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Revision as of 22:33, 28 February 2018

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dildar Hussain, MBBS [2]

Obstructive lung disease DD

Obstructive lung disease

Diseases Clinical manifestations Diagnosis
Symptoms Signs Lab findings PFT Imaging Gold standard Other features
Cough Dyspnea Hemoptysis Fever Weight loss Cyanosis Clubbing JVD Peripheral edema Auscultation ABGs FEV1/FVC TLC DLCO
CXR CT scan Other tests
Asthma Stable Asthma + +
  • Normal

FEV1:FVC

=<0.7

  • Normal/↑
  • Pulmonary hyperinflation
  • Extensive air trapping[1]
Associated with:
  • Allergic rhinitis
  • GERD and obesity can mimic asthma
Status Asthmaticus + + - ± - - - + -
  • Wheeze
  • Absent or ↓Breath sounds
  • ↑TLC
  • ↑Glucose
  • ↑PCO2
  • ↓PO2
  • ↓FEV1:FVC
  • < 30% of predictive value
  • ↑TLC
  • ↑DLCO
  • Pulmonary hyperinflation
  • Atypical presentation
-
  • Peak expiratory flow<50% of baseline
  • Clinical diagnosis
  • Pulses paradoxus
COPD Chronic bronchitis + + ± +
  • Normal
  • ↓FEV1
  • Normal
  • Thickening of the bronchial walls in the lower lobes
  • Thickening of the bronchial walls in the lower lobes[2]
Microbiological testing is done in cases of:
  • Influenza
  • Pertusis
  • Clinical diagnosis
  • Chest radiograph
  • Secondary to URTI
Emphysema + + + + + +
  • Expiratory wheeze
  • Hyperinflation
  • ↓alpha-1 antitrypsin deficency
  • Respiratory alkalosis
  • Metabolic acidosis
  • ↓FEV1
  • Flattening of the diaphragm
  • Vertical heart
  • Small subpleural collections of gas
  • Centriacinar emphysema
  • Panacinar emphysema
  • Paraseptal emphysema
  • Pulse oximetry
  • Physical Exam
  • Spirometery
  • Barrel Chest
Bronchiolitis + + +
  • Wheeze
  • Crackles
  • Normal
  • Bronchovascular markings
  • Air trapping
  • Bronchial wall thickening
  • Bronchoscopy
  • Lung biopsy
  • Thoracoscopic lung biopsy

Can be associated with:

  • Organ transplantation
Bronchiectasis  + + + + + +
  • Rhonci
  • Wheeze
  • Crackles
  • ↑Neutrophils
  • ↓FEV1:FVC
  • Tram track opacities
  • Signet-ring sign
  • Airway dilation
  • Flexible bronchoscopy
  • Chronic productive cough
Heart failure + + + + +
  • S3 gallop
  • Wheeze
  • Rales
  • Respiratory alkalosis
  • Normal
  • Normal
  • MRI
  • Cardiac catheterization
  • Exercise testing
  • Ambulatory ECG monitoring
Tuberculosis + + + + +
  • Diminished breath sounds
  • Rhonci/wheeze
  • Upper lobe infiltrate
  • Upper lobe cavitation
  • Hilar adenopathy
  • Solitary nodules
  • Pleural effusion
  • Mediastinal lymphadenopathy
  • Fibrotic leisons
  • Distortion of the lung parenchyma
  • Centrilobular 2 to 4 mm nodules
  • Branching linear lesions
  • Patchy small lower lobe infiltrates
Lymphangioleiomyomatosis + + +(<5%) - - - +(rare) - +
  • Wheeze
  • Hyperinflation
  • Absent or ↓Breath sounds
  • ↑Vascular endothelial growth factor-D
  • Respiratory acidosis in severe disease
  • ↓FEV1:FVC
  • Normal
  • ↓DLCO
  • Ground glass appearance
  • Interstetial pulmonary edema
  • Septal thickening
  • Pulmonary cyst
  • Pnuemothorax
  • Pleural masses
  • Pleural thickening
  • Mediastianl lymphadenopathy
  • Pleural effusion
  • VQ Scan
  • PET Scan
  • Advanced lymphatic imaging
  • Surgical lung biopsy
  • Chylothorax(most common lymphatic manifestation)
  • Chyloperitonium
  • Renalangiomyolipoma
Cystic fibrosis + + + + - + + - -
  • Crackles
  • Sweat Chloride test: >60 mEq/L
  • ↑PCO2
  • ↓PO2
  • ↓FEV1:FVC
  • ↑TLC
  • ↓ In severe lung impairment[3]

SCLC

SCLC accounts for approximately 15% of bronchogenic carcinomas.

At the time of diagnosis, approximately 30% of patients with SCLC will have tumors confined to the hemithorax of origin, the mediastinum, or the supraclavicular lymph nodes. These patients are designated as having limited-stage disease (LD).[1] Patients with tumors that have spread beyond the supraclavicular areas are said to have extensive-stage disease (ED).

SCLC is more responsive to chemotherapy and radiation therapy than other cell types of lung cancer; however, a cure is difficult to achieve because SCLC has a greater tendency to be widely disseminated by the time of diagnosis.

Incidence and Mortality The overall incidence and mortality rates of SCLC in the United States have decreased during the past few decades.[2]

Estimated new cases and deaths from lung cancer (SCLC and non-small cell lung cancer [NSCLC] combined) in the United States in 2018:[3]

New cases: 234,030. Deaths: 154,050. Risk Factors Increasing age is the most important risk factor for most cancers. Other risk factors for lung cancer include:

Current or history of tobacco use: cigarettes, pipes, and cigars.[4] Exposure to cancer-causing substances in secondhand smoke.[5,6] Occupational exposure to asbestos, arsenic, chromium, beryllium, nickel, and other agents.[7] Radiation exposure from any of the following: Radiation therapy to the breast or chest.[8] Radon exposure in the home or workplace.[9] Medical imaging tests, such as computed tomography (CT) scans.[10] Atomic bomb radiation.[11] Living in an area with air pollution.[12-14] Family history of lung cancer.[15] Human immunodeficiency virus infection.[16] Beta carotene supplements in heavy smokers.[17,18] Clinical Features Lung cancer may present with symptoms or be found incidentally on chest imaging. Symptoms and signs may result from the location of the primary local invasion or compression of adjacent thoracic structures, distant metastases, or paraneoplastic phenomena. The most common symptoms at presentation are worsening cough, shortness of breath, and dyspnea. Other presenting symptoms include the following:

Chest pain. Hoarseness. Malaise. Anorexia. Weight loss. Hemoptysis. Symptoms may result from local invasion or compression of adjacent thoracic structures, such as compression involving the esophagus causing dysphagia, compression involving the laryngeal nerves causing hoarseness, or compression involving the superior vena cava causing facial edema and distension of the superficial veins of the head and neck. Symptoms from distant metastases may also be present and include neurological defect or personality change from brain metastases or pain from bone metastases.

Infrequently, patients with SCLC may present with symptoms and signs of one of the following paraneoplastic syndromes:

Inappropriate antidiuretic hormone secretion. Cushing syndrome from secretion of adrenocorticotropic hormone. Paraneoplastic cerebellar degeneration. Lambert-Eaton myasthenic syndrome.[2] Physical examination may identify enlarged supraclavicular lymphadenopathy, pleural effusion or lobar collapse, unresolved pneumonia, or signs of associated disease such as chronic obstructive pulmonary disease.

Diagnosis Treatment options for patients are determined by histology, stage, and general health and comorbidities of the patient. Investigations of patients with suspected SCLC focus on confirming the diagnosis and determining the extent of the disease.

The procedures used to determine the presence of cancer include the following:

History. Physical examination. Routine laboratory evaluations. Chest x-ray. Chest CT scan with infusion of contrast material. Biopsy. Before a patient begins lung cancer treatment, an experienced lung cancer pathologist must review the pathologic material. This is critical because SCLC, which responds well to chemotherapy and is generally not treated surgically, can be confused on microscopic examination with NSCLC.[19] Immunohistochemistry and electron microscopy are invaluable techniques for diagnosis and subclassification, but most lung tumors can be classified by light microscopic criteria.

(Refer to the Staging Evaluation section in the Stage Information for SCLC section of this summary for more information about tests and procedures used for staging.)

Prognosis and Survival Regardless of stage, the current prognosis for patients with SCLC is unsatisfactory despite improvements in diagnosis and therapy made during the past 25 years. Without treatment, SCLC has the most aggressive clinical course of any type of pulmonary tumor, with median survival from diagnosis of only 2 to 4 months. About 10% of the total population of SCLC patients remains free of disease during the 2 years from the start of therapy, which is the time period during which most relapses occur. Even these patients, however, are at risk of dying from lung cancer (both small and non-small cell types).[20] The overall survival at 5 years is 5% to 10%.[1,20-22]

An important prognostic factor for SCLC is the extent of disease. Patients with LD have a better prognosis than patients with ED. For patients with LD, median survival of 16 to 24 months and 5-year survivals of 14% with current forms of treatment have been reported.[1,21,23,24] Patients diagnosed with LD who smoke should be encouraged to stop smoking before undergoing combined-modality therapy because continued smoking may compromise survival.[25]

Improved long-term survival in patients with LD has been shown with combined-modality therapy.[24,26][Level of evidence: 1iiA] Although long-term survivors have been reported among patients who received either surgery or chemotherapy alone, chemotherapy combined with thoracic radiation therapy (TRT) is considered the standard of care.[27] Adding TRT increases absolute survival by approximately 5% over chemotherapy alone.[26,28] The optimal timing of TRT relative to chemotherapy has been evaluated in multiple trials and meta-analyses with the weight of evidence suggesting a small benefit to early TRT.[1,29,30][Level of evidence: 1iiA]

In patients with ED, median survival of 6 to 12 months is reported with currently available therapy, but long-term disease-free survival is rare.

Prophylactic cranial radiation prevents central nervous system recurrence and can improve survival in patients with good performance status who have had a complete response or a very good partial response to chemoradiation in LD or chemotherapy in ED.[31,32][Level of evidence: 1iiA]

Thoracic radiation may also improve long-term outcomes for these patients.[33]

All patients with this type of cancer may appropriately be considered for inclusion in clinical trials at the time of diagnosis. Information about ongoing clinical trials is available from the NCI website.

