Cancer, Lung Small Cell (Oat Cell)

Article Author:
Neil Basumallik
Article Editor:
Manuj Agarwal
Updated:
2/14/2019 7:56:38 AM
PubMed Link:
Cancer, Lung Small Cell (Oat Cell)

Introduction

Lung cancer is the second most diagnosed cancer in the United States. It is the leading cause of cancer death in both men and women, accounting for approximately a quarter of all cancer deaths. Lung cancer is histologically divided into 2 main types: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). SCLC comprises about 15% of lung cancer while NSCLC comprises approximately 85%. Since the late 1980s, there has been a decline in the incidence of lung cancer coincident with a decline in smoking, the leading cause of lung cancer. Current treatments include surgery, chemotherapy, radiotherapy, and immunotherapy. The high incidence and prevalence of lung cancer provide a foundation for new insights into the role of public health interventions, genetics, and novel treatment modalities.[1][2][3]

Etiology

Smoking is the leading cause of lung cancer, accounting for 85% of cases. Additional risk factors for lung cancer include second-hand smoke, asbestos, radon, and other environmental factors. Smoking is associated with all types of lung cancer. However, the strongest associations are with SCLC and squamous cell lung cancer.

Cigarette smoke contains many organic and inorganic carcinogens including polycyclic aromatic hydrocarbons (PAHs), aromatic amines, N-nitrosamines, benzene, vinyl chloride, arsenic, and chromium among many others. There is a dose-dependent relationship between the degree of smoke exposure and the relative risk of lung cancer. The dosage of smoke depends on the type of cigarette, duration of inhalation, and presence of a filter.[4][5]

Epidemiology

Lung cancer is the leading cause of cancer death worldwide killing approximately 1.5 million people in 2012. In the United States, there are over 200,000 new cases per year and over 150,000 deaths per year attributed to lung cancer. SCLC comprises about 15% of cases.

Smoking is strongly associated with developing lung cancer and particularly with SCLC. The relative incidence of SCLC has decreased over the last 4 decades reflecting decreases in smoking prevalence, changes to cigarettes, and reduced occupational hazards.

There is a higher incidence of SCLC in males. However, the incidence gap between males and females has narrowed over the past 3 decades. Caucasians have had a higher incidence of SCLC than African Americans. Survival gaps between races and socioeconomic status (SES) have narrowed since 1983.

From 1983 to 2012, median survival and overall survival of SCLC patients have remained stable. Five-year survival rates have increased from 4.9% (1983 through 1993) to 6.4% (2002 through 2012). Median survival has remained stable at 7 months. Relative survival rates (RSRs) have remained stable. However, there have been greater survival improvements in younger patient groups.[6]

Pathophysiology

SCLC is divided into the 2 subtypes: oat cell carcinoma and combined-SCLC. Combined SCLC is defined as SCLC with non-small cell components such as squamous cell or adenocarcinoma.

SCLC carcinogenesis can occur by various pathways that disrupt normal DNA repair mechanisms. Common mutations in SCLC include loss of RB1 tumor suppressor gene and TP53(17p13) mutations which decrease the pro-apoptotic activity of cancer cells. Almost all SCLC tumors have a deletion in a section of the short arm of chromosome 3p which contains the tumor suppressor gene FHIT. [7][8]

Histopathology

According to the World Health Organization (WHO) Classification of Tumors, “SCLC is defined by light microscopy as a tumor with cells that have a small size, a round-to-fusiform shape, scant cytoplasm, finely granular nuclear chromatin and absent or inconspicuous nucleoli.” Necrosis may be extensive, and cells manifest a high mitotic rate. SCLCs originate from epithelial cells, and up to 90% will express thyroid transcription factor-1 (TTF1). Epithelial cell markers including cytokeratin can be used to distinguish SCLC from lymphoma and other neuroendocrine tumors.

History and Physical

A presenting patient is usually a male, older than 70, and a current or former smoker. Patients often have multiple cardiovascular or pulmonary comorbidities.

