Symptomatic at Presentation

There is no effective screening test to detect SCLC early. By the time of diagnosis, patients present with multiple symptoms, consistent with the rapid progression of the disease.1-5

  • Due to its rapid spread, ~70% of patients are diagnosed with extensive disease at the time of diagnosis, creating observable symptoms3,6,7

  • STUDY ANALYSIS

    This was corroborated by the National Lung Screening Trial,a during which annual lung screenings did not reduce the number of patients who were diagnosed with extensive-stage disease, nor did it have an impact on survival in SCLC.5,8,b

High Percentage of Extensive-Stage SCLC Detected by Low-Dose CT2

Year 1 Extensive-Stage Small Cell Lung Cancer (ES-SCLC) Pie Chart - 92.3% Year 2 Extensive-Stage Small Cell Lung Cancer (ES-SCLC) Pie Chart - 66.7%

ES=extensive-stage; CT=computed tomography; OS=overall survival.

aStudy was conducted to determine whether annual screenings of low-dose CT scans could reduce mortality from lung cancer. 53,454 participants at high risk for lung cancer were enrolled from August 2002 through April 2004, screening took place from August 2002 through September 2007, and individuals were followed for events that occurred through December 31, 2009.8

bLung cancer was inclusive of bronchioloalveolar carcinoma, adenocarcinoma, squamous-cell carcinoma, large-cell carcinoma, non-small-cell carcinoma or other, small-cell carcinoma, carcinoid, and unknown.8

RAPID-ONSET SMALL CELL LUNG CANCER SYMPTOMS

  • SCLC typically presents as a large hilar mass and bulky mediastinal lymphadenopathy and is characterized by rapid-onset symptoms that begin prior to initial diagnosis4,9,10
  • Due to rapid tumor growth and widespread metastases, most patients with SCLC are symptomatic at presentation. The duration of symptoms is typically less than 3 months3
    • In a Surveillance, Epidemiological, and End Results (SEER) analysis of Medicare claims data, 75% of patients were hospitalized within the first 90 days following diagnosis11,*
  • Signs and symptoms depend on the type of tumor growth and spread3

*5498 patients with ES-SCLC were identified as aged ≥66 years between January 1, 2007 and December 31, 2011. Patients were followed from diagnosis until death, coverage change, or December 31, 2013.11

Presentation and Select Symptomology, Diagnosis, and Metastases

Medical Clipboard Drawing

PRESENTATION AND SELECT SYMPTOMOLOGY3,4,7,9,10,a

LIMITED-STAGE SCLC

  • Respiratory conditions:
    • Worsening cough, hemoptysis, wheezing, dyspnea
  • Compression of the:
    • Esophagus, with dysphagia
    • Laryngeal nerve, left vocal cord paralysis

EXTENSIVE-STAGE SCLC

  • In addition to the symptoms listed above, there are additional symptoms from distant metastases:
    • Fatigue, anorexia
    • Neurological compromise
    • Bone pain from bone mets
    • Weight loss and debility
Lungs with Small Cell Lung Cancer (SCLC) Diagnosis Drawing

DIAGNOSIS4,12,13

Continues with:

  • CT imaging of the chest, abdomen, and pelvis
  • Biopsy
  • CT or MRI imaging of the brain
Metastatic Spread of Small Cell Lung Cancer (SCLC) Drawing

METASTASES3

  • Mediastinal lymph nodes are common, and metastatic spread is often radiologically evident
  • Distant metastatic spread commonly involves the lymph nodes and reaches the contralateral lung, brain, liver, adrenal glands, bone; and into blood vessels

MRI=magnetic resonance imaging.

aThis is not a comprehensive list of symptoms.

Common Sites of Metastases in SCLC3

Common Sites of Metastases in Small Cell Lung Cancer (SCLC) Diagram
Common Sites of Metastases in Small Cell Lung Cancer (SCLC) Diagram

RECOGNITION OF ONCOLOGIC EMERGENCIES CAN BE IMPERATIVE, AS DIAGNOSIS TYPICALLY OCCURS AFTER A RELATED CONDITION EMERGES14,a

Condition

Common Presenting Signs and Symptoms

Syndrome of
inappropriate antidiuretic hormone (SIADH)14

  • Hyponatremia
  • Nausea
  • Vomiting
  • Constipation
  • Muscle weakness

Superior vena cava syndrome14

  • Facial edema
  • Cough
  • Dyspnea at rest
  • Hoarseness
  • Chest and shoulder pain
  • Collateral venous circulation (chest wall)

aOther oncologic emergencies that could be associated with SCLC include: tumor lysis syndrome, hypercalcemia of malignancy, febrile neutropenia, hyperviscosity syndrome, malignant epidural spinal cord compression, malignant pericardial effusions, and extravasation.14

