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Initial Evaluation of the Patient With Lung Cancer^*

Symptoms, Signs, Laboratory Tests, and Paraneoplastic Syndromes

^* From the Department of Respiratory Medicine (Dr. Beckles), Royal Free Hospital, London, UK; Department of Respiratory Medicine (Dr. Spiro), Middlesex Hospital, London, UK; Pulmonary, Critical Care and Respiratory Services (Dr. Colice), Washington Hospital Center, Washington, DC; and Department of Medical Oncology (Dr. Rudd), St. Bartholomew’s Hospital, Smithfield, London, UK.

Correspondence to: Stephen G. Spiro, MD, Department of Respiratory Medicine, The Middlesex Hospital, Mortimer St, London W1T 3AA, United Kingdom; e-mail: stephen.spiro{at}uclh.org

	Abstract

TOP Abstract Introduction Chest Radiography Symptoms, Signs, and Laboratory... Symptoms and Signs Related... Signs and Symptoms of... Symptoms, Signs, and Laboratory... Paraneoplastic Syndromes Summary Summary of Recommendations References

 
This chapter describes the components of the initial evaluation for a patient either suspected or known to have lung cancer. The components of the initial evaluation are based on the recognized manifestations of localized lung cancer, ie, symptoms referable to the primary tumor, intrathoracic spread of lung cancer, and patterns of metastatic dissemination. Features of the history and physical signs may be useful indicators of the extent of disease. A standardized evaluation, relying on symptoms, signs, and routinely available laboratory tests, can serve as a useful screen for metastatic disease. Also described are the common features of the various paraneoplastic syndromes associated with lung cancer.

Key Words: evaluation • laboratory test • paraneoplastic • signs • symptoms

	Introduction

TOP Abstract Introduction Chest Radiography Symptoms, Signs, and Laboratory... Symptoms and Signs Related... Signs and Symptoms of... Symptoms, Signs, and Laboratory... Paraneoplastic Syndromes Summary Summary of Recommendations References

 
Lung cancer, like most other solid tumors, is unfortunately usually recognized late in its natural history. The 5-year mortality from the time of presentation remains at approximately 85 to 90%. Of 100 newly presenting patients with lung cancer, 80 patients will be inoperable at presentation and approximately 20 patients will proceed to attempted resection, of whom 5 to 10 patients will be alive 5 years later.¹

More than 90% of patients with lung cancer will be symptomatic at presentation. The diagnosis is usually suspected following a chest radiograph. In a series of 678 consecutive patients with newly diagnosed lung cancer, only 44 patients (6%) were asymptomatic.² A minority (183 patients, 27%) presented with symptoms related to the primary tumor. Most patients had either nonspecific systemic symptoms, including anorexia, weight loss, and fatigue (232 patients, 27%), or specific symptoms indicating metastatic disease (219 patients, 32%) at initial presentation. Prognosis was clearly related to the type of presenting symptoms. There was a better 5-year survival in asymptomatic patients (18%), than for those with symptoms related to the primary tumor (12%). Those with nonspecific symptoms had a 6% 5-year survival, and those with symptoms indicating metastatic disease fared the worst, with none alive at 5 years.

	Chest Radiography

TOP Abstract Introduction Chest Radiography Symptoms, Signs, and Laboratory... Symptoms and Signs Related... Signs and Symptoms of... Symptoms, Signs, and Laboratory... Paraneoplastic Syndromes Summary Summary of Recommendations References

 
The chest radiograph plays a pivotal role in the recognition of lung cancer. Certainly, in the asymptomatic patient, an abnormality on the chest radiograph would be the first clue to the presence of lung cancer. In patients with symptoms related to the primary tumor, the chest radiograph may often strongly support a suspicion of carcinoma of the lung. For patients presenting with either nonspecific systemic complaints or symptoms suggestive of metastatic disease, the chest radiograph will be helpful in focusing attention quickly on the lung as the most likely primary site.