SCLC typically occurs in the central airways and is often aggressive with a short doubling time and high mitotic rate. Symptoms are usually rapid-onset and begin 8 to 12 weeks before presentation. Signs and symptoms depend on the location and bulk of the primary tumor. They may include a cough, wheezing, and hemoptysis. Local intrathoracic tumor growth can affect the superior vena cava (resulting in superior vena cava syndrome), chest wall, or esophagus. Extrapulmonary distant spread can present with neurological problems, recurrent nerve pain, fatigue, and anorexia. Nearly 60% of patients present with metastatic disease. Most common sites of metastases include the brain, liver, adrenal glands, bone, and bone marrow. If left untreated, SCLC is characterized by rapid tumor progression with a median survival of 2 to 4 months.

SCLC is the most common solid tumor to cause paraneoplastic syndromes. Paraneoplastic syndromes are caused by ectopic hormone production or immune-mediated tissue destruction.

The most common paraneoplastic syndromes include:

  • SIADH (syndrome of inappropriate antidiuresis) in 15% to 40% of patients. This may present as weakness, dysgeusia, and clinical euvolemia.
  • Ectopic Cushing syndrome in 2% to 5% of patients. Production of ectopic corticotropin (ACTH) resulting in elevated free cortisol levels. Can present with edema, proximal myopathy, and hypokalemic alkalosis.
  • Lambert-Eaton Myasthenic syndrome in 3% of patients. This presents as a weakness of proximal arms and legs, relieved temporarily after exercise. Can involve autonomic nervous system.

Evaluation

Lung cancer should always be considered in a smoker or former smoker who presents with new onset cough or hemoptysis. It is important to compare new imaging with prior imaging, noting any changes. Patient’s suspected of having lung cancer will undergo an extensive imaging workup and biopsy for diagnosis with most patients being diagnosed based on small biopsy and cytology specimens.[9][10][11]

Initial imaging workup includes plain film radiography and contrast-enhanced computed tomography (CT) scans of the chest and upper abdomen, brain MRI and PET/CT.

Laboratory studies ordered to evaluate for the presence of neoplastic syndromes include complete blood count (CBC), electrolytes, calcium, alkaline phosphatase, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), total bilirubin, and creatinine.

The method of attaining tissue depends on tumor location. A biopsy is typically obtained via CT-guided biopsy or transbronchial.

Treatment / Management

Treatment is highly dependent on stage. Patients with limited-stage SCLC are candidates for curative-intent radiation therapy and chemotherapy. Patients with extensive-stage disease are treated with chemotherapy with radiation (RT) reserved for select candidates and palliation.[12][13]

Limited Stage

While the majority of patients present with locally advanced disease, a small minority may present with T1-2N0 disease. These patients may be candidates for lobectomy with mediastinal sampling or dissection. If surgery demonstrates mediastinal nodal involvement, adjuvant chemoradiation is indicated. If they are not surgical candidates, stereotactic ablative body therapy (SABR) may be employed. Adjuvant cisplatin-based systemic therapy typically follows both local approaches.

The remainder of limited stage patients is treated with concurrent chemotherapy and radiation. Cisplatin and etoposide is the current standard of care. The addition of radiation to chemotherapy significantly increases local control and overall survival. The early incorporation of RT with CT has been shown to further increase overall survival compared to late incorporation. Prophylactic cranial irradiation (PCI) is indicated for patients with a complete or partial response to therapy. PCI significantly increases overall survival and decreases the incidence of brain metastases.[14][15]

Extensive Stage

The mainstay of therapy for patients with the extensive stage is systemic chemotherapy. Patients who have a complete or partial response to therapy can be evaluated for consolidative thoracic RT. This therapy has been associated with an increase in overall survival and is typically well tolerated. PCI is also indicated for ES and has been associated with an increase in survival with a decrease in brain metastases incidence. There is currently no role for the addition of consolidation radiation to limited volume metastatic sites.

Novel agents for SCLC are currently under investigation and include immunotherapies and targeted therapies previously approved for NSCLC and other malignancies. Immunotherapies include immune checkpoint inhibitors Nivolumab (PD-1 inhibitor antibody), Pembrolizumab (anti-PD1 antibody), Ipilimumab (CTLA-4 inhibitor antibody). Targeted therapies in clinical trials include Rovalpituzumab tesirine (Delta-like protein three antibody-drug conjugate).[16]

Differential Diagnosis

  • Hamartoma
  • Granuloma
  • Lymphoma
  • Non small cell lung cancer
  • Carcinoid

Staging

SCLC is distinguished according to the Veterans Administration Lung Cancer Study Group staging system into Limited Disease (LD) and Extensive Disease (ED). The main criteria for determining LD and ED are whether a reasonable radiation plan can safely encompass disease extent. Two-thirds of patients present with extensive stage or metastatic disease.

