contrast, asymptomatic patients with early-stage cancers are more likely to experience long-term survival with treatment.

Large studies performed since the 1970s evaluating chest radiography, sputum cytologic analysis, and low-radiation-dose chest computed tomography (CT) scanning for lung cancer screening have consistently demonstrated an increase in the number of lung cancers diagnosed and a shift toward identifying earlier-stage disease accompanied by an improvement in survival, but notably without a decrease in lung cancer mortality rates. The National Lung Screening Trial (NLST) is the first large-scale clinical trial to demonstrate a benefit in lung cancer mortality related to screening with low-dose chest CT scanning. The NLST enrolled 53,000 subjects aged 55 to 74 years who were current or former smokers with at least a 30 pack-year history, and who had no previous history of lung cancer. The study compared low-dose chest CT scanning and chest radiography as screening tools, with participants randomized to receiving three annual screens with one or the other modality, with follow-up over another 5 years. The trial was closed in late 2010 when initial results demonstrated that subjects assigned to the CT screening group had 20% less lung cancer deaths than those assigned to chest radiography screening. The disadvantages of screening include a high rate of false-positive findings, which incur additional diagnostic evaluation with the potential for risk or harm related to such evaluation; the anticipated high cost of screening and subsequent evaluation; and the potential consequences of cumulative exposure to radiation from multiple scans. The optimal approach to lung cancer screening inevitably will need to evolve over the coming years, as the results of the NLST are applied to clinical practice, and outcomes related to both benefit and disadvantages can be longitudinally examined.

The Solitary Pulmonary Nodule

The typical presentation of an asymptomatic early stage lung cancer is as a solitary pulmonary nodule (SPN), defined as a solitary lesion 3 cm or less in diameter, surrounded by normal lung and not associated with other thoracic abnormalities such as hilar or mediastinal adenopathy, atelectasis, or pleural effusion. SPNs are common radiographic lesions, frequently identified as incidental findings on chest imaging studies done for issues unrelated to lung cancer. Typical scenarios include routine preoperative evaluation in which a lung nodule or mass is found on the plain chest radiograph, or is identified on a chest CT scan performed for screening purposes or for other reasons unrelated to any chest symptoms, and investigation featuring a CT scan of the abdomen, heart, or spine, in which a portion of the lungs is almost inevitably included.

In evaluating SPNs, it is useful to distinguish small (8 mm or less in diameter) from larger nodules. Small SPNs are very common findings in patients who have participated in CT screening studies for lung cancer, as well as in those undergoing CT scanning for non-lung-related reasons, as noted earlier. In the feasibility study for the NLST performed within the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, 21% of subjects had abnormalities identified on the baseline screening CT scan, most of which were small SPNs. Similarly, in the Mayo Clinic lung cancer screening study, 51% of subjects had abnormalities found on the baseline screening study, with an increase to 69% by the second annual screen, the vast majority of which were small SPNs. The enormous number of small SPNs generated by an increased volume of CT scanning prompted a position statement from the Fleischner Society proposing guidelines for the management of small (8 mm or less) SPNs detected on CT scans. The recommendations are outlined in Table 66-2. Appropriately applied, the guidelines outline algorithms for patients based on their risk of lung cancer, providing timelines for follow-up of incidentally discovered nodules that minimize the number of CT scans necessary in the course of evaluation. These practical recommendations will become even more relevant if CT screening for lung cancer becomes the standard of practice. Of note, these recommendations apply only to patients in whom SPNs are discovered incidentally, unrelated to any known underlying disease, and only for solid SPNs 8 mm or less in diameter. Specifically, the guidelines are not intended to apply to patients known to have or suspected of having malignant disease, patients younger than 35 years of age, or patients with unexplained fever. Furthermore, the recommendations are not fully applicable to persons with nonsolid (ground glass appearance) or partially solid nodules, who may require longer follow-up to permit exclusion of biologically indolent cancers with greater confidence.

Table 66-2 Fleischner Society Guidelines for Management of Small Pulmonary Nodules Detected on Computed Tomography (CT) Scans

Nodule Size*	Low-Risk Patient†	High-Risk Patient‡
≤4 mm	No follow-up needed§	Follow-up CT at 12 months; if unchanged, no further follow-up¶
>4-6 mm	Follow-up CT at 12 months; if unchanged, no further follow-up¶	Initial follow-up CT at 6-12 months, then at 18-24 months if no change¶
>6-8 mm	Initial follow-up CT at 6-12 months, then at 18-24 months if no change	Initial follow-up CT at 3-6 months, then at 9-12 months and 24 months if no change
>8 mm	Follow-up CT at around 3, 9, and 24 months, then dynamic contrast-enhanced CT, PET, and/or biopsy	Same as for low-risk patient

NOTE: Guidelines refer to newly detected indeterminate nodules in persons 35 years of age or older.

PET, positron emission tomography.

* Average of length and width.

† Minimal or absent history of smoking and of other known risk factors.

‡ History of smoking or of other known risk factors.

§ The risk of malignancy in this category (<1%) is substantially less than that determined with a baseline CT scan in an asymptomatic smoker.

¶ Nonsolid (ground glass) or partly solid nodules may require longer follow-up period to exclude indolent adenocarcinoma.

Modified from MacMahon H, Austin JH, Gamsu G, et al: Guidelines for management of small pulmonary nodules detected on CT scans: a statement from the Fleischner Society, Radiology 237:395–400, 2005.

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