References Murray N, Coy P, Pater JL, et al.: Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 11 (2): 336-44, 1993. [PUBMED Abstract] Govindan R, Page N, Morgensztern D, et al.: Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol 24 (28): 4539-44, 2006. [PUBMED Abstract] American Cancer Society: Cancer Facts and Figures 2018. Atlanta, Ga: American Cancer Society, 2018. Available onlineExit Disclaimer. Last accessed January 5, 2018. Alberg AJ, Ford JG, Samet JM, et al.: Epidemiology of lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 132 (3 Suppl): 29S-55S, 2007. [PUBMED Abstract] Tulunay OE, Hecht SS, Carmella SG, et al.: Urinary metabolites of a tobacco-specific lung carcinogen in nonsmoking hospitality workers. Cancer Epidemiol Biomarkers Prev 14 (5): 1283-6, 2005. [PUBMED Abstract] Anderson KE, Kliris J, Murphy L, et al.: Metabolites of a tobacco-specific lung carcinogen in nonsmoking casino patrons. Cancer Epidemiol Biomarkers Prev 12 (12): 1544-6, 2003. [PUBMED Abstract] Straif K, Benbrahim-Tallaa L, Baan R, et al.: A review of human carcinogens--part C: metals, arsenic, dusts, and fibres. Lancet Oncol 10 (5): 453-4, 2009. [PUBMED Abstract] Friedman DL, Whitton J, Leisenring W, et al.: Subsequent neoplasms in 5-year survivors of childhood cancer: the Childhood Cancer Survivor Study. J Natl Cancer Inst 102 (14): 1083-95, 2010. [PUBMED Abstract] Gray A, Read S, McGale P, et al.: Lung cancer deaths from indoor radon and the cost effectiveness and potential of policies to reduce them. BMJ 338: a3110, 2009. [PUBMED Abstract] Berrington de González A, Kim KP, Berg CD: Low-dose lung computed tomography screening before age 55: estimates of the mortality reduction required to outweigh the radiation-induced cancer risk. J Med Screen 15 (3): 153-8, 2008. [PUBMED Abstract] Shimizu Y, Kato H, Schull WJ: Studies of the mortality of A-bomb survivors. 9. Mortality, 1950-1985: Part 2. Cancer mortality based on the recently revised doses (DS86). Radiat Res 121 (2): 120-41, 1990. [PUBMED Abstract] Katanoda K, Sobue T, Satoh H, et al.: An association between long-term exposure to ambient air pollution and mortality from lung cancer and respiratory diseases in Japan. J Epidemiol 21 (2): 132-43, 2011. [PUBMED Abstract] Cao J, Yang C, Li J, et al.: Association between long-term exposure to outdoor air pollution and mortality in China: a cohort study. J Hazard Mater 186 (2-3): 1594-600, 2011. [PUBMED Abstract] Hales S, Blakely T, Woodward A: Air pollution and mortality in New Zealand: cohort study. J Epidemiol Community Health 66 (5): 468-73, 2012. [PUBMED Abstract] Lissowska J, Foretova L, Dabek J, et al.: Family history and lung cancer risk: international multicentre case-control study in Eastern and Central Europe and meta-analyses. Cancer Causes Control 21 (7): 1091-104, 2010. [PUBMED Abstract] Shiels MS, Cole SR, Kirk GD, et al.: A meta-analysis of the incidence of non-AIDS cancers in HIV-infected individuals. J Acquir Immune Defic Syndr 52 (5): 611-22, 2009. [PUBMED Abstract] The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med 330 (15): 1029-35, 1994. [PUBMED Abstract] Omenn GS, Goodman GE, Thornquist MD, et al.: Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 334 (18): 1150-5, 1996. [PUBMED Abstract] Travis WD, Colby TV, Corrin B, et al.: Histological typing of lung and pleural tumours. 3rd ed. Berlin: Springer-Verlag, 1999. Johnson BE, Grayson J, Makuch RW, et al.: Ten-year survival of patients with small-cell lung cancer treated with combination chemotherapy with or without irradiation. J Clin Oncol 8 (3): 396-401, 1990. [PUBMED Abstract] Fry WA, Menck HR, Winchester DP: The National Cancer Data Base report on lung cancer. Cancer 77 (9): 1947-55, 1996. [PUBMED Abstract] Lassen U, Osterlind K, Hansen M, et al.: Long-term survival in small-cell lung cancer: posttreatment characteristics in patients surviving 5 to 18+ years--an analysis of 1,714 consecutive patients. J Clin Oncol 13 (5): 1215-20, 1995. [PUBMED Abstract] Turrisi AT 3rd, Kim K, Blum R, et al.: Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 340 (4): 265-71, 1999. [PUBMED Abstract] Jänne PA, Freidlin B, Saxman S, et al.: Twenty-five years of clinical research for patients with limited-stage small cell lung carcinoma in North America. Cancer 95 (7): 1528-38, 2002. [PUBMED Abstract] Videtic GM, Stitt LW, Dar AR, et al.: Continued cigarette smoking by patients receiving concurrent chemoradiotherapy for limited-stage small-cell lung cancer is associated with decreased survival. J Clin Oncol 21 (8): 1544-9, 2003. [PUBMED Abstract] Pignon JP, Arriagada R, Ihde DC, et al.: A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 327 (23): 1618-24, 1992. [PUBMED Abstract] Chandra V, Allen MS, Nichols FC 3rd, et al.: The role of pulmonary resection in small cell lung cancer. Mayo Clin Proc 81 (5): 619-24, 2006. [PUBMED Abstract] Warde P, Payne D: Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A meta-analysis. J Clin Oncol 10 (6): 890-5, 1992. [PUBMED Abstract] Perry MC, Eaton WL, Propert KJ, et al.: Chemotherapy with or without radiation therapy in limited small-cell carcinoma of the lung. N Engl J Med 316 (15): 912-8, 1987. [PUBMED Abstract] Takada M, Fukuoka M, Kawahara M, et al.: Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: results of the Japan Clinical Oncology Group Study 9104. J Clin Oncol 20 (14): 3054-60, 2002. [PUBMED Abstract] Aupérin A, Arriagada R, Pignon JP, et al.: Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med 341 (7): 476-84, 1999. [PUBMED Abstract] Slotman B, Faivre-Finn C, Kramer G, et al.: Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 357 (7): 664-72, 2007. [PUBMED Abstract] Slotman BJ, van Tinteren H, Praag JO, et al.: Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. Lancet 385 (9962): 36-42, 2015. [PUBMED Abstract]

Treatment options

Chemotherapy and radiation therapy have been shown to improve survival for patients with small cell lung cancer (SCLC).

Chemotherapy Chemotherapy improves the survival of patients with limited-stage disease (LD) or extensive-stage disease (ED), but it is curative in only a minority of patients.[1,2] Because patients with SCLC tend to develop distant metastases, localized forms of treatment, such as surgical resection or radiation therapy, rarely produce long-term survival.[3] With incorporation of current chemotherapy regimens into the treatment program, however, survival is prolonged, with at least a fourfold to fivefold improvement in median survival compared with patients who are given no therapy.

The combination of platinum and etoposide is the most widely used standard chemotherapeutic regimen.[4-6][Level of evidence: 1iiA] No consistent survival benefit has resulted from platinum versus nonplatinum combinations, increased dose intensity or dose density, altered mode of administration (e.g., alternating or sequential administration) of various chemotherapeutic agents, or maintenance chemotherapy.[7-12][Level of evidence: 1iiA]

Radiation Therapy SCLC is highly radiosensitive and thoracic radiation therapy improves survival of patients with LD and ED tumors.[13-16][Level of evidence: 1iiA] Prophylactic cranial ir (PCI) prevents central nervous system recurrence and may improve the long-term survival of patients with good performance status who have responded to chemoradiation therapy [17-19][Level of evidence: 1iiA] and offers palliation of symptomatic metastatic disease.

Treatment for patients with LD, ED, or recurrent SCLC is summarized in Table 1.

Table 1. Standard Treatment Options for Patients With SCLC Stage Standard Treatment Options ED = extensive-stage disease; LD = limited stage disease (LD) Chemotherapy and radiation therapy Combination chemotherapy alone Surgery followed by chemotherapy or chemoradiation therapy Prophylactic cranial irradiation (ED) Combination chemotherapy Radiation therapy Prophylactic cranial irradiation Recurrent disease Chemotherapy Palliative therapy Despite treatment advances, most patients with SCLC die of their tumor even with the best available therapy. Most of the improvements in the survival of patients with SCLC are attributable to clinical trials that have attempted to improve on the best available and most accepted therapy. Patient entry into such studies is highly desirable.

Information about ongoing clinical trials is available from the NCI website.

References Comis RL, Friedland DM, Good BC: Small-cell lung cancer: a perspective on the past and a preview of the future. Oncology (Huntingt) 12 (1 Suppl 2): 44-50, 1998. [PUBMED Abstract] Agra Y, Pelayo M, Sacristan M, et al.: Chemotherapy versus best supportive care for extensive small cell lung cancer. Cochrane Database Syst Rev (4): CD001990, 2003. [PUBMED Abstract] Prasad US, Naylor AR, Walker WS, et al.: Long term survival after pulmonary resection for small cell carcinoma of the lung. Thorax 44 (10): 784-7, 1989. [PUBMED Abstract] Johnson BE, Grayson J, Makuch RW, et al.: Ten-year survival of patients with small-cell lung cancer treated with combination chemotherapy with or without irradiation. J Clin Oncol 8 (3): 396-401, 1990. [PUBMED Abstract] Lassen U, Osterlind K, Hansen M, et al.: Long-term survival in small-cell lung cancer: posttreatment characteristics in patients surviving 5 to 18+ years--an analysis of 1,714 consecutive patients. J Clin Oncol 13 (5): 1215-20, 1995. [PUBMED Abstract] Fry WA, Menck HR, Winchester DP: The National Cancer Data Base report on lung cancer. Cancer 77 (9): 1947-55, 1996. [PUBMED Abstract] Ihde DC, Mulshine JL, Kramer BS, et al.: Prospective randomized comparison of high-dose and standard-dose etoposide and cisplatin chemotherapy in patients with extensive-stage small-cell lung cancer. J Clin Oncol 12 (10): 2022-34, 1994. [PUBMED Abstract] Arriagada R, Le Chevalier T, Pignon JP, et al.: Initial chemotherapeutic doses and survival in patients with limited small-cell lung cancer. N Engl J Med 329 (25): 1848-52, 1993. [PUBMED Abstract] Klasa RJ, Murray N, Coldman AJ: Dose-intensity meta-analysis of chemotherapy regimens in small-cell carcinoma of the lung. J Clin Oncol 9 (3): 499-508, 1991. [PUBMED Abstract] Elias AD, Ayash L, Frei E 3rd, et al.: Intensive combined modality therapy for limited-stage small-cell lung cancer. J Natl Cancer Inst 85 (7): 559-66, 1993. [PUBMED Abstract] Murray N, Livingston RB, Shepherd FA, et al.: Randomized study of CODE versus alternating CAV/EP for extensive-stage small-cell lung cancer: an Intergroup Study of the National Cancer Institute of Canada Clinical Trials Group and the Southwest Oncology Group. J Clin Oncol 17 (8): 2300-8, 1999. [PUBMED Abstract] Amarasena IU, Walters JA, Wood-Baker R, et al.: Platinum versus non-platinum chemotherapy regimens for small cell lung cancer. Cochrane Database Syst Rev (4): CD006849, 2008. [PUBMED Abstract] Pignon JP, Arriagada R, Ihde DC, et al.: A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 327 (23): 1618-24, 1992. [PUBMED Abstract] Warde P, Payne D: Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A meta-analysis. J Clin Oncol 10 (6): 890-5, 1992. [PUBMED Abstract] Murray N, Coy P, Pater JL, et al.: Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 11 (2): 336-44, 1993. [PUBMED Abstract] Slotman BJ, van Tinteren H, Praag JO, et al.: Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. Lancet 385 (9962): 36-42, 2015. [PUBMED Abstract] Turrisi AT 3rd, Glover DJ: Thoracic radiotherapy variables: influence on local control in small cell lung cancer limited disease. Int J Radiat Oncol Biol Phys 19 (6): 1473-9, 1990. [PUBMED Abstract] Aupérin A, Arriagada R, Pignon JP, et al.: Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med 341 (7): 476-84, 1999. [PUBMED Abstract] Slotman B, Faivre-Finn C, Kramer G, et al.: Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 357 (7): 664-72, 2007. [PUBMED Abstract]

Limited-Stage SCLC Treatment

Standard Treatment Options for Patients With Limited-Stage SCLC Chemotherapy and radiation therapy Combination chemotherapy alone Surgery followed by chemotherapy or chemoradiation therapy PCI Neurologic sequelae Treatment options for older patients Treatment Options Under Clinical Evaluation Current Clinical Trials Standard Treatment Options for Patients With Limited-Stage SCLC Standard treatment options for patients with limited-stage small-cell lung cancer (SCLC) include the following:

Chemotherapy and radiation therapy. Combination chemotherapy alone. Surgery followed by chemotherapy or chemoradiation therapy. Prophylactic cranial irradiation (PCI). Chemotherapy and radiation therapy Combined-modality treatment with etoposide and cisplatin with thoracic radiation therapy (TRT) is the most widely used treatment for patients with limited-stage disease (LD) SCLC.