TNM staging is useful for patients who are candidates for surgical resection, clinical research, and cancer registries.

Complications

The majority of complications are from the lung cancer itself or chemotherapy and radiation. 

Patients may also develop paraneoplastic syndromes like hypercalcemia, myasthenia gravis like symptoms and SIADH.

Consultations

  • Pulmonologist
  • Thoracic Surgeon
  • Oncologist
  • Cardiologist
  • Intensivist

Deterrence and Patient Education

Discontinue smoking

Pearls and Other Issues

Lung cancer is the second most diagnosed cancer in the United States.

It is the leading cause of cancer death in both men and women, accounting for approximately a quarter of all cancer deaths.

Lung cancer is histologically divided into 2 main types: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC).

Treatment is highly dependent on stage. Patients with limited-stage SCLC are candidates for curative-intent radiation therapy and chemotherapy.

Patients with extensive-stage disease are treated with chemotherapy with radiation (RT) reserved for select candidates and palliation.

Enhancing Healthcare Team Outcomes

Because small cell lung cancer has a very poor prognosis, the emphasis today is on screening and prevention. The role of the pharmacist and nurse is indispensable as they are always the first and last to see these patients. There is ample evidence that cessation of smoking can decrease the incidence of small cell cancer. The pharmacist has several antismoking aids that can be recommended to these patients. Early evidence shows that the rates of smoking have started to decline in males; but unfortunately for females, the reverse is true.

The role of screening for lung cancer is debatable and only approved for people with several risk factors like smokers, family history, and workers in the asbestos industry.[17] (Level III)

Evidence-Based Outcomes

Close to 70% of patients with small cell lung cancer have disseminated disease at the time of presentation.  At this stage, the cancer is not curable, and the prognosis is poor. Even with chemotherapy, the majority of patients are dead within 24 months, and less than 2% are alive at five years. For individuals with localized lung disease, treatment with chemotherapy and radiation does offer a better survival of 80% at two years, but less than 15% are alive at five years. [18][19][20](Level 2) Factors that affect survival include:

  • Loss of body weight more than 10% of baseline
  • Hyponatremia
  • Disease recurrence
  • Poor performance status

