PATHOLOGY
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Characteristic ovoid, small cells with scant cytoplasm. Crush artifact commonly seen ( Fig. 32-1 ).
Figure 32-1
High-power photomicrograph showing clusters of small round to ovoid cells with scant cytoplasm, typical for small cell lung cancer.
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Histologic subtypes include small cell (90%) and combined small and non–small cell components, including large cell neuroendocrine.
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Neuroendocrine markers of differentiation help make the diagnosis (chromagranin, synaptophysin, and CD 56 Neural Cell Adhesion Molecule [NCAM]).
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Electron microscopy shows dense-core neurosecretory granules.
INCIDENCE
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Decreasing incidence and mortality rate over the last few decades. Possibly due to decreasing smoking incidence and increasing use of low tar filters.
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Rising incidence of women who present with small cell lung cancer (SCLC), approaching 50%. This is attributed to rising smoking incidence in women.
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SCLC has the strongest association with smoking of all lung cancers.
PATHOGENESIS
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Strong linkage to tobacco. Ninety-five percent of patients have a prior smoking history.
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Interplay of environmental factors with genome of respiratory epithelium:
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Autocrine growth loops with peptides that perpetuate cell growth.
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Oncogene overexpression (myc oncogene, tumor suppressor gene underexpression-p53, Rb gene inactivation)
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Apoptosis (programmed cell death) inhibited by BCL-2 overexpression in over 90% of patients.
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PRESENTATION
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Historically male predominant; now equal ( Tables 32-1 and 32-2 )
TABLE 32-1 ▪
SYMPTOMS OF SMALL CELL LUNG CANCER
Symptom
Percent of Patients
Cough
50
Weakness
40
Dyspnea
40
Chest pain
35
Anorexia
30
Hemoptysis
20
TABLE 32-2 ▪
SIGNS OF SMALL CELL LUNG CANCER
Sign
Percent of Patients
Weight loss
50
Paraneoplastic process
1–15
Fever
10
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Typical patient is older than 50 years of age.
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Respiratory symptoms are the most common (see Table 32-1 ).
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Majority present with advanced disease (66%).
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Higher incidence of paraneoplastic syndromes, mainly neurologic and endocrinologic.
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Endocrine entities parallel disease activity, whereas neurologic complications progress independently of illness.
CLINICAL FEATURES
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“Central disease” with hilar, mediastinal, large volume, bulky radiographic features.
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Most common malignant etiology of superior vena caval syndrome, with facial and neck swelling, jugular and anterior chest venous engorgement.
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Ten percent present with peripheral, solitary pulmonary nodule.
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The majority present with metastatic disease, most commonly to liver, bone, adrenals, brain, and bone marrow.
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Paraneoplastic syndromes ( Tables 32-3 and 32-4 )
TABLE 32-3 ▪
ENDOCRINE PARANEOPLASTIC SYNDROMES IN SMALL CELL LUNG CANCER
Syndrome
Clinical Presentation
Protein
Inappropriate secretion of antidiuretic hormone (SIADH)
Hyponatremia
ADH
Cushing’s syndrome
Hypokalemia, hypertension
ACTH
Acromegaly
Acromegaly, Hypertension, Glucose Intolerance
Growth hormone release hormone (GHRH)
ACTH, adrenocorticotropic hormone; ADH, antidiuretic hormone.
TABLE 32-4 ▪
NEUROLOGIC PARANEOPLASTIC SYNDROMES IN SMALL CELL LUNG CANCER
Syndrome
Clinical
Pathophysiology
Lambert-Eaton
Proximal limb muscle weakness, Initial increase in strength with activity (i.e., transient postrecruitment augmentation)
Antibody directed against voltage gated calcium channel antigens
Encephalomyelitis (includes cortical, limbic, and brainstem, as well as cerebellar, cord, and peripheral nervous system involvement)
Lethargy, sensory neuropathy, autonomic neuropathy
Antineuronal antibody, (Hu) (also anti-Ri with brainstem encephalitis)
Cerebellar degeneration
Ataxia, poor coordination, nystagmus.
Purkinje cell antibody mediated; Anti-Tr
Stiff man syndrome *
Progressive muscle rigidity; superimposed painful muscle spasms and gait impairment due to continuous motor activity
Antiamphiphysin
Subacute pandysautonomia
Cholinergic and/or adrenergic dysfunction
Antineuronal acetylcholine receptor antibody
* Benzodiazepines (for muscle relaxation) and immune modulators such as intravenous immunoglobulin, plasmapheresis, and prednisone may provide effective treatment.
Endocrine (Protein Mediated)
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Inappropriate antidiuretic hormone (ADH)—hyponatremia (15%)
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Cushing’s syndrome—hypertension, hypokalemia related to increased adrenocorticotropic hormone production.
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Acromegaly—secondary to increased growth hormone–related protein production.
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Hypercalcemia—related to increased parahormone-related protein (much more common in non–small cell cancer).
Neurologic (Antibody Mediated)
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Definition of neurologic paraneoplastic syndromes :
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A classic neurologic syndrome associated with SCLC, developing within 5 years of neurologic presentation
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Nonclassic syndrome that significantly improves or resolves after cancer treatment
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The presence of “paraneoplastic antibodies”
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Syndromes:
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Eaton-Lambert syndrome:
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Occurs in about 3% of patients with SCLC
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Tumor-associated antigens cross-react with voltage-gated calcium channels on presynaptic nerve terminals, with generation of antibodies directed against these channels in 95% of patients.
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Ptosis is common, but diplopia is rare.
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Muscle weakness in the pelvic girdle exceeds that of muscle groups around the shoulder girdle
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Respiratory muscle involvement and respiratory failure can occur.
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Repetitive nerve stimulation studies typically produces augmentation of the amplitude of compound action potentials initially (opposite with myasthenia gravis)
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Can coexist with either cerebellar degeneration or encephalomyelitis
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Successful therapy results in improvement in 50% of cases.
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Plasma exchange, intravenous immunoglobulin and 3,4, diaminopyridine (enhances acetylcholine release from nerve terminals) has been used to treat the disorder per se.
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Other syndromes:
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See Table 32-4 .
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Neurologic syndromes are generally progressive and run a course independent of the therapeutic response of the tumor.
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STAGING
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The concept of limited and extensive disease is the currently employed staging system in patients with SCLC ( Table 32-5 ).
TABLE 32-5 ▪
CLINICAL AND INVESTIGATIVE STAGING OF SMALL CELL LUNG CANCER
History and physical
CT scan of chest, abdomen and pelvis
Brain imaging (CT scan or MRI)
PET/CT scan (acceptable)
Bone scan
Chemistry panel, CBC, LDH, CEA
Bone marrow (only if abnormal CBC, high LDH and potential to change treatment plan)
CBC, complete blood count; CEA, carcinoembryonic antigen; CT, computed tomography; LDH, lactate dehydrogenase; MRI, magnetic resonance imaging scan; PET, positron emission tomography.
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Limited disease is disease confined to one hemithorax, with the tumor encompassing one radiation port. Disease that is beyond those confines is defined as extensive disease.
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The International Association for the Study of Lung Cancer Lung Cancer Staging Project has published proposals regarding the clinical staging of SCLC in the forthcoming (Seventh) Edition of the Tumor, Node, Metastasis Classification for Lung Cancer (see chapter 21 on Lung Cancer Staging). Use of TNM staging for early stage SCLC was recommended in future trials.
STAGING WORKUP
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The staging workup and studies described below classify the patient into either category and determine therapeutic goals, treatment strategy and prognosis.
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History and physical with attention to lymph nodes, upper body venous distension (superior vena cava syndrome), and organomegaly.
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Complete blood count (CBC), chemistry panel, lactate dehydrogenase (LDH), and carcinoembryonic antigen (CEA).
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Computed tomography (CT) scan of chest, abdomen, and pelvis.
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Brain imaging (CT scan or magnetic resonance imaging [MRI]).
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Positron emission tomography (PET)/CT scan is an acceptable modality for staging, complementing the anatomic focus of CT scanning with the enhanced metabolic uptake of malignant cells of PET technology.
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Bone scan.
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Bone marrow is rarely needed, unless an abnormal CBC on presentation, and the likelihood of changing treatment decisions. In addition, increased LHD levels often correlate with bone marrow involvement.
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THERAPY
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The natural history of untreated SCLC is a 6- to 12-week survival.
Limited Disease (30% of Patients)
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Concurrent chemoradiotherapy is treatment of choice.
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Radiation adds to overall survival (about 5% at 3 years). No role for surgery except in rare circumstances (see later).
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Chemotherapy: Cisplatin/etoposide is the chemotherapy regimen of choice, but numerous drug combinations show similar activity ( Table 32-6 ). The usual course of treatment is four cycles.