Comprehensive reviews of the abnormalities seen on the chest radiograph in patients with carcinoma of the lung may be obtained elsewhere.^{3 4} However, it is useful to appreciate that clues from the chest radiograph may not only suggest the diagnosis of lung cancer, but may also point toward the histologic subtype. Adenocarcinoma is the most common type of lung cancer, accounting for 30 to 35% of all cases.⁵ Adenocarcinomas are more frequently seen peripherally. Squamous cell carcinoma, which accounts for up to 30% of all lung cancers, typically arises in the central bronchi and commonly extends into the hilum and mediastinum. They may be slower growing and metastasize late.⁶ Squamous cell carcinoma may also occur in the lung parenchyma where they may cavitate.^{6 7} Large cell carcinoma comprises 10 to 20% of all lung cancers and is also seen more commonly peripherally.³ Small cell lung carcinoma comprises 15 to 25% of all lung cancers and, like squamous cell carcinoma, also usually develops in the proximal airways and involves the hilum and mediastinum.³

	Symptoms, Signs, and Laboratory Tests in Lung Cancer

TOP Abstract Introduction Chest Radiography Symptoms, Signs, and Laboratory... Symptoms and Signs Related... Signs and Symptoms of... Symptoms, Signs, and Laboratory... Paraneoplastic Syndromes Summary Summary of Recommendations References

 
Symptoms, signs and abnormalities in laboratory tests relating to the lung cancer can be classified as follows: (1) those related to the primary lesion, (2) those related to intrathoracic spread, (3) those related to distant metastasis, and (4) those related to paraneoplastic syndromes.

	Symptoms and Signs Related to the Primary Tumor

TOP Abstract Introduction Chest Radiography Symptoms, Signs, and Laboratory... Symptoms and Signs Related... Signs and Symptoms of... Symptoms, Signs, and Laboratory... Paraneoplastic Syndromes Summary Summary of Recommendations References

 
The frequencies of local and systemic symptoms in patients with lung cancer are summarized in Table 1 . ^{8 9 10 11 12 13}

Dyspnea
Dyspnea develops early in up to 60% of patients. It is usually associated with increasing cough and sputum. If the tumor is occluding a main airway, it can cause breathlessness, which may be associated with a unilateral wheeze.

Hemoptysis
Hemoptysis is a common presenting symptom. It is rarely severe and usually only consists of blood streaking of the sputum. The most common description is that of coughing up blood for several days in succession. Although chest radiograph findings are usually abnormal in patients with hemoptysis from lung cancer, in a small percentage of patients the finding will either be normal or not show a localizing abnormality.¹⁴ In patients > 40 years old with COPD and a smoking history presenting with hemoptysis, even though chest radiograph findings may be unremarkable there should still be a high index of suspicion for lung cancer. Besides careful observation, the clinician may consider further diagnostic tests, including sputum cytology, bronchoscopy, or chest CT.

Chest Discomfort
Chest discomfort is common and occurs in up to 50% of patients at diagnosis. This is often of an ill-defined nature, intermittent and aching in quality. Definite pleuritic pain may occur as a result of direct spread of the tumor to the pleural surface.

	Signs and Symptoms of Intrathoracic Spread

TOP Abstract Introduction Chest Radiography Symptoms, Signs, and Laboratory... Symptoms and Signs Related... Signs and Symptoms of... Symptoms, Signs, and Laboratory... Paraneoplastic Syndromes Summary Summary of Recommendations References

 
Intrathoracic spread of lung cancer, either by direct extension or lymphatic spread, produces a variety of symptoms and signs. These may be caused by involvement of the following structures: (1) nerves, eg, recurrent laryngeal nerve, phrenic nerve, brachial plexus, and sympathetic nerve trunks; (2) chest wall and pleura; (3) vascular involvement, eg, superior vena cava (SVC), pericardium, and heart; and (4) viscera, including esophagus.

Recurrent Laryngeal Nerve Palsy
Recurrent laryngeal nerve palsy has been reported in 2 to 18% of cases, and is more common in left-sided tumors because of the circuitous route of the left recurrent laryngeal nerve around the aortic arch, and causes hoarseness. It is associated with poor expectoration with coughing, and an increased risk of aspiration.

Phrenic Nerve Paralysis
Phrenic nerve dysfunction may be noted on the chest radiograph by the presence of an elevated hemidiaphragm, or can present with breathlessness in patients already compromised by lung disease.