Evidence (combined modality treatment):

Survival. The following results have been reported in clinical trials: Mature results of prospective randomized trials suggest that combined-modality therapy produces a modest but significant improvement in survival of 5% at 3 years compared with chemotherapy alone.[1-3][Level of evidence: 1iiA] Clinical trials have consistently achieved median survivals of 18 to 24 months and 40% to 50% 2-year survival rates with less than a 3% treatment-related mortality.[3-7][Level of evidence: 1iiA] No consistent survival benefit has resulted from the following:[8-16] Increased dose intensity. Increased dose density. Administration of additional drugs or other (non–etoposide-containing) platinum-based combination regimens. Altered modes of administration of various chemotherapeutic agents. Maintenance chemotherapy. Length of treatment. The optimal duration of chemotherapy for patients with LD SCLC is not clearly defined, but no improvement exists in survival after the duration of drug administration exceeds 3 to 6 months. The preponderance of evidence available from randomized trials indicates that maintenance chemotherapy does not prolong survival for patients with LD SCLC.[8-15][Level of evidence: 1iiA] Dose and timing. The optimal dose and timing of TRT remain controversial. Multiple clinical trials and meta-analyses addressing the timing of TRT have been published, with the weight of evidence suggesting a small benefit to early TRT (i.e., TRT administered during the first or second cycle of chemotherapy administration).[3-6,8,9,15,17-20][Level of evidence: 1iiA] The amount of time from start to completion of TRT in LD SCLC may also effect overall survival (OS). In an analysis of four trials, the completion of therapy in less than 30 days was associated with an improved 5-year survival rate (relative risk, 0.62; 95% confidence interval, 0.49–0.80; P = .0003).[20][Level of evidence: 1iiA] Both once-daily and twice-daily chest radiation schedules have been used in regimens with etoposide and cisplatin. One randomized study showed a modest survival advantage in favor of twice-daily radiation therapy given for 3 weeks compared with once-daily radiation therapy to 45 Gy given for 5 weeks (26% vs. 16% at 5 years; P = .04).[17][Level of evidence: 1iiA] Esophagitis was increased with twice-daily treatment. Twice-daily radiation therapy has not been broadly adopted. Once-daily fractions to higher doses of greater than 60 Gy are feasible and commonly used; their clinical benefits are yet to be defined in phase III trials.[21-25][Level of evidence: 3iiiA] Combination chemotherapy alone Patients with a contraindication to radiation therapy could be treated with chemotherapy alone. Patients presenting with superior vena cava syndrome are treated immediately with combination chemotherapy, radiation therapy, or both, depending on the severity of presentation.[26,27] (Refer to the PDQ summary on Cardiopulmonary Syndromes for more information.)

Surgery followed by chemotherapy or chemoradiation therapy The role of surgery in the management of patients with SCLC is unproven. Small case series and population studies have reported favorable outcomes for the minority of LD patients with very limited disease, with small tumors pathologically confined to the lung of origin or the lung and ipsilateral hilar lymph nodes from surgical resection with adjuvant chemotherapy.[28-32][Level of evidence: 3iiiDii] Patients who have undergone surgery and then been diagnosed with SCLC generally receive adjuvant chemotherapy with or without radiation therapy. In patients who receive chemotherapy with radiation therapy, there is no improvement in survival with the addition of surgery.[32][Level of evidence: 3iiiDii] Given the absence of data from randomized trials, the role of surgery in the management of individual patients with SCLC must be considered, both in terms of potential benefit and risk from the surgical procedure.

Evidence (role of surgery):

A randomized study evaluating the role of surgery in addition to chemoradiation therapy enrolled 328 patients with LD SCLC and found no OS benefit with the addition of pulmonary resection.[33][Level of evidence: 1iiA] PCI Patients who have achieved a complete remission can be considered for administration of PCI. Patients whose cancer can be controlled outside the brain have a 60% actuarial risk of developing central nervous system (CNS) metastases within 2 to 3 years after starting treatment.[32,34,35] Most of these patients relapse only in their brain, and nearly all of those who relapse in their CNS die of their cranial metastases. The risk of developing CNS metastases can be reduced by more than 50% with the administration of PCI.[34]

Evidence (role of PCI):

A meta-analysis of seven randomized trials evaluating the value of PCI in patients in complete remission reported improvement in brain recurrence, disease-free survival, and OS with the addition of PCI. The 3-year OS was improved from 15% to 21% with PCI.[34][Level of evidence: 1iiA] A randomized study (RTOG-0212) of 720 patients with LD SCLC in complete remission after chemoradiation therapy demonstrated that standard-dose PCI (25 Gy in 10 fractions) was as effective as and less toxic than higher doses of brain radiation.[36] Randomized trials such as EORTC-22003-08004 (NCT00005062) showed that doses higher than 25 Gy in 10 daily fractions do not improve long-term survival.[36-38] Neurologic sequelae Retrospective studies have shown that long-term survivors of SCLC (>2 years from the start of treatment) have a high incidence of CNS impairment.[32,35,39-41] Prospective studies have shown that patients treated with PCI do not have significantly worse neuropsychological function than patients not treated.[41] Most patients with SCLC have neuropsychological abnormalities present before the start of PCI and have no detectable decline in their neurological status for as long as 2 years after the start of their PCI.[41] Patients treated for SCLC continue to have declining neuropsychologic function after 2 years from the start of treatment.[39-41] Additional neuropsychologic testing of patients beyond 2 years from the start of treatment will be needed before concluding that PCI does not contribute to the decline in intellectual function.

Treatment options for older patients The optimal therapeutic approach in older patients remains unclear. A population analysis showed that increasing age was associated with a decreased performance status and increased comorbidity.[42] Older patients were less likely to be treated with combined chemoradiation therapy, more intensive chemotherapy, and PCI. Older patients were also less likely to respond to therapy and had poorer survival outcomes. Whether this was a result of age and its associated comorbidities or suboptimal treatment delivery remains uncertain.

No specific phase III trial in older patients with LD SCLC has been reported; however, three secondary analyses of two cooperative group trials have been published evaluating outcomes in patients aged 70 years or older.[43-45] The survival outcomes for the older patients were identical to their younger counterparts in both trials. The older patients experienced more toxic effects, particularly hematologic, compared with younger patients. There was a significant increase in treatment-related mortality in the EST-3588 trial that compared etoposide and cisplatin with either once-daily or twice-daily radiation therapy (1% for patients aged <70 years vs. 10% for patients aged ≥70 years; P = .01).[44] Because the older patients enrolled in these phase III trials may not be representative of LD SCLC patients in the general population, caution must be exercised in extrapolating these results to the general population of older patients.

Treatment Options Under Clinical Evaluation Treatment options under clinical evaluation for patients with LD SCLC include the following:

New drug regimens. Surgical resection of the primary tumor. New radiation therapy schedules and techniques (e.g., timing, three-dimensional treatment planning, and dose fractionation). Current Clinical Trials Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References Pignon JP, Arriagada R, Ihde DC, et al.: A meta-analysis of thoracic radiotherapy for small-cell lung cancer. N Engl J Med 327 (23): 1618-24, 1992. [PUBMED Abstract] Warde P, Payne D: Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A meta-analysis. J Clin Oncol 10 (6): 890-5, 1992. [PUBMED Abstract] Murray N, Coy P, Pater JL, et al.: Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 11 (2): 336-44, 1993. [PUBMED Abstract] Turrisi AT 3rd, Glover DJ: Thoracic radiotherapy variables: influence on local control in small cell lung cancer limited disease. Int J Radiat Oncol Biol Phys 19 (6): 1473-9, 1990. [PUBMED Abstract] McCracken JD, Janaki LM, Crowley JJ, et al.: Concurrent chemotherapy/radiotherapy for limited small-cell lung carcinoma: a Southwest Oncology Group Study. J Clin Oncol 8 (5): 892-8, 1990. [PUBMED Abstract] Takada M, Fukuoka M, Kawahara M, et al.: Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: results of the Japan Clinical Oncology Group Study 9104. J Clin Oncol 20 (14): 3054-60, 2002. [PUBMED Abstract] Johnson BE, Bridges JD, Sobczeck M, et al.: Patients with limited-stage small-cell lung cancer treated with concurrent twice-daily chest radiotherapy and etoposide/cisplatin followed by cyclophosphamide, doxorubicin, and vincristine. J Clin Oncol 14 (3): 806-13, 1996. [PUBMED Abstract] Spiro SG, James LE, Rudd RM, et al.: Early compared with late radiotherapy in combined modality treatment for limited disease small-cell lung cancer: a London Lung Cancer Group multicenter randomized clinical trial and meta-analysis. J Clin Oncol 24 (24): 3823-30, 2006. [PUBMED Abstract] De Ruysscher D, Pijls-Johannesma M, Vansteenkiste J, et al.: Systematic review and meta-analysis of randomised, controlled trials of the timing of chest radiotherapy in patients with limited-stage, small-cell lung cancer. Ann Oncol 17 (4): 543-52, 2006. [PUBMED Abstract] Giaccone G, Dalesio O, McVie GJ, et al.: Maintenance chemotherapy in small-cell lung cancer: long-term results of a randomized trial. European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol 11 (7): 1230-40, 1993. [PUBMED Abstract] Goodman GE, Crowley JJ, Blasko JC, et al.: Treatment of limited small-cell lung cancer with etoposide and cisplatin alternating with vincristine, doxorubicin, and cyclophosphamide versus concurrent etoposide, vincristine, doxorubicin, and cyclophosphamide and chest radiotherapy: a Southwest Oncology Group Study. J Clin Oncol 8 (1): 39-47, 1990. [PUBMED Abstract] Fukuoka M, Furuse K, Saijo N, et al.: Randomized trial of cyclophosphamide, doxorubicin, and vincristine versus cisplatin and etoposide versus alternation of these regimens in small-cell lung cancer. J Natl Cancer Inst 83 (12): 855-61, 1991. [PUBMED Abstract] Bleehen NM, Girling DJ, Machin D, et al.: A randomised trial of three or six courses of etoposide cyclophosphamide methotrexate and vincristine or six courses of etoposide and ifosfamide in small cell lung cancer (SCLC). I: Survival and prognostic factors. Medical Research Council Lung Cancer Working Party. Br J Cancer 68 (6): 1150-6, 1993. [PUBMED Abstract] Sculier JP, Paesmans M, Bureau G, et al.: Randomized trial comparing induction chemotherapy versus induction chemotherapy followed by maintenance chemotherapy in small-cell lung cancer. European Lung Cancer Working Party. J Clin Oncol 14 (8): 2337-44, 1996. [PUBMED Abstract] Fried DB, Morris DE, Poole C, et al.: Systematic review evaluating the timing of thoracic radiation therapy in combined modality therapy for limited-stage small-cell lung cancer. J Clin Oncol 22 (23): 4837-45, 2004. [PUBMED Abstract] Kubota K, Hida T, Ishikura S, et al.: Etoposide and cisplatin versus irinotecan and cisplatin in patients with limited-stage small-cell lung cancer treated with etoposide and cisplatin plus concurrent accelerated hyperfractionated thoracic radiotherapy (JCOG0202): a randomised phase 3 study. Lancet Oncol 15 (1): 106-13, 2014. [PUBMED Abstract] Turrisi AT 3rd, Kim K, Blum R, et al.: Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 340 (4): 265-71, 1999. [PUBMED Abstract] Huncharek M, McGarry R: A meta-analysis of the timing of chest irradiation in the combined modality treatment of limited-stage small cell lung cancer. Oncologist 9 (6): 665-72, 2004. [PUBMED Abstract] Pijls-Johannesma MC, De Ruysscher D, Lambin P, et al.: Early versus late chest radiotherapy for limited stage small cell lung cancer. Cochrane Database Syst Rev (1): CD004700, 2005. [PUBMED Abstract] De Ruysscher D, Pijls-Johannesma M, Bentzen SM, et al.: Time between the first day of chemotherapy and the last day of chest radiation is the most important predictor of survival in limited-disease small-cell lung cancer. J Clin Oncol 24 (7): 1057-63, 2006. [PUBMED Abstract] Bogart JA, Herndon JE 2nd, Lyss AP, et al.: 70 Gy thoracic radiotherapy is feasible concurrent with chemotherapy for limited-stage small-cell lung cancer: analysis of Cancer and Leukemia Group B study 39808. Int J Radiat Oncol Biol Phys 59 (2): 460-8, 2004. [PUBMED Abstract] Salama JK, Hodgson L, Pang H, et al.: A pooled analysis of limited-stage small-cell lung cancer patients treated with induction chemotherapy followed by concurrent platinum-based chemotherapy and 70 Gy daily radiotherapy: CALGB 30904. J Thorac Oncol 8 (8): 1043-9, 2013. [PUBMED Abstract] Choi NC, Herndon JE 2nd, Rosenman J, et al.: Phase I study to determine the maximum-tolerated dose of radiation in standard daily and hyperfractionated-accelerated twice-daily radiation schedules with concurrent chemotherapy for limited-stage small-cell lung cancer. J Clin Oncol 16 (11): 3528-36, 1998. [PUBMED Abstract] Miller AA, Wang XF, Bogart JA, et al.: Phase II trial of paclitaxel-topotecan-etoposide followed by consolidation chemoradiotherapy for limited-stage small cell lung cancer: CALGB 30002. J Thorac Oncol 2 (7): 645-51, 2007. [PUBMED Abstract] Kelley MJ, Bogart JA, Hodgson LD, et al.: Phase II study of induction cisplatin and irinotecan followed by concurrent carboplatin, etoposide, and thoracic radiotherapy for limited-stage small-cell lung cancer, CALGB 30206. J Thorac Oncol 8 (1): 102-8, 2013. [PUBMED Abstract] Urban T, Lebeau B, Chastang C, et al.: Superior vena cava syndrome in small-cell lung cancer. Arch Intern Med 153 (3): 384-7, 1993. [PUBMED Abstract] Würschmidt F, Bünemann H, Heilmann HP: Small cell lung cancer with and without superior vena cava syndrome: a multivariate analysis of prognostic factors in 408 cases. Int J Radiat Oncol Biol Phys 33 (1): 77-82, 1995. [PUBMED Abstract] Osterlind K, Hansen M, Hansen HH, et al.: Treatment policy of surgery in small cell carcinoma of the lung: retrospective analysis of a series of 874 consecutive patients. Thorax 40 (4): 272-7, 1985. [PUBMED Abstract] Shepherd FA, Ginsberg RJ, Patterson GA, et al.: A prospective study of adjuvant surgical resection after chemotherapy for limited small cell lung cancer. A University of Toronto Lung Oncology Group study. J Thorac Cardiovasc Surg 97 (2): 177-86, 1989. [PUBMED Abstract] Prasad US, Naylor AR, Walker WS, et al.: Long term survival after pulmonary resection for small cell carcinoma of the lung. Thorax 44 (10): 784-7, 1989. [PUBMED Abstract] Smit EF, Groen HJ, Timens W, et al.: Surgical resection for small cell carcinoma of the lung: a retrospective study. Thorax 49 (1): 20-2, 1994. [PUBMED Abstract] Chandra V, Allen MS, Nichols FC 3rd, et al.: The role of pulmonary resection in small cell lung cancer. Mayo Clin Proc 81 (5): 619-24, 2006. [PUBMED Abstract] Lad T, Piantadosi S, Thomas P, et al.: A prospective randomized trial to determine the benefit of surgical resection of residual disease following response of small cell lung cancer to combination chemotherapy. Chest 106 (6 Suppl): 320S-323S, 1994. [PUBMED Abstract] Nugent JL, Bunn PA Jr, Matthews MJ, et al.: CNS metastases in small cell bronchogenic carcinoma: increasing frequency and changing pattern with lengthening survival. Cancer 44 (5): 1885-93, 1979. [PUBMED Abstract] Aupérin A, Arriagada R, Pignon JP, et al.: Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med 341 (7): 476-84, 1999. [PUBMED Abstract] Le Péchoux C, Dunant A, Senan S, et al.: Standard-dose versus higher-dose prophylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer in complete remission after chemotherapy and thoracic radiotherapy (PCI 99-01, EORTC 22003-08004, RTOG 0212, and IFCT 99-01): a randomised clinical trial. Lancet Oncol 10 (5): 467-74, 2009. [PUBMED Abstract] Le Péchoux C, Laplanche A, Faivre-Finn C, et al.: Clinical neurological outcome and quality of life among patients with limited small-cell cancer treated with two different doses of prophylactic cranial irradiation in the intergroup phase III trial (PCI99-01, EORTC 22003-08004, RTOG 0212 and IFCT 99-01). Ann Oncol 22 (5): 1154-63, 2011. [PUBMED Abstract] Wolfson AH, Bae K, Komaki R, et al.: Primary analysis of a phase II randomized trial Radiation Therapy Oncology Group (RTOG) 0212: impact of different total doses and schedules of prophylactic cranial irradiation on chronic neurotoxicity and quality of life for patients with limited-disease small-cell lung cancer. Int J Radiat Oncol Biol Phys 81 (1): 77-84, 2011. [PUBMED Abstract] Johnson BE, Patronas N, Hayes W, et al.: Neurologic, computed cranial tomographic, and magnetic resonance imaging abnormalities in patients with small-cell lung cancer: further follow-up of 6- to 13-year survivors. J Clin Oncol 8 (1): 48-56, 1990. [PUBMED Abstract] Laukkanen E, Klonoff H, Allan B, et al.: The role of prophylactic brain irradiation in limited stage small cell lung cancer: clinical, neuropsychologic, and CT sequelae. Int J Radiat Oncol Biol Phys 14 (6): 1109-17, 1988. [PUBMED Abstract] Cull A, Gregor A, Hopwood P, et al.: Neurological and cognitive impairment in long-term survivors of small cell lung cancer. Eur J Cancer 30A (8): 1067-74, 1994. [PUBMED Abstract] Ludbrook JJ, Truong PT, MacNeil MV, et al.: Do age and comorbidity impact treatment allocation and outcomes in limited stage small-cell lung cancer? a community-based population analysis. Int J Radiat Oncol Biol Phys 55 (5): 1321-30, 2003. [PUBMED Abstract] Schild SE, Stella PJ, Geyer SM, et al.: The outcome of combined-modality therapy for stage III non-small-cell lung cancer in the elderly. J Clin Oncol 21 (17): 3201-6, 2003. [PUBMED Abstract] Yuen AR, Zou G, Turrisi AT, et al.: Similar outcome of elderly patients in intergroup trial 0096: Cisplatin, etoposide, and thoracic radiotherapy administered once or twice daily in limited stage small cell lung carcinoma. Cancer 89 (9): 1953-60, 2000. [PUBMED Abstract] Siu LL, Shepherd FA, Murray N, et al.: Influence of age on the treatment of limited-stage small-cell lung cancer. J Clin Oncol 14 (3): 821-8, 1996. [PUBMED Abstract]

Extensive-Stage SCLC Treatment

Standard Treatment Options for Patients With Extensive-Stage SCLC Combination chemotherapy Radiation therapy Treatment Options Under Clinical Evaluation Current Clinical Trials Standard Treatment Options for Patients With Extensive-Stage SCLC Standard treatment options for patients with extensive-stage small-cell lung cancer (SCLC) include the following:

Combination chemotherapy. Radiation therapy. Thoracic radiation therapy for patients who respond to chemotherapy. Prophylactic cranial irradiation (PCI). Combination chemotherapy Chemotherapy for patients with extensive-stage disease (ED) SCLC is commonly given as a two-drug combination of platinum and etoposide in doses associated with at least moderate toxic effects (as in limited-stage [LD] SCLC).[1] Cisplatin is associated with significant toxic effects and requires fluid hydration, which can be problematic in patients with cardiovascular disease. Carboplatin is active in SCLC, is dosed according to renal function, and is associated with less nonhematological toxic effects.

Other regimens appear to produce similar survival outcomes but have been studied less extensively or are in less common use.

Table 2. Combination Chemotherapy For Extensive-Stage SCLC Standard treatment Etoposide + cisplatin Etoposide + carboplatin Other regimens Cisplatin + irinotecan Ifosfamide + cisplatin + etoposide Cyclophosphamide + doxorubicin + etoposide Cyclophosphamide + doxorubicin + etoposide + vincristine Cyclophosphamide + etoposide + vincristine Cyclophosphamide + doxorubicin + vincristine Doses and schedules used in current programs yield overall response rates of 50% to 80% and complete response rates of 0% to 30% in patients with ED.[2,3][Level of evidence: 1iiA]

Intracranial metastases from small cell carcinoma may respond to chemotherapy as readily as metastases in other organs.[4,5]

Evidence (standard regimens):

Two meta-analyses evaluating the role of platinum combinations versus nonplatinum combinations have been published. A Cochrane analysis did not identify a difference in 6-, 12-, or 24-month survival.[6] A meta-analysis of 19 trials published between 1981 and 1999 showed a significant survival advantage for patients receiving platinum-based chemotherapy compared with those not receiving a platinum agent.[3][Level of evidence: 1iiA] The Hellenic Oncology Group conducted a phase III trial comparing cisplatin and etoposide with carboplatin plus etoposide.[7] The median survival was 11.8 months in the cisplatin arm and 12.5 months in carboplatin-treated patients.[7][Level of evidence: 1iiA] Although this difference was not statistically significant, the trial was underpowered to prove equivalence of the two treatment regimens in patients with either LD or ED. Evidence (other combination chemotherapy regimens):

Irinotecan. Five trials and two meta-analyses have evaluated the combination of etoposide and cisplatin versus irinotecan and cisplatin. Only one of the trials showed the superiority of the irinotecan and cisplatin combination.[8][Level of evidence: 1iiA] Subsequent trials and the meta-analyses support that the regimens provide equivalent clinical benefit with differing toxicity profiles.[9-14][Level of evidence: 1iiA] Irinotecan and cisplatin regimens led to less grade 3 to 4 anemia, neutropenia, and thrombocytopenia but more grade 3 to 4 vomiting and diarrhea than etoposide and cisplatin regimens. Treatment-related deaths were comparable between the two groups. Topotecan. In a randomized trial of 784 patients, the combination of oral topotecan given with cisplatin for 5 days was not found to be superior to etoposide and cisplatin.[15] The 1-year survival rate was 31% (95% confidence interval [CI], 27%–36%) and was deemed to be noninferior, as the difference of -0.03 met the predefined criteria of no more than 10% absolute difference in 1-year survival.[15][Level of evidence: 1iiA] Paclitaxel. No consistent survival benefit has resulted from the addition of paclitaxel to etoposide and cisplatin.[16,17] Evidence (duration of treatment):

The optimal duration of chemotherapy is not clearly defined, but no obvious improvement in survival occurs when the duration of drug administration exceeds 6 months.[7,18,19] No clear evidence is available from reported data from randomized trials that maintenance chemotherapy will improve survival duration.[20-22][Level of evidence: 1iiA] However, a meta-analysis of 14 published, randomized trials assessing the benefit of duration/maintenance therapy reported an odds ratio of 0.67 for both 1- and 2-year overall survival (OS) of 0.67 (95% CI, 0.56–0.79; P < .001 for 1-year OS and 0.53–0.86; P < .001 for 2-year OS). This corresponded to an increase of 9% in 1-year OS and 4% in 2-year OS.[23][Level of evidence: 1iiA] Evidence (dose intensification):