References

[1] Ju MH,Kim HR,Kim JB,Kim YH,Kim DK,Park SI, Surgical outcomes in small cell lung cancer. The Korean journal of thoracic and cardiovascular surgery. 2012 Feb     [PubMed PMID: 22363907]
[2] Travis WD, Update on small cell carcinoma and its differentiation from squamous cell carcinoma and other non-small cell carcinomas. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2012 Jan     [PubMed PMID: 22214967]
[3] Wilcox HB,Al-Zoughool M,Garner MJ,Jiang H,Klotz JB,Krewski D,Nicholson WJ,Schoenberg JB,Villeneuve PJ,Zielinski JM, Case-control study of radon and lung cancer in New Jersey. Radiation protection dosimetry. 2008     [PubMed PMID: 17611199]
[4] Parent ME,Siemiatycki J,Renaud G, Case-control study of exposure to carbon black in the occupational setting and risk of lung cancer. American journal of industrial medicine. 1996 Sep     [PubMed PMID: 8876796]
[5] Bhimji SS,Wallen JM, Cancer, Lung, Adenocarcinoma null. 2018 Jan     [PubMed PMID: 30137862]
[6] Rybarczyk-Kasiuchnicz A,Ramlau R, Current views on molecularly targeted therapy for lung cancer - a review of literature from the last five years. Kardiochirurgia i torakochirurgia polska = Polish journal of cardio-thoracic surgery. 2018 Jun     [PubMed PMID: 30069193]
[7] Oh IJ,Hur JY,Park CK,Kim YC,Kim SJ,Lee MK,Kim HJ,Lee KY,Lee JC,Choi CM, Clinical Activity of Pan-HER Inhibitors Against HER2-Mutant Lung Adenocarcinoma. Clinical lung cancer. 2018 Sep     [PubMed PMID: 30149884]
[8] Moon SH,Kim J,Joung JG,Cha H,Park WY,Ahn JS,Ahn MJ,Park K,Choi JY,Lee KH,Kim BT,Lee SH, Correlations between metabolic texture features, genetic heterogeneity, and mutation burden in patients with lung cancer. European journal of nuclear medicine and molecular imaging. 2018 Aug 25     [PubMed PMID: 30145701]
[9] Morita S,Suda T,Oda C,Kobayashi M,Hoshi T,Kanefuji T,Yagi K,Hasegawa G,Terai S, The Value of {sup}18{/sup}F-FDG PET in the Diagnosis of Intertrabecular Vertebral Metastasis in a Small Cell Lung Cancer Patient with a High Serum CEA Level. Internal medicine (Tokyo, Japan). 2018 Aug 24     [PubMed PMID: 30146594]
[10] Duffy MJ,O'Byrne K, Tissue and Blood Biomarkers in Lung Cancer: A Review. Advances in clinical chemistry. 2018     [PubMed PMID: 30144837]
[11] Iqbal MA,Arora S,Prakasam G,Calin GA,Syed MA, MicroRNA in lung cancer: role, mechanisms, pathways and therapeutic relevance. Molecular aspects of medicine. 2018 Aug 17     [PubMed PMID: 30102929]
[12] Eze C,Roengvoraphoj O,Schmidt-Hegemann NS,Käsmann L,Dantes M,Manapov F, Chemoradiotherapy of stage III small cell lung cancer: can we further optimize multimodal treatment of N3 disease based on current evidence? The clinical respiratory journal. 2018 Aug 3     [PubMed PMID: 30073781]
[13] Dickhoff C,Rodriguez Schaap PM,Otten RHJ,Heymans MW,Heineman DJ,Dahele M, Salvage surgery for local recurrence after stereotactic body radiotherapy for early stage non-small cell lung cancer: a systematic review. Therapeutic advances in medical oncology. 2018     [PubMed PMID: 30023008]
[14] Qin J,Lu H, Combined small-cell lung carcinoma. OncoTargets and therapy. 2018     [PubMed PMID: 29950855]
[15] Mitin T,Jain A,Degnin C,Chen Y,Henderson M,Thomas CR Jr, Current patterns of care for patients with extensive stage small cell lung cancer: Survey of US radiation oncologists on their recommendations regarding thoracic consolidation radiotherapy. Lung cancer (Amsterdam, Netherlands). 2016 Oct     [PubMed PMID: 27597285]
[16] Kalemkerian GP, Running in Place: The 20th Anniversary of the NCCN Small Cell Lung Cancer Guidelines Panel. Journal of the National Comprehensive Cancer Network : JNCCN. 2015 Jun     [PubMed PMID: 26085385]
[17] Kalemkerian GP,Akerley W,Bogner P,Borghaei H,Chow LQ,Downey RJ,Gandhi L,Ganti AK,Govindan R,Grecula JC,Hayman J,Heist RS,Horn L,Jahan T,Koczywas M,Loo BW Jr,Merritt RE,Moran CA,Niell HB,O'Malley J,Patel JD,Ready N,Rudin CM,Williams CC Jr,Gregory K,Hughes M, Small cell lung cancer. Journal of the National Comprehensive Cancer Network : JNCCN. 2013 Jan 1     [PubMed PMID: 23307984]
[18] Sone H,Igawa S,Kasajima M,Ishihara M,Hiyoshi Y,Hosotani S,Ohe S,Ito H,Kaizuka N,Manaka H,Fukui T,Mitsufuji H,Kubota M,Katagiri M,Sasaki J,Naoki K, Amrubicin monotherapy for elderly patients with relapsed extensive-disease small-cell lung cancer: A retrospective study. Thoracic cancer. 2018 Aug 20     [PubMed PMID: 30126051]
[19] Engelhardt KE,Feinglass JM,DeCamp MM,Bilimoria KY,Odell DD, Treatment trends in early-stage lung cancer in the United States, 2004 to 2013: A time-trend analysis of the National Cancer Data Base. The Journal of thoracic and cardiovascular surgery. 2018 Sep     [PubMed PMID: 30119287]
[20] Nakamura M,Onozawa M,Motegi A,Hojo H,Zenda S,Nakamura N,Udagawa H,Kirita K,Matsumoto S,Umemura S,Yoh K,Niho S,Goto K,Akimoto T, Impact of prophylactic cranial irradiation on pattern of brain metastases as a first recurrence site for limited-disease small-cell lung cancer. Journal of radiation research. 2018 Aug 9     [PubMed PMID: 30102326]