Pancoast Tumor
Pancoast tumor is also called superior sulcus tumor, and arises posteriorly in the apex of an upper lobe near the brachial plexus, commonly infiltrating the eighth cervical and first and second thoracic nerve roots. This causes pain, cutaneous temperature change, and muscle wasting along the relevant nerve root. There is often a delay of many months before the true diagnosis is revealed.

Horner Syndrome
This is due to involvement of the sympathetic chain and stellate ganglion causing unilateral enophthalmos, ptosis, small pupil, and ipsilateral lack of facial sweating.

Chest Wall
Pain from chest wall involvement is a common presenting symptom. More than 50% of patients with lung cancer complain of chest pain during the course of their disease. The pain is usually dull, tends to be persistent, poorly localized, and unrelated to breathing or coughing. Retrosternal pain may be due to massive hilar and mediastinal nodal involvement. When chest pain is particularly severe and localized, it is usually related to either direct invasion of the pleura or chest wall by the primary tumor, or due to a rib metastasis. Tenderness may be elicited at the site of rib involvement and, rarely, a soft-tissue mass can be palpated.

Pleura
Pleural involvement occurs in 8 to 15% of patients with lung cancer. Pleuritic chest pain can occur with the early phase of neoplastic pleural invasion and can disappear with the onset of a pleural effusion. Pleural effusion, which may result in dyspnea, is generally caused by direct pleural extension, but may also be secondary to mediastinal node involvement and lymphatic obstruction. Signs of a pleural effusion include dullness to percussion and decreased breath sounds.

SVC Obstruction
Lung cancer accounts for 46 to 75% of all cases of SVC obstruction (SVCO); the most common histologic subtype associated with SVCO is small cell carcinoma^{10 15 16} and is due to direct invasion by the primary tumor, or from enlarged right paratracheal metastatic lymph nodes. The patient will complain of facial swelling, including the neck and eyelids, with dilated veins visible over the upper torso, shoulders, and arms. There may also be headache, dizziness (particularly on bending forwards), drowsiness, blurring of vision, cough, and dysphagia.^{15 17}

Heart and Pericardium
Metastases to the heart and pericardium usually occur by direct lymphatic spread. At autopsy, cardiac involvement occurs in approximately 15% of cases, and a small number will have tamponade.¹⁸ In primary lung cancer, the pericardium is the most common site of cardiac involvement.¹⁹

Esophagus
Enlargement of hilar and mediastinal nodes is usually due to metastatic spread and seldom causes symptoms unless it is massive, when it can compress the esophagus and limit swallowing.

	Symptoms, Signs, and Laboratory Tests Indicating Extrathoracic Metastases

TOP Abstract Introduction Chest Radiography Symptoms, Signs, and Laboratory... Symptoms and Signs Related... Signs and Symptoms of... Symptoms, Signs, and Laboratory... Paraneoplastic Syndromes Summary Summary of Recommendations References

 
Approximately one third of patients present with symptoms as a result of distant metastases. The most common sites of distant metastasis from lung cancer are the bones; liver, adrenal glands, and intraabdominal lymph nodes; brain and spinal cord; and lymph nodes and skin.

Bones
Lung cancer can metastasize to virtually any bone, although the axial skeleton and proximal long bones are most commonly involved. The primary symptom resulting from bone involvement is pain, which may have a pleuritic component when the ribs are involved. Bone pain is present in up to 25% of all patients at presentation.

Liver, Adrenal Glands, and Intra-abdominal Lymph Nodes
Liver metastases occur commonly with lung cancer. However, liver function test results are seldom abnormal until the metastases are numerous and large. Hepatic metastases most commonly produce symptoms of weakness and weight loss. When present, hepatic metastases carry a very poor prognosis. Adrenal lesions and para-aortic lymph node metastases may occur and are most commonly seen with small cell lung cancers; in the latter cell type, they are often discovered during staging. Clinical evidence of adrenal insufficiency is rarely seen.