The role of dose intensification in patients with SCLC remains unclear.[24-28] Early studies showed that under-treatment compromised outcome and suggested that early dose intensification may improve survival.[24,25] A number of clinical trials have examined the use of colony-stimulating factors to support dose-intensified chemotherapy in SCLC.[26-34] These studies have yielded conflicting results. Four studies have shown that a modest increase in dose intensity (25%–34%) was associated with a significant improvement in survival with no compromise in quality of life (QOL).[26-29][Level of evidence: 1iiA] Two of three studies that examined combinations of the variables of interval, dose per cycle, and number of cycles showed no advantage.[29-32][Level of evidence: 1iiA] The European Organization for Research and Treatment of Cancer trial (EORTC-08923) reported a randomized comparison of standard-dose cyclophosphamide, doxorubicin, and etoposide given every 3 weeks for five cycles versus intensified treatment given at 125% of the dose every 2 weeks for four cycles with granulocyte colony-stimulating factor (G-CSF) support.[32] The median dose intensity delivered was 70% higher in the experimental arm; the median cumulative dose was similar in both arms. There was no difference between treatment groups in median or 2-year survival. A randomized, phase III trial compared ifosfamide, cisplatin, and etoposide (ICE), which was given every 4 weeks, with twice weekly ICE with G-CSF and autologous blood support.[33] Despite achieving a relative dose intensity of 1.84 in the dose-accelerated arm, there was no difference in response rate (88% vs. 80%, respectively), median survival (14.4 vs. 13.9 months, respectively), or 2-year survival (19% vs. 22%, respectively) for dose-dense treatment compared with standard treatment.[33][Level of evidence: 1iiA] Patients who received dose-dense treatment spent less time on treatment and had fewer episodes of infection. A randomized, phase II study of identical design reported a significantly better median survival for the dose-dense arm (29.8 vs. 17.4 months, respectively; P = .02) and 2-year survival (62% vs. 36%, respectively; P = .05).[34] However, given the small study size (only 70 patients), these results should be viewed with caution. Factors influencing treatment with chemotherapy Performance status More patients with ED SCLC have greatly impaired performance status at the time of diagnosis than patients with LD. Such patients have a poor prognosis and tolerate aggressive chemotherapy or combined-modality therapy poorly. Single-agent intravenous, oral, and low-dose biweekly regimens have been developed for these patients.[30,35-41]

Prospective, randomized studies have shown that patients with a poor prognosis who are treated with conventional regimens live longer than those treated with the single-agent, low-dose regimens or abbreviated courses of therapy. A study comparing chemotherapy every 3 weeks with treatment given as required for symptom control showed an improvement in QOL in those patients receiving regular treatment.[38][Level of evidence: 1iiDii]

Other studies have tested intensive one-drug or two-drug regimens. A study conducted by the Medical Research Council demonstrated similar efficacy for an etoposide plus vincristine regimen and a four-drug regimen.[39] The latter regimen was associated with a greater risk of toxic effects and early death but was superior with respect to palliation of symptoms and psychological distress.[39][Level of evidence: 1iiC] Studies comparing a convenient oral treatment with single-agent oral etoposide versus combination therapy showed that the overall response rate and OS were significantly worse in the oral etoposide arm.[35,40][Level of evidence: 1iiA]

Age Subgroup analyses of phase II and phase III trials of SCLC patients by age showed that myelosuppression and doxorubicin-induced cardiac toxic effects were more severe in older patients than in younger patients and that the incidence of treatment-related death tended to be higher in older patients.[41] About 80% of older patients, however, received optimal treatment, and their survival was comparable with that of younger patients. The standard chemotherapy regimens for the general population could be applied to older patients in good general condition (i.e., performance status of 0–1, normal organ function, and no comorbidity). There is no evidence of a difference in response rate, disease-free survival (DFS), or OS in older patients compared with younger patients.

Radiation therapy Radiation therapy to sites of metastatic disease unlikely to be immediately palliated by chemotherapy, especially brain, epidural, and bone metastases, is a standard treatment option for patients with ED SCLC. Brain metastases are treated with whole-brain radiation therapy.

Chest radiation therapy is sometimes given for superior vena cava syndrome, but chemotherapy alone, with radiation reserved for nonresponding patients, is appropriate initial treatment. (Refer to the PDQ summary on Cardiopulmonary Syndromes for more information.)

Thoracic radiation therapy for patients who respond to chemotherapy Patients with ED treated with chemotherapy who have achieved a response can be considered for thoracic radiation therapy.

Evidence (thoracic radiation therapy):

A randomized trial of 498 patients who responded after receiving four to six cycles of chemotherapy compared thoracic radiation therapy with 30 Gy in 10 fractions versus no radiation therapy. All patients received PCI.[42][Level of evidence: 1iiA] OS was the primary study endpoint and not statistically different between the two groups at 1 year (33% for the thoracic radiation therapy group vs. 28% for the control group, P = .066). However, in a secondary analysis, 2-year OS was 13% in the thoracic radiation group (95% CI, 9–19) versus 3% in the control group (95% CI, 2–8; P = .004). The OS during the entire course of follow-up was not reported. Thoracic radiation therapy resulted in 6-month progression-free survival (PFS) of 24% in the thoracic radiation group (95% CI, 19–30) versus 7% in the control group (95% CI, 4–11; P = .001). Intrathoracic recurrences, both isolated (19.8% vs. 46.0%) and in combination with recurrences at other sites (43.7% vs. 79.8%), were reduced by approximately 50%. Thoracic radiation therapy was well tolerated. PCI Patients with ED treated with chemotherapy who have achieved a response can be considered for administration of PCI.

Evidence (PCI):

A randomized trial of 286 patients who responded after four to six cycles of chemotherapy compared PCI with no further therapy.[43][Level of evidence: 1iiD The cumulative risk of brain metastases within 1 year was 14.6% in the radiation group (95% CI, 8.3–20.9) and 40.4% in the control group (95% CI, 32.1– 48.6). Radiation was associated with an increase in median DFS from 12.0 weeks to 14.7 weeks and in median OS from 5.4 months to 6.7 months after randomization. The 1-year survival rate was 27.1% (95% CI, 19.4–35.5) in the radiation group and 13.3% (95% CI, 8.1–19.9) in the control group.[43] Radiation had side effects but did not have a clinically significant effect on global health status.[43] Only 29% of the randomly assigned patients had brain imaging at diagnosis.[44] Combination chemotherapy and radiation therapy Combination chemotherapy plus chest radiation therapy does not appear to improve survival compared with chemotherapy alone in patients with ED SCLC.

Treatment Options Under Clinical Evaluation Treatment options under clinical evaluation for patients with ED SCLC include the following:

New drug regimens. Alternative drug doses and schedules. Current Clinical Trials Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References Okamoto H, Watanabe K, Kunikane H, et al.: Randomised phase III trial of carboplatin plus etoposide vs split doses of cisplatin plus etoposide in elderly or poor-risk patients with extensive disease small-cell lung cancer: JCOG 9702. Br J Cancer 97 (2): 162-9, 2007. [PUBMED Abstract] Roth BJ, Johnson DH, Einhorn LH, et al.: Randomized study of cyclophosphamide, doxorubicin, and vincristine versus etoposide and cisplatin versus alternation of these two regimens in extensive small-cell lung cancer: a phase III trial of the Southeastern Cancer Study Group. J Clin Oncol 10 (2): 282-91, 1992. [PUBMED Abstract] Pujol JL, Carestia L, Daurès JP: Is there a case for cisplatin in the treatment of small-cell lung cancer? A meta-analysis of randomized trials of a cisplatin-containing regimen versus a regimen without this alkylating agent. Br J Cancer 83 (1): 8-15, 2000. [PUBMED Abstract] Twelves CJ, Souhami RL, Harper PG, et al.: The response of cerebral metastases in small cell lung cancer to systemic chemotherapy. Br J Cancer 61 (1): 147-50, 1990. [PUBMED Abstract] Nugent JL, Bunn PA Jr, Matthews MJ, et al.: CNS metastases in small cell bronchogenic carcinoma: increasing frequency and changing pattern with lengthening survival. Cancer 44 (5): 1885-93, 1979. [PUBMED Abstract] Amarasena IU, Walters JA, Wood-Baker R, et al.: Platinum versus non-platinum chemotherapy regimens for small cell lung cancer. Cochrane Database Syst Rev (4): CD006849, 2008. [PUBMED Abstract] Controlled trial of twelve versus six courses of chemotherapy in the treatment of small-cell lung cancer. Report to the Medical Research Council by its Lung Cancer Working Party. Br J Cancer 59 (4): 584-90, 1989. [PUBMED Abstract] Noda K, Nishiwaki Y, Kawahara M, et al.: Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med 346 (2): 85-91, 2002. [PUBMED Abstract] Hanna N, Bunn PA Jr, Langer C, et al.: Randomized phase III trial comparing irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer. J Clin Oncol 24 (13): 2038-43, 2006. [PUBMED Abstract] Lara PN Jr, Natale R, Crowley J, et al.: Phase III trial of irinotecan/cisplatin compared with etoposide/cisplatin in extensive-stage small-cell lung cancer: clinical and pharmacogenomic results from SWOG S0124. J Clin Oncol 27 (15): 2530-5, 2009. [PUBMED Abstract] Schmittel A, Sebastian M, Fischer von Weikersthal L, et al.: A German multicenter, randomized phase III trial comparing irinotecan-carboplatin with etoposide-carboplatin as first-line therapy for extensive-disease small-cell lung cancer. Ann Oncol 22 (8): 1798-804, 2011. [PUBMED Abstract] Zatloukal P, Cardenal F, Szczesna A, et al.: A multicenter international randomized phase III study comparing cisplatin in combination with irinotecan or etoposide in previously untreated small-cell lung cancer patients with extensive disease. Ann Oncol 21 (9): 1810-6, 2010. [PUBMED Abstract] Jiang J, Liang X, Zhou X, et al.: A meta-analysis of randomized controlled trials comparing irinotecan/platinum with etoposide/platinum in patients with previously untreated extensive-stage small cell lung cancer. J Thorac Oncol 5 (6): 867-73, 2010. [PUBMED Abstract] Guo S, Liang Y, Zhou Q: Complement and correction for meta-analysis of patients with extensive-stage small cell lung cancer managed with irinotecan/cisplatin versus etoposide/cisplatin as first-line chemotherapy. J Thorac Oncol 6 (2): 406-8; author reply 408, 2011. [PUBMED Abstract] Eckardt JR, von Pawel J, Papai Z, et al.: Open-label, multicenter, randomized, phase III study comparing oral topotecan/cisplatin versus etoposide/cisplatin as treatment for chemotherapy-naive patients with extensive-disease small-cell lung cancer. J Clin Oncol 24 (13): 2044-51, 2006. [PUBMED Abstract] Mavroudis D, Papadakis E, Veslemes M, et al.: A multicenter randomized clinical trial comparing paclitaxel-cisplatin-etoposide versus cisplatin-etoposide as first-line treatment in patients with small-cell lung cancer. Ann Oncol 12 (4): 463-70, 2001. [PUBMED Abstract] Niell HB, Herndon JE 2nd, Miller AA, et al.: Randomized phase III intergroup trial of etoposide and cisplatin with or without paclitaxel and granulocyte colony-stimulating factor in patients with extensive-stage small-cell lung cancer: Cancer and Leukemia Group B Trial 9732. J Clin Oncol 23 (16): 3752-9, 2005. [PUBMED Abstract] Spiro SG, Souhami RL, Geddes DM, et al.: Duration of chemotherapy in small cell lung cancer: a Cancer Research Campaign trial. Br J Cancer 59 (4): 578-83, 1989. [PUBMED Abstract] Bleehen NM, Girling DJ, Machin D, et al.: A randomised trial of three or six courses of etoposide cyclophosphamide methotrexate and vincristine or six courses of etoposide and ifosfamide in small cell lung cancer (SCLC). I: Survival and prognostic factors. Medical Research Council Lung Cancer Working Party. Br J Cancer 68 (6): 1150-6, 1993. [PUBMED Abstract] Giaccone G, Dalesio O, McVie GJ, et al.: Maintenance chemotherapy in small-cell lung cancer: long-term results of a randomized trial. European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol 11 (7): 1230-40, 1993. [PUBMED Abstract] Sculier JP, Paesmans M, Bureau G, et al.: Randomized trial comparing induction chemotherapy versus induction chemotherapy followed by maintenance chemotherapy in small-cell lung cancer. European Lung Cancer Working Party. J Clin Oncol 14 (8): 2337-44, 1996. [PUBMED Abstract] Schiller JH, Adak S, Cella D, et al.: Topotecan versus observation after cisplatin plus etoposide in extensive-stage small-cell lung cancer: E7593--a phase III trial of the Eastern Cooperative Oncology Group. J Clin Oncol 19 (8): 2114-22, 2001. [PUBMED Abstract] Bozcuk H, Artac M, Ozdogan M, et al.: Does maintenance/consolidation chemotherapy have a role in the management of small cell lung cancer (SCLC)? A metaanalysis of the published controlled trials. Cancer 104 (12): 2650-7, 2005. [PUBMED Abstract] Cohen MH, Creaven PJ, Fossieck BE Jr, et al.: Intensive chemotherapy of small cell bronchogenic carcinoma. Cancer Treat Rep 61 (3): 349-54, 1977 May-Jun. [PUBMED Abstract] Arriagada R, Le Chevalier T, Pignon JP, et al.: Initial chemotherapeutic doses and survival in patients with limited small-cell lung cancer. N Engl J Med 329 (25): 1848-52, 1993. [PUBMED Abstract] Fukuoka M, Masuda N, Negoro S, et al.: CODE chemotherapy with and without granulocyte colony-stimulating factor in small-cell lung cancer. Br J Cancer 75 (2): 306-9, 1997. [PUBMED Abstract] Woll PJ, Hodgetts J, Lomax L, et al.: Can cytotoxic dose-intensity be increased by using granulocyte colony-stimulating factor? A randomized controlled trial of lenograstim in small-cell lung cancer. J Clin Oncol 13 (3): 652-9, 1995. [PUBMED Abstract] Steward WP, von Pawel J, Gatzemeier U, et al.: Effects of granulocyte-macrophage colony-stimulating factor and dose intensification of V-ICE chemotherapy in small-cell lung cancer: a prospective randomized study of 300 patients. J Clin Oncol 16 (2): 642-50, 1998. [PUBMED Abstract] Thatcher N, Girling DJ, Hopwood P, et al.: Improving survival without reducing quality of life in small-cell lung cancer patients by increasing the dose-intensity of chemotherapy with granulocyte colony-stimulating factor support: results of a British Medical Research Council Multicenter Randomized Trial. Medical Research Council Lung Cancer Working Party. J Clin Oncol 18 (2): 395-404, 2000. [PUBMED Abstract] James LE, Gower NH, Rudd RM, et al.: A randomised trial of low-dose/high-frequency chemotherapy as palliative treatment of poor-prognosis small-cell lung cancer: a Cancer research Campaign trial. Br J Cancer 73 (12): 1563-8, 1996. [PUBMED Abstract] Pujol JL, Douillard JY, Rivière A, et al.: Dose-intensity of a four-drug chemotherapy regimen with or without recombinant human granulocyte-macrophage colony-stimulating factor in extensive-stage small-cell lung cancer: a multicenter randomized phase III study. J Clin Oncol 15 (5): 2082-9, 1997. [PUBMED Abstract] Ardizzoni A, Tjan-Heijnen VC, Postmus PE, et al.: Standard versus intensified chemotherapy with granulocyte colony-stimulating factor support in small-cell lung cancer: a prospective European Organization for Research and Treatment of Cancer-Lung Cancer Group Phase III Trial-08923. J Clin Oncol 20 (19): 3947-55, 2002. [PUBMED Abstract] Lorigan P, Woll PJ, O'Brien ME, et al.: Randomized phase III trial of dose-dense chemotherapy supported by whole-blood hematopoietic progenitors in better-prognosis small-cell lung cancer. J Natl Cancer Inst 97 (9): 666-74, 2005. [PUBMED Abstract] Buchholz E, Manegold C, Pilz L, et al.: Standard versus dose-intensified chemotherapy with sequential reinfusion of hematopoietic progenitor cells in small cell lung cancer patients with favorable prognosis. J Thorac Oncol 2 (1): 51-8, 2007. [PUBMED Abstract] Girling DJ: Comparison of oral etoposide and standard intravenous multidrug chemotherapy for small-cell lung cancer: a stopped multicentre randomised trial. Medical Research Council Lung Cancer Working Party. Lancet 348 (9027): 563-6, 1996. [PUBMED Abstract] Murray N, Grafton C, Shah A, et al.: Abbreviated treatment for elderly, infirm, or noncompliant patients with limited-stage small-cell lung cancer. J Clin Oncol 16 (10): 3323-8, 1998. [PUBMED Abstract] Westeel V, Murray N, Gelmon K, et al.: New combination of the old drugs for elderly patients with small-cell lung cancer: a phase II study of the PAVE regimen. J Clin Oncol 16 (5): 1940-7, 1998. [PUBMED Abstract] Earl HM, Rudd RM, Spiro SG, et al.: A randomised trial of planned versus as required chemotherapy in small cell lung cancer: a Cancer Research Campaign trial. Br J Cancer 64 (3): 566-72, 1991. [PUBMED Abstract] Randomised trial of four-drug vs less intensive two-drug chemotherapy in the palliative treatment of patients with small-cell lung cancer (SCLC) and poor prognosis. Medical Research Council Lung Cancer Working Party. Br J Cancer 73 (3): 406-13, 1996. [PUBMED Abstract] Souhami RL, Spiro SG, Rudd RM, et al.: Five-day oral etoposide treatment for advanced small-cell lung cancer: randomized comparison with intravenous chemotherapy. J Natl Cancer Inst 89 (8): 577-80, 1997. [PUBMED Abstract] Sekine I, Yamamoto N, Kunitoh H, et al.: Treatment of small cell lung cancer in the elderly based on a critical literature review of clinical trials. Cancer Treat Rev 30 (4): 359-68, 2004. [PUBMED Abstract] Slotman BJ, van Tinteren H, Praag JO, et al.: Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. Lancet 385 (9962): 36-42, 2015. [PUBMED Abstract] Slotman B, Faivre-Finn C, Kramer G, et al.: Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 357 (7): 664-72, 2007. [PUBMED Abstract] Shivnani AT: Prophylactic cranial irradiation in small-cell lung cancer. N Engl J Med 357 (19): 1977; author reply 1978, 2007. [PUBMED Abstract]