PARANEOPLASTIC SYNDROMES CAN BE AN IMPORTANT DISTINCTION BETWEEN SCLC AND OTHER TUMORS

  • Because SCLC is the most common solid tumor to cause paraneoplastic syndromes,10,15 understanding these syndromes provides opportunities for early intervention and management15
  • Paraneoplastic syndromes are a collection of signs and symptoms associated with neoplastic disease, caused by primary tumors from a distant site and does not involve the primary tumor15
    • These syndromes can precede diagnosis or present with limited-stage SCLC, and can also occur at the time of recurrence or metastatic disease15

Common Paraneoplastic Syndromes

  • ECTOPIC CUSHING SYNDROME15,16

    Caused by inappropriate production of ACTH and cortisol

    Occurs in 1%-5% of patients

    Symptoms include edema, muscle weakness, hypertension, weight gain, and metabolic alkalosis with hypokalemia

  • LAMBERT EATON MYASTHENIC SYNDROME15,17,18

    Caused by onconeural antibodies binding to calcium channels

    Occurs in 1%-3% of patients

    Symptoms include proximal muscle weakness

  • LIMBIC ENCEPHALITIS AND ENCEPHALOMYELITIS15,17,19

    Caused by onconeural antibodies leading to site-specific inflammation and neuronal loss

    Occurs in 1% of patients

    Symptoms include cognitive dysfunction with severe memory impairment, seizures, and psychiatric features, including depression, anxiety, and hallucinations

ACTH=adrenocorticotropic hormone.

SCLC is a rapidly progressive and aggressive tumor.
As patients are typically symptomatic at presentation, early recognition of symptoms and timely diagnosis are important.3,4,6

DIAGNOSING SCLC

  • To distinguish SCLC from NSCLC and other neuroendocrine cancers, a tissue sample is required. Evaluation and/or diagnosis is based upon light microscopy4,20-22
  • Depending on tumor location and size, a biopsy may be obtained9
  • The World Health Organization recognizes only 2 subtypes of SCLC: SCLC and combined SCLC3
    • Combined SCLC has an additional component of non-small cell carcinoma, which can be of any non-small cell histological subtype3

HISTOPATHOLOGY OF SCLC TUMORS

  • Histopathological diagnostic criteria include tumor cells of small size, a round-to-fusiform shape, scant cytoplasm, finely granular nuclear chromatin, and absent or inconspicuous nucleoli4,22

Pathology of a Tumor23

Small Cell Lung Cancer (SCLC) Tumor Cells Close Up Small Cell Lung Cancer (SCLC) Tumor Cells Close Up

Reproduced, with permission, from Carter BW, Glisson BS, Truong MT, Erasmus JJ. Small cell lung carcinoma: staging, imaging, and treatment considerations. RadioGraphics. 2014;34(6):1707-1721.

There are standard immunohistochemical markers for lung origin and neuroendocrine differentiation that are useful for distinguishing SCLC from other tumor types.4

About Neuroendocrine Tumors

  • SCLC is a poorly differentiated, high-grade neuroendocrine tumor, characterized by its aggressive spread throughout the body3,24
About Neuroendocrine Tumors Chart

KEY PATHOLOGY FEATURES

  • SCLC cells frequently exhibit expression of genetic abnormalities and other molecular characteristics implicated in driving oncogenesis25

Select Molecular Characteristics of SCLC

  • GENETIC ABNORMALITIES26,27

    Driver mutations include:

    • P53 and RB mutations, detected in up to 90% of SCLC tumors
    • In contrast to NSCLC, mutations in the EGFR and KRAS oncogenes are rare, except in occasional cases of SCLC transformation of EGFR-mutated lung adenocarcinomas

  • LACK OF BIOMARKERS3,26,28

    There are no established biomarkers for SCLC.

    • Clinical trials are ongoing

    PDL-1 expression is associated with longer survival in SCLC patients. However, it is uncertain if PDL-1 expression is a determinant predictive biomarker.

  • DEREGULATED TRANSCRIPTION FACTORS26,29,30

    Amplification of MYC promotes tumor progression by deregulating oncogenic transcription, cell cycle control, and metabolism.

    • Genomic amplifications in MYC are observed in 6%-24% of patient tumors, and are more prevalent (32%-44%) in SCLC cell lines

    Increased ASCL1, NEUROD1, and POU2F3 may regulate differentiation of pulmonary neuroendocrine cells which may lead to malignancy.

    Red Triangle

    Misregulation of multiple transcription factors leads to abnormal neuroendocrine development, leading to tumor growth.

ASCL1=achaete-scute-like 1; EGFR=epidermal growth factor receptor; KRAS=Kirsten rat sarcoma virus;
NEUROD1=neurogenic differentiation 1; P53=tumor protein 53; POU2F3=POU Class 2 Homeobox 3; RB=retinoblastoma.

  • Gaps in the characterization of SCLC still remain, and clinical progress lags behind other disease states in discovering targetable pathways3

These select molecular characteristics may contribute to SCLC pathogenesis, and as such, could form the basis of pharmacologic treatment approaches.25,26

NCCN=National Comprehensive Cancer Network® (NCCN®)

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