Brain And Spinal Cord
Intracranial metastases occur in 10% of patients at presentation. Spinal cord metastases are less common and tend to occur in patients with cerebral metastases. Brain metastasis may produce headache, nausea and vomiting, focal neurologic symptoms or signs, seizures, confusion, and personality changes. The lung is the primary site of approximately 70% of cancers that initially present with symptomatic brain metastases.²⁰

Lymph Nodes and Skin
The most common site of palpable lymphadenopathy is the supraclavicular fossa, which can be involved in 15 to 20% of cases during the course of the disease. Identifying an enlarged lymph node or subcutaneous nodule due to metastatic lung cancer is extremely helpful in facilitating both diagnosis and staging. Fine needle aspiration can be performed quickly at the bedside or as an outpatient with little morbidity and with a high sensitivity.²¹

Standardized Evaluation For Systemic Metastases
Carbone et al² and Feinstein and Wells^{22 23 24 25 26} have explored the relationship between symptoms at presentation and prognosis in a large cohort of consecutive patients with lung cancer. Patients with the best prognosis were either asymptomatic or had symptoms referable only to the primary tumor. In patients with either systemic symptoms of anorexia, weight loss, and fatigue or symptoms attributable to metastatic disease, prognosis was especially poor. The relationship between systemic symptoms and prognosis was conserved with standard staging of lung cancer. Within any individual tumor stage, there was a gradient of worsening prognosis in patients who presented with anorexia, weight loss, and fatigue. The biological association between systemic symptoms and worse prognosis was not entirely clear, although, intuitively, patients with systemic symptoms would be clinically suspected of having extensive disease.

Hooper and colleagues^{27 28} incorporated the concept of systemic symptoms as a reflection of more extensive disease into an approach for identifying lung cancer patients more likely to have evidence of metastases on radiographic studies. They used a cluster of clinical factors, consisting of symptoms, signs, and standard laboratory tests, which were thought to reflect metastatic disease. Included within these clinical factors were the nonspecific variables weight loss and anemia. They found that abnormalities in these clinical factors were associated with radiographic evidence of metastatic disease. The more abnormalities noted in the clinical assessment, the more likely that metastases would be detected. They also found that patients with no abnormalities in these clinical factors were extremely unlikely to have scan evidence of metastatic disease. Silvestri et al^{29 30} adapted Hooper’s criteria (Table 2 ) and retrospectively asked whether they would be a useful screen for detecting adrenal metastases. As with the work of Hooper and colleagues,^{27 28} if no clinical abnormalities were noted adrenal metastases were not found by CT. The more clinical abnormalities found, the more likely adrenal metastases would be found. Both the work of Silvestri et al^{29 30} and a study by Quinn and coworkers³¹ pointed out that abnormalities in the clinical assessment would often not be helpful in identifying the site of metastases. However, the recognition of abnormalities in the clinical screen strongly suggested the presence of metastases.

Recommendation

1. All patients with known or suspected lung cancer should undergo a thorough history, physical examination, and standard laboratory tests as a screen for metastatic disease. Level of evidence, fair; benefit, substantial; grade of recommendation, B
   

	Paraneoplastic Syndromes

TOP Abstract Introduction Chest Radiography Symptoms, Signs, and Laboratory... Symptoms and Signs Related... Signs and Symptoms of... Symptoms, Signs, and Laboratory... Paraneoplastic Syndromes Summary Summary of Recommendations References

 
Paraneoplastic syndromes are a group of clinical disorders associated with malignant diseases that are not directly related to the physical effects of primary or metastatic tumor. The exact mechanism by which paraneoplastic syndromes occur is not fully understood. Paraneoplastic syndromes occur in at least 10% of patients with bronchogenic carcinoma.^{8 9}

The extent of paraneoplastic symptoms is unrelated to the size of the primary tumor, and in some cases can precede the diagnosis of malignant disease. At other times they may occur late in the illness, or herald the first sign of recurrence. The paraneoplastic syndromes may be due to the production of biologically active substances either by the tumor, or in response to the tumor (eg, polypeptide hormones, hormone-like peptides, antibodies or immune complexes, prostaglandins, or cytokines). Some of the more common paraneoplastic syndromes are outlined below. There are comprehensive reviews elsewhere.^{32 33}