Staging

Staging Systems Several staging systems have been proposed for small cell lung cancer (SCLC). These staging systems include the following:

American Joint Committee on Cancer (AJCC) Tumor, Node, and Metastasis (TNM).[1] Veterans Administration Lung Study Group (VALG).[2] International Association for the Study of Lung Cancer (IASLC).[3] Limited-Stage Disease No universally accepted definition of this term is available. Limited-stage disease (LD) SCLC is confined to the hemithorax of origin, the mediastinum, or the supraclavicular nodes, which can be encompassed within a tolerable radiation therapy port.

Patients with pleural effusion, massive pulmonary tumor, and contralateral supraclavicular nodes have been both included within and excluded from LD by various groups.

Extensive-Stage Disease Extensive-stage disease (ED) SCLC has spread beyond the supraclavicular areas and is too widespread to be included within the definition of LD. Patients with distant metastases (M1) are always considered to have ED.[3,4]

IASLC-AJCC TNM Staging System The AJCC TNM defines LD as any T, except for T3-4, due to multiple lung nodules that do not fit in a tolerable radiation field, any N, and M0.[1] This corresponds to TNM stages I to IIIB. Extensive disease is TNM stage IV with distant metastases (M1) including malignant pleural effusions.[3,4]

The IASLC conducted an analysis of clinical TNM staging for SCLC using the sixth edition of the AJCC TNM staging system for lung cancer. Survivals for patients with clinical stages I and II disease are significantly different from those for patients with stage III disease with N2 or N3 involvement.[3] Patients with pleural effusion have an intermediate prognosis between LD and ED with hematogenous metastases and will be classified as having M1 disease (or ED). Application of the TNM system will not change how patients are managed; however, the analysis suggests that, in the context of clinical trials in LD, accurate TNM staging and stratification may be important.[3]

Staging Evaluation Staging procedures for SCLC are important to distinguish patients with disease limited to their thorax from those with distant metastases. At the time of initial diagnosis, approximately two-thirds of patients with SCLC have clinical evidence of metastases; most of the remaining patients have clinical evidence of extensive nodal involvement in the hilar, mediastinal, and sometimes supraclavicular regions.

Determining the stage of cancer allows an assessment of prognosis and a determination of treatment, particularly when chest radiation therapy or surgical excision is added to chemotherapy for patients with LD. If ED is confirmed, further evaluation should be individualized according to the signs and symptoms unique to the individual patient. Standard staging procedures include the following:

A thorough physical examination. Routine blood counts and serum chemistries. Chest and upper abdominal computed tomography (CT) scanning. A radionuclide bone scan. A brain magnetic resonance imaging scan or CT scan. Bone marrow aspirate or biopsy in selected patients in which treatment would change based on the results. The role of positron emission tomography (PET) is still under study. SCLC is fluorine F 18-fludeoxyglucose (18F-FDG) avid at the primary site and at metastatic sites. PET may be used in staging patients with SCLC who are potential candidates for the addition of thoracic radiation therapy to chemotherapy, as PET may lead to upstaging or downstaging of patients and to alteration of radiation fields resulting from the identification of additional sites of nodal metastases.

Evidence (18F-FDGPET):

In a study of 120 patients with LD SCLC or ED SCLC, ten patients were upstaged and three patients were downstaged.[5] PET was more sensitive and specific than CT scans for nonbrain distant metastases. In a small series of 24 patients with LD by conventional staging, two patients were upstaged to ED.[2] Unsuspected nodal metastases were documented in 25% of patients, which altered the radiation plan in these patients. At this time, sensitivity, specificity, and positive- or negative-predictive value of PET scanning and its enhancement of staging accuracy are uncertain. References Lung. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 253-70. Bradley JD, Dehdashti F, Mintun MA, et al.: Positron emission tomography in limited-stage small-cell lung cancer: a prospective study. J Clin Oncol 22 (16): 3248-54, 2004. [PUBMED Abstract] Shepherd FA, Crowley J, Van Houtte P, et al.: The International Association for the Study of Lung Cancer lung cancer staging project: proposals regarding the clinical staging of small cell lung cancer in the forthcoming (seventh) edition of the tumor, node, metastasis classification for lung cancer. J Thorac Oncol 2 (12): 1067-77, 2007. [PUBMED Abstract] Ihde D, Souhami B, Comis R, et al.: Small cell lung cancer. Lung Cancer 17 (Suppl 1): S19-21, 1997. [PUBMED Abstract] Brink I, Schumacher T, Mix M, et al.: Impact of [18F]FDG-PET on the primary staging of small-cell lung cancer. Eur J Nucl Med Mol Imaging 31 (12): 1614-20, 2004. [PUBMED Abstract]

Pathologic classification

Before initiating treatment of a patient with small cell lung cancer (SCLC), an experienced lung cancer pathologist should review the pathologic material.

Pathologic Classification The current classification of subtypes of SCLC includes the following:[1]

Small cell carcinoma. Combined small cell carcinoma (i.e., SCLC combined with neoplastic squamous and/or glandular components). SCLC arising from neuroendocrine cells forms one extreme of the spectrum of neuroendocrine carcinomas of the lung.

Neuroendocrine tumors include the following:

Low-grade typical carcinoid. Intermediate-grade atypical carcinoid. High-grade neuroendocrine tumors including large-cell neuroendocrine carcinoma (LCNEC) and SCLC. Because of differences in clinical behavior, therapy, and epidemiology, these tumors are classified separately in the World Health Organization (WHO) revised classification. The variant form of SCLC called mixed small cell/large cell carcinoma was not retained in the revised WHO classification. Instead, SCLC is now described with only one variant, SCLC combined, when at least 10% of the tumor bulk is made of an associated non-small cell component.

SCLC presents as a proliferation of small cells with the following morphological features:[2]

Scant cytoplasm. Ill-defined borders. Finely granular "salt and pepper" chromatin. Absent or inconspicuous nucleoli. Frequent nuclear molding. A high mitotic count. Combined small cell carcinoma includes a mixture of small cell and large cell or any other non-small cell component. Any cases showing at least 10% of SCLC are diagnosed as combined SCLC, and SCLC is limited to tumors with pure SCLC histology. SCLC associated with LCNEC is diagnosed as SCLC combined with LCNEC.

Nearly all SCLC are immunoreactive for keratin, thyroid transcription factor 1, and epithelial membrane antigen. Neuroendocrine and neural differentiation result in the expression of dopa decarboxylase, calcitonin, neuron-specific enolase, chromogranin A, CD56 (also known as nucleosomal histone kinase 1 or neural-cell adhesion molecule), gastrin-releasing peptide, and insulin-like growth factor 1. One or more markers of neuroendocrine differentiation can be found in approximately 75% of SCLC.[3]

Although preinvasive and in situ malignant changes are frequently found in patients with non-small cell lung cancer, these findings are rare in patients with SCLC.[4]

References Travis WD, Colby TV, Corrin B, et al.: Histological typing of lung and pleural tumours. 3rd ed. Berlin: Springer-Verlag, 1999. Brambilla E, Travis WD, Colby TV, et al.: The new World Health Organization classification of lung tumours. Eur Respir J 18 (6): 1059-68, 2001. [PUBMED Abstract] Guinee DG Jr, Fishback NF, Koss MN, et al.: The spectrum of immunohistochemical staining of small-cell lung carcinoma in specimens from transbronchial and open-lung biopsies. Am J Clin Pathol 102 (4): 406-14, 1994. [PUBMED Abstract] Kumar V, Abbas A, Fausto N, eds.: Robins and Cotran Pathologic Basis of Disease. 7th ed. Philadelphia, Pa: Elsevier Inc, 2005.

Radiation therapy

Depending on the stage of small cell lung cancer (SCLC) and other factors, radiation therapy might be used in several situations:

In limited stage SCLC, radiation therapy can be given at the same time as chemotherapy (chemo) to treat the tumor and lymph nodes in the chest. Giving chemo and radiation together is called concurrent chemoradiation. The radiation may be started with the first or second cycle of chemo. Radiation can also be given after the chemo is finished. This is sometimes done for patients with extensive stage disease, or it can be used for people with limited stage disease who have trouble getting chemotherapy and radiation at the same time (as an alternative to chemoradiation). SCLC often spreads to the brain. Radiation can be given to the brain to help lower the chances of problems from cancer spread there. This is called prophylactic cranial irradiation. This is most often used to treat people with limited stage SCLC, but it can also help some people with extensive stage SCLC. Radiation can be used to shrink tumors to relieve (palliate) symptoms of lung cancer such as pain, bleeding, trouble swallowing, cough, shortness of breath, and problems caused by spread to other organs such as the brain. Types of radiation therapy The type of radiation therapy most often used to treat SCLC is called external beam radiation therapy (EBRT). It delivers radiation from outside the body and focuses it on the cancer.

Before treatments start, your radiation team will take careful measurements to find the correct angles for aiming the radiation beams and the proper dose of radiation. This planning session, called simulation, usually includes getting imaging tests such as CT scans.

Treatment is much like getting an x-ray, but the radiation is more intense. The procedure itself is painless. Each treatment lasts only a few minutes, although the setup time – getting you into place for treatment – usually takes longer.

Most often, radiation as part of the initial treatment for SCLC is given once or twice daily, 5 days a week, for 3 to 7 weeks. Radiation to relieve symptoms and prophylactic cranial radiation are given for shorter periods of time, typically less than 3 weeks.

In recent years, newer EBRT techniques have been shown to help doctors treat lung cancers more accurately while lowering the radiation exposure to nearby healthy tissues. These include:

Three-dimensional conformal radiation therapy (3D-CRT): 3D-CRT uses special computer programs to precisely map the location of the tumor(s). Radiation beams are shaped and aimed at the tumor(s) from several directions, which makes it less likely to damage normal tissues.

Intensity modulated radiation therapy (IMRT): IMRT is an advanced form of 3D therapy. It uses a computer-driven machine that moves around the patient as it delivers radiation. Along with shaping the beams and aiming them at the tumor from several angles, the intensity (strength) of the beams can be adjusted to limit the dose reaching nearby normal tissues. This technique is used most often if tumors are near important structures such as the spinal cord. Many major cancer centers now use IMRT.

A variation of IMRT is called volumetric modulated arc therapy (VMAT). It uses a machine that delivers radiation quickly as it rotates once around the body. Each treatment is given over just a few minutes.

Possible side effects of radiation therapy If you are going to get radiation therapy, it’s important to ask your doctor beforehand about the possible side effects so that you know what to expect. Common side effects of radiation therapy can include:

Skin changes in the area being treated, which can range from mild redness to blistering and peeling Hair loss (in the area where the radiation enters the body) Fatigue (tiredness) Nausea and vomiting Loss of appetite and weight loss Most of these side effects go away after treatment, but some can last a long time. When chemotherapy is given with radiation, the side effects are often worse.

Radiation therapy to the chest may damage your lungs, which might cause a cough, problems breathing, and shortness of breath. These usually improve after treatment is over, although sometimes they may not go away completely.

Your esophagus, which is in the middle of your chest, may be exposed to radiation, which could cause a sore throat and trouble swallowing during or shortly after treatment. This might make it hard to eat anything other than soft foods or liquids for a while.

Radiation therapy to large areas of the brain can sometimes cause memory loss, fatigue, headaches, trouble thinking, or reduced sexual desire. Usually these symptoms are minor compared with those caused by cancer that has spread to the brain, but they can affect your quality of life.

Surgery

The feasibility of surgery depends on the stage of small cell carcinoma at diagnosis. In small cell carcinoma of the lung (SCCL), surgery should only be considered among patients with clinical stage I (T1-2, N0). Postoperative chemotherapy with or without radiation therapy is recommended based on the presence or absence of lymph node involvement.

Surgery

  • Surgery should only be considered among patients with clinical stage I (T1-2, N0). Given that the majority of patients are not diagnosed with clinical stage I (T1-2,N0), surgery is rarely performed among SCCL patients.[4][5]
  • Before a patient is considered for surgical resection of the tumor, investigation for occult nodal involvement by either mediastinoscopy or mediastinal node dissection should be performed.
  • Post-operative palliative treatment following surgery includes:
    • Chemotherapy if there is no nodal involvement
    • Chemotherapy PLUS radiation therapy if there is nodal involvement
    • Prophylactic cranial irradiation is recommended among patients who undergo complete resection of the tumor,[6] as long as their performance status is good and they do not have any neurological cognitive impairment.

MRI

Overview

There are no MRI findings associated with small cell carcinoma. However, a MRI may be helpful in the diagnosis of complications of small cell carcinoma, which include brain metastasis

MRI

  • There are no MRI findings associated with small cell carcinoma. However, a MRI may be helpful in the diagnosis of complications of small cell carcinoma, which include:
    • Brain metastasis

CT

Overview CT SCLC

Chest CT scan, preferably with intravenous contrast administration, may be helpful in the diagnosis of small cell carcinoma. Findings on CT scan suggestive of small cell carcinoma include hilar mass, mediastinal involvement, numerous lymphadenopathy, direct infiltration of adjacent structures, necrosis and hemorrhage. Small cell carcinoma of the lung is the most common cause of SVC obstruction, due to both compression/thrombosis and/or direct infiltration 2. All patients with confirmed diagnosis of SCLC by histopathological findings should undergo a CT scan of the abdomen for staging purposes. CT scan of the abdomen helps identify metastasis to organs, such as the liver or the adrenal glands. Brain imaging is also mandatory for staging; however, brain MRI is preferred over brain CT scan due to its superior sensitivity for the detection of brain metastasis. In addition, when limited stage small cell lung cancer is suspected, PET CT scan should be performed.

CT

Chest CT scan, preferably with intravenous contrast administration, may be helpful in the diagnosis of small cell carcinoma. Findings on CT scan suggestive of small cell carcinoma include:[5]

  • Hilar mass
  • Mediastinal involvement
  • Numerous lymphadenopathy
  • Direct infiltration of adjacent structures
  • Necrosis
  • Hemorrhage
  • Small cell carcinoma of the lung is the most common cause of SVC obstruction, due to both compression/thrombosis and/or direct infiltration 2.
  • CT is used to stage small cell lung cancer.
  • CT scan of the abdomen helps identify metastasis to organs, such as the liver or the adrenal glands.
  • Brain imaging is also mandatory for staging; however, brain MRI is preferred over brain CT scan due to its superior sensitivity for the detection of brain metastasis.
  • PET CT scan should be performed if limited stage small cell lung cancer is suspected.

Pathology SCLC

Small cell carcinoma is considered a neuroendocrine tumour of the lung. It arises from the bronchial mucosa. Local invasion occurs in the submucosa with subsequent invasion of peribronchial connective tissue. Cells are small, oval, with scant cytoplasm and a high mitotic count.

It is the most common lung cancer subtype to produce necrosis, superior vena cava (SVC) infiltration/SVC obstruction, and paraneoplastic syndromes (see bronchogenic carcinoma).

Location

Approximately 90-95% of SCLCs occur centrally, and usually arising in a lobar or main bronchus 3.

Small cell lung cancer X rays

Small cell carcinoma of Lung
Chest x-ray: Small cell carcinoma of the lung. Antero-posterior view, Case courtesy of A.Prof Frank Gaillard, via,Radiopaedia.org [7]
Chest x-ray: Small cell carcinoma of the lung.Case courtesy of Dr Henry Knipe, via, Radiopaedia.org[8]

Lung cancer

Surgery

If investigations confirm lung cancer, CT scan and often positron emission tomography (PET) are used to determine whether the disease is localised and amenable to surgery or whether it has spread to the point where it cannot be cured surgically.

Blood tests and spirometry (lung function testing) are also necessary to assess whether the patient is well enough to be operated on. If spirometry reveals poor respiratory reserve (often due to chronic obstructive pulmonary disease), surgery may be contraindicated.

Surgery itself has an operative death rate of about 4.4%, depending on the patient's lung function and other risk factors.[1] Surgery is usually only an option in non-small cell lung carcinoma limited to one lung, up to stage IIIA. This is assessed with medical imaging (computed tomography, positron emission tomography). A sufficient pre-operative respiratory reserve must be present to allow adequate lung function after the tissue is removed.

Pulmonary Reserve The American College of Chest Physicians established clinical practice guidelines for the physiologic evaluation of patients with lung cancer being considered for resectional surgery.[2] The preoperative physiologic assessment should include a cardiac evaluation and spirometry to measure the FEV1 and carbon monoxide diffusion capacity (DLCO). Depending on these results the patients can be stratified into different risk groups and further testing may be required or surgery can be initiated. Pulmonary reserve is measured by spirometry. The minimum forced vital capacity (FVC) for pneumonectomy in men is 2 liters. The minimum for lobectomy is 1.5 liters. In women, the minimum FVC values for pneumonectomy and lobectomy are 1.75 liters and 1.25 liters respectively.[3]

Surgery

Procedures include wedge resection (removal of part of a lobe), lobectomy (one lobe), bilobectomy (two lobes) or pneumonectomy (whole lung). In patients with adequate respiratory reserve, lobectomy is the preferred option, as this minimizes the chance of local recurrence. If the patient does not have enough functional lung for this, wedge resection may be performed.[4] Radioactive iodine brachytherapy at the margins of wedge excision may reduce recurrence to that of lobectomy.[5]

Also, many times during lung cancer surgery, the doctor will remove some of the lymph nodes to test for cancer. If the lymph nodes test positive for cancer then that is indicative of the disease spreading beyond the lung. There will most likely be subsequent treatments to help eliminate the remaining cancer.

Patient Selection Not all patients are suitable for operation. The stage, location and cell type are important limiting factors. In addition, patients who are very ill with a poor performance status or who have inadequate pulmonary reserve would be unlikely to survive. Even with careful selection, the overall operative death rate is about 4.4%.[1]

Stage "Stage" refers to the degree of spread of the cancer.

See non-small cell lung cancer staging

In non-small cell lung cancer, stages IA, IB, IIA, and IIB are suitable for surgical resection.[6] Stages IIIA, IIIB, and IV tend to involve the spreading out of the cancer. In that case chemotherapy or radiation is usually deemed the appropriate action to take because surgery will not adequately solve the diseased lungs.

Types of Surgery Lobectomy (removal of a lobe of the lung) Pneumonectomy (removal of an entire lung) Wedge resection Sleeve resection

Overview

Surgery is the best treatment option of lung cancer for patients with resectable tumors. The feasibility of surgery depends on the stage of lung cancer at the time of diagnosis.