Table 3 and 3A shows the myriad manifestations of paraneoplastic syndromes associated with lung cancer. The neurologic syndromes associated with lung cancer may occasionally occur through autoimmune mechanisms.^{34 35} Small cell carcinoma is the most common type of lung cancer associated with paraneoplastic autoimmune neurologic syndromes. Direct metastatic effects or metabolic or infectious processes must be excluded as contributors to the neurologic findings. The severity of the neurologic symptoms is unrelated to the tumor bulk; in fact, a primary malignant lesion may be undetected before death despite disabling symptoms.³⁶

Syndrome of Inappropriate Antidiuretic Hormone Production
Antidiuretic hormone (ADH) is produced in the hypothalamus and secreted from the posterior lobe of the pituitary gland. This hormone is involved in the maintenance of the extracellular fluid environment by reducing free water clearance. Although excess ADH production can be documented in up to 70% of patients with lung cancer, syndrome of inappropriate ADH (SIADH) is not as common. However, all patients with hyponatremia related to SIADH in lung cancer do have elevated serum levels of ADH.³⁸ Atrial natriuretic peptide is another hormone produced ectopically by lung cancer cells, which affects renal salt and water handling. In individual patients, increased levels of atrial natriuretic peptide may contribute to hyponatremia by causing a natriuresis.³⁸ SIADH is mainly associated with small cell lung cancer, although other malignant tumors of the lung may rarely be associated with this syndrome.^{39 40 41} The production of excess ADH is not always related to symptoms attributed to SIADH.^{39 42 43} Only 1 to 5% of patients have symptoms attributable to the SIADH. Manifestations of SIADH include confusion, unexplained seizures, decreased level of consciousness, and coma. Biochemically, the syndrome is defined as low serum sodium, a dilute plasma osmolality with a higher, or "inappropriate" urine osmolality, in the presence of continued urinary sodium excretion. The syndrome resolves promptly (< 3 weeks) with the initiation of combination cytotoxic chemotherapy in 80% of patients with small cell lung cancer, but commonly recurs with tumor progression.⁴⁴

Cushing Syndrome
Adrenocorticotrophic hormone (ACTH) is the most commonly produced ectopic hormone in lung cancer. It is derived from the parent hormone, pro-opiomelanocortin polypeptide. As with ADH above, it is not unusual to find increased serum levels of ACTH in patients with lung cancer; it may be detectable in up to 50% of patients with lung cancer.⁴⁵ However, despite the presence of increased levels of ACTH, Cushing syndrome is rarely seen. Signs and symptoms of Cushing syndrome develop in only 1 to 5% of patients with small cell lung cancer.^{46 47} This limited clinical expression is due partly to the rapid progression of small cell lung cancer and also the release of a biologically inactive form of the hormone. The most common features associated with this condition are clinical symptoms of weakness, muscle wasting, drowsiness, confusion and psychosis, dependent edema, hypokalemic alkalosis, and hyperglycemia.

Digital Clubbing and Hypertrophic Osteoarthropathy
These disorders may be associated with any cell type of lung cancer, although they are most frequently associated with squamous and adenocarcinoma and least frequently associated with small cell lung carcinoma. The exact mechanism for clubbing and hypertrophic osteoarthropathy is unknown, although suggestions include neurogenic, hormonal, and vascular mechanisms.⁴⁸

Clubbing is much more common than hypertrophic osteoarthropathy. In one study of 111 consecutive patients with pathologically proven lung cancer, clubbing was present in 29%. The phenomenon was more common among women than men (40% vs 19%) and more common in non-small cell lung cancer than small cell lung cancer (35% vs 4%).⁴⁹ Hypertrophic osteoarthropathy is seen in < 5% of patients with non small cell lung cancer⁵⁰ and is characterized by a painful symmetrical arthropathy (usually of the ankles, wrists, and knees) and periosteal new bone formation on the distal long bones of the limbs. Small cell lung cancer is a rarer cause; in one series, it accounted for only 1% of the cases with hypertrophic osteoarthropathy.⁵¹ Anecdotal observations indicate that clubbing and hypertrophic osteoarthropathy may resolve with successful treatment of the primary tumor, particularly surgical resection of a non-small cell lung cancer.

Neurologic Syndromes
A variety of poorly understood neurologic syndromes may occur in lung cancer, and affect 4 to 5% of patients.⁵² The diagnosis of a neurologic paraneoplastic syndrome is made once other causes, such as electrolyte imbalance, metastatic disease, cerebral and spinal vascular disease, infections, and treatment toxicity, are excluded. Small cell carcinoma is the most common type of lung cancer associated with paraneoplastic autoimmune neurologic syndromes. The syndromes involved include Lambert-Eaton myasthenic syndrome, peripheral neuropathy, cortical cerebellar degeneration, and several other CNS syndromes. Some of these syndromes may be identified by the presence of antibodies either in the serum or the cerebrospinal fluid.³⁵ A more extensive review of these and other paraneoplastic syndromes may be found elsewhere.³³

Effective chemotherapy in patients with small cell lung cancer and a neurologic paraneoplastic syndrome may result in sustained improvements in the neurologic symptoms.⁵³ In a small series of patients with small cell lung cancer, overall prognosis was more favorable in those with the Lambert-Eaton myasthenic syndrome than those without this paraneoplastic syndrome.⁵⁴

Recommendation

• Patients with lung cancer and a paraneoplastic syndrome should not be precluded from potentially curative therapy on the basis of these symptoms alone. Level of evidence, fair; benefit, substantial; grade of recommendation, C
  

	Summary

TOP Abstract Introduction Chest Radiography Symptoms, Signs, and Laboratory... Symptoms and Signs Related... Signs and Symptoms of... Symptoms, Signs, and Laboratory... Paraneoplastic Syndromes Summary Summary of Recommendations References

 
More than 90% of patients with lung cancer will be symptomatic at presentation. A minority present with symptoms related to the primary tumor, and most patients present with either nonspecific systemic symptoms, including anorexia, weight loss and fatigue, or specific symptoms indicating metastatic disease. Prognosis is related to the type of presenting symptoms. Asymptomatic patients and patients with symptoms related to the primary tumor have better 5-year survivals than those with systemic symptoms or symptoms indicating metastatic disease. Assessing symptoms, signs and standard laboratory tests in a standardized manner in patients presenting with known or suspected lung cancer may serve as a useful screen for identifying those patients with a higher likelihood of metastatic disease.

Paraneoplastic syndromes, which occur in up to 10% of patients with lung cancer, are a group of clinical disorders associated with malignant diseases that are not directly related to the physical effects of primary or metastatic tumor. These syndromes may be due to the production of biologically active substances or other, presently unclear, mechanisms. Paraneoplastic symptoms are unrelated to the size of the primary tumor, in some cases can precede the diagnosis of malignant disease, and at other times may occur late in the illness, or herald the first sign of recurrence.

	Summary of Recommendations

TOP Abstract Introduction Chest Radiography Symptoms, Signs, and Laboratory... Symptoms and Signs Related... Signs and Symptoms of... Symptoms, Signs, and Laboratory... Paraneoplastic Syndromes Summary Summary of Recommendations References

 

1. All patients with known or suspected lung cancer should undergo a thorough history, physical examination, and standard laboratory tests as a screen for metastatic disease. Level of evidence, fair; benefit, substantial; grade of recommendation, B
   
2. Patients with lung cancer and a paraneoplastic syndrome should not be precluded from potentially curative therapy on the basis of these symptoms alone. Level of evidence, fair; benefit, substantial; grade of recommendation, C
   

	Footnotes

 
Abbreviations: ACTH = adrenocorticotrophin hormone; ADH = antidiuretic hormone; SIADH = syndrome of inappropriate antidiuretic hormone; SVC = superior vena cava; SVCO = superior vena cava obstruction

	References

TOP Abstract Introduction Chest Radiography Symptoms, Signs, and Laboratory... Symptoms and Signs Related... Signs and Symptoms of... Symptoms, Signs, and Laboratory... Paraneoplastic Syndromes Summary Summary of Recommendations References

 

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