Indications

  • Surgical intervention is not recommended for the management of [disease name].

OR

  • Surgery is not the first-line treatment option for patients with [disease name]. Surgery is usually reserved for patients with either:
    • [Indication 1]
    • [Indication 2]
    • [Indication 3]
  • The mainstay of treatment for [disease name] is medical therapy. Surgery is usually reserved for patients with either:
    • [Indication 1]
    • [Indication 2]
    • [Indication 3]

Surgery

  • Surgery is the best treatment option of lung cancer for patients with resectable tumors.
  • The feasibility of surgery depends on the stage of lung cancer at the time of diagnosis.
  • The procedures for lung cancer imclude:[9][10]
    • Wedge resection (removal of part of a lobe)
      • Wedge resection is performed in the patients who do not have adequate respiratory reserve.
      • Radioactive iodine brachytherapy at the margins of wedge resection may reduce recurrence to that of lobectomy.
    • Lobectomy (one lobe)
      • Lobectomy is the preferred option for patients with adequate respiratory reserve because it reduces the chances of local recurrence.
    • Bilobectomy (two lobes)
    • Pneumonectomy (whole lung)

Contraindications

References

  1. Gaeta M, Minutoli F, Girbino G, Murabito A, Benedetto C, Contiguglia R, Ruggeri P, Privitera S (2013). "Expiratory CT scan in patients with normal inspiratory CT scan: a finding of obliterative bronchiolitis and other causes of bronchiolar obstruction". Multidiscip Respir Med. 8 (1): 44. doi:10.1186/2049-6958-8-44. PMC 3710098. PMID 23835554.
  2. Park JE, Kim Y, Lee SW, Shim SS, Lee JK, Lee JH (2016). "The usefulness of low-dose CT scan in elderly patients with suspected acute lower respiratory infection in the emergency room". Br J Radiol. 89 (1060): 20150654. doi:10.1259/bjr.20150654. PMC 4846199. PMID 26861744.
  3. Espiritu JD, Ruppel G, Shrestha Y, Kleinhenz ME (June 2003). "The diffusing capacity in adult cystic fibrosis". Respir Med. 97 (6): 606–11. PMID 12814143.
  4. Jackman, David M; Johnson, Bruce E (2005). "Small-cell lung cancer". The Lancet. 366 (9494): 1385–1396. doi:10.1016/S0140-6736(05)67569-1. ISSN 0140-6736.
  5. 5.0 5.1 NCCN Clinical Practice Guidelines in Oncology. Small Cell Lung Cancer, version 2.2014
  6. Aupérin A, Arriagada R, Pignon JP, Le Péchoux C, Gregor A, Stephens RJ; et al. (1999). "Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group". N Engl J Med. 341 (7): 476–84. doi:10.1056/NEJM199908123410703. PMID 10441603.
  7. href="https://radiopaedia.org/">Radiopaedia.org</a>. From the case <a href="https://radiopaedia.org/cases/10494">rID: 10494
  8. href="https://radiopaedia.org/">Radiopaedia.org</a>. From the case <a href="https://radiopaedia.org/cases/30005">rID: 30005</a>
  9. El-Sherif, A (Aug 2006). "Outcomes of sublobar resection versus lobectomy for stage I non-small cell lung cancer: a 13-year analysis". Annals of Thoracic Surgery. 82 (2): 408–415. PMID 16863738. Unknown parameter |coauthors= ignored (help)
  10. Fernando, HC (Feb 2005). "Lobar and sublobar resection with and without brachytherapy for small stage IA non-small cell lung cancer". Journal of Thoracic and Cardiovascular Surgery. 129 (2): 261–267. PMID 15678034. Unknown parameter |coauthors= ignored (help)

Lung Cancer Differential

Condition/disease Signs/symptoms Tests
Pneumonia/bronchitis Typical symptoms include fever, cough, dyspnea, and chest pain; recurrent pneumonia or bronchitis in a smoker or former smoker should raise the suspicion of lung cancer CXR is the first test performed; CT imaging can be helpful to evaluate pulmonary masses that might not be well visualised with chest x-ray; bronchoscopy can also be used to assess for endobronchial lesions or to biopsy suspicious pulmonary masses
Carcinoid tumor Often asymptomatic with normal physical examination; may cause cough, dyspnea, hemoptysis, unilateral wheezing, or post-obstructive pneumonia if the tumor is endobronchial or compressing the central bronchi CT chest: 80% of carcinoid tumors appear as an endobronchial nodule and 20% as a parenchymal nodule, with smooth, rounded borders and is highly vascularized; flexible bronchoscopy shows raised, pink, vascular, lobulated lesions; endobronchial forceps biopsy is usually required for pathology to be diagnostic; bronchial brushings, sputum specimens, and lavage fluid rarely provide sufficient tissue for a conclusive diagnosis
Metastatic cancer from a non-thoracic primary site Signs and symptoms depend on the location of the primary tumor and distant disease and may include pain, weight loss, malaise, cough, dyspnea, clubbing, or focal wheezing; physical findings may be present depending on the location and extent of the disease CT chest shows one or multiple nodules of variable sizes from diffuse micronodular opacities (miliary) to well-defined masses, lesions are often irregular and in the periphery of the lower lung zones; CT/MRI head, CT abdomen and pelvis: extrapulmonary cancers that commonly metastasis to the lung include melanoma, thyroid carcinoma, esophageal cancer; ovarian cancer; sarcomas; and adenocarcinomas of the colon, breast, kidney, and testis; PET-FDG scan shows increased uptake in both primary and distant sites, certain metastatic lesions, such as renal cell carcinoma, have a lower probability of 18-fluorodeoxyglucose (FDG) uptake; CT-guided transthoracic needle aspiration (TTNA) can reveal characteristic malignant cells, pneumothorax complicates 20% to 30% of TTNA procedures, the choice between bronchoscopy and TTNA is based on lesion size, location, risks, and local expertise; biopsy during flexible bronchoscopy and biopsy may show characteristic malignant cells, bronchoscopy has a 100% yield for endobronchial lesions (which are extremely rare in metastatic deposits from other primary tumors)
Infectious granuloma History may include travel to endemic areas, pet/animal exposures, and specific leisure activities (e.g., caving); may feature cough, dyspnea, hemoptysis, weight loss, fever, joint aches, skin lesions, and night sweats, or no symptoms; many possible causes: Histoplasma capsulatum, Mycobacterium tuberculosis, Coccidioides immitis, Cryptococcus neoformans, Aspergillus, Pseudallescheria boydii, Fusarium species, zygomycetes, and others; non-specific skin findings may be seen in atypical mycobacteria and cryptococcosis; lymphadenopathy may be present with active disease CT-guided TTNA can be used for diagnostic sampling, pneumothorax complicates 20% to 30% of TTNA procedures, the choice between bronchoscopy and TTNA is based on lesion size, location, risks, and local expertise; CT chest typically shows lesions <2 cm diameter and round with smooth borders, old granulomatous disease may feature central, laminated, or diffuse calcification pattern, mediastinal lymphadenopathy without calcifications is sometimes present, nodules from angioinvasive fungi (e.g., Aspergillus, Pseudallescheria boydii, Fusarium species, and zygomycetes) may demonstrate the "halo sign" (ground-glass opacity surrounding the nodule), occasionally, calcifications can be seen in the spleen or liver; fungal serologies: positive during active infection; flexible bronchoscopy and biopsy can sometimes provide sample for identification and culture and sensitivity of organism; PET: usually negative (<2.5 standardised uptake values), may be positive in active infectious processes
Sarcoidosis Cough, dyspnea, fatigue weight loss, fever, night sweats, rash, eye pain, photophobia blurred vision, and red eye; pulmonary examination is usually unrevealing; can affect any organ, so physical findings depend on specific organs affected; skin lesions including maculopapular eruptions, subcutaneous nodular lesions, and red-purple skin lesions CT chest: mediastinal adenopathy often present with sarcoid. Sarcoid nodules have predilection for upper zones, although can be located throughout the lung; flexible bronchoscopy and biopsy can demonstrate presence of non-caseating granulomas; CT-guided TTNA can provide access to material from some lesions inaccessible to flexible bronchoscopy; laboratory markers: ACE elevation may be seen in sarcoidosis but is non-specific
Rheumatoid arthritis Arthralgias, pain, skin nodules, pleural effusions, pleuritis, joint pain, and deformity CT chest typically shows lung nodule 3 mm to 7 cm, predominantly in peripheral upper and mid-lung zones, may show cavitation; flexible bronchoscopy and biopsy shows rheumatoid necrobiotic nodule, necrobiotic nodules demonstrate a central zone of eosinophilic fibrinoid necrosis surrounded by palisading fibroblasts, the nodule often centered on necrotic inflamed blood vessels; laboratory markers: patients with lung nodules due to rheumatoid arthritis frequently have high levels of rheumatoid factor, although seronegative cases have been reported
Wegener's granulomatosis Cough, chest pain, dyspnea, hemoptysis, rhinorrhoea, epistaxis, ear/sinus pain, hoarseness, fever, fatigue, anorexia, weight loss, palpable purpura, painful ulcers, uveitis, upper airway inflammation, and sinus pain CT chest shows solitary or multiple lung nodules, airways are frequently affected; Flexible bronchoscopy or CT-guided TTNA may show necrotising granulomatous inflammation; laboratory markers: anti-neutrophil cytoplasmic antibody (ANCA), ANCA testing results depend on the extent and severity of the disease
Arteriovenous malformation Dyspnea is uncommon, may cause hemoptysis, pulmonary bruit, arteriovenous communications, or hemorrhagic telangiectasia in the skin, mucous membranes, and other organs, cyanosis and finger clubbing may be present, eurological symptoms from cerebral aneurysms, cerebral emboli CT chest shows round or oval nodule(s) with feeding artery and draining vein often identified, most common in lower lobes, multiple lesions in 30% of cases, usually round or oval, ranging from 1 cm to several cm in diameter; pulmonary angiography confirms presence and location of AVMs, identifies feeding arterial and venous structures, in cases of significant hemoptysis, pulmonary angiogram is combined with bronchial artery embolisation; ABG analysis may show decreased pO2 and decreased oxygen saturation when AV flow is severe., in cases of severe systemic AVMs, chronic hypoxemia may cause polycythemia
Amyloidosis Weight loss, paresthesias, dyspnea, and fatigue are the most common symptoms associated with amyloidosis and are common to all systemic forms; weight loss of >9 kg is common; small vessel involvement can cause jaw or limb claudication, and rarely angina; amyloid purpura is present in about 1 in 6 patients, typically peri-orbital; eyelid petechiae are common; hepatomegaly >5 cm below the right costal margin is seen in 10% of patients and splenomegaly is usually of modest degree CT chest shows lung involvement characterised by focal pulmonary nodules, tracheobronchial lesions, or diffuse alveolar deposits; serum immunofixation shows presence of monoclonal protein; urine immunofixation shows presence of monoclonal protein; immunoglobulin free light chain assay shows abnormal kappa to lambda ratio
Bronchiolitis obliterans organizing pneumonia (BOOP) Normally presents as a flu-like illness followed by a second illness lasting 1 to 4 months, with low-grade fever, non-productive cough, malaise, dyspnea, and weight loss; sometimes features pleuritic chest pain and hemoptysis; in most patients, auscultation reveals fine, dry lung crackles; finger clubbing is unusual CT chest typical features include: patchy "ground-glass" opacities in a sub-pleural and/or peribronchovascular distribution; thickening of bronchial walls and cylindrical dilation; 3 to 5 mm diameter centrilobular nodules or other ill-defined nodules, mediastinal lymphadenopathy, pleural effusions; pulmonary function tests typically show a restrictive pattern; bronchoalveolar lavage (BAL shows a mixed cell pattern, with an increase in lymphocytes, neutrophils, eosinophils, mast cells, foamy macrophages, and occasional plasma cells, CD4+/CD8+ cell ratio is decreased, the ratio of lymphocytes to CD8+ cells is significantly increased; transbronchial lung biopsy in combination with BAL can be a useful approach, prior to possible open biopsy; open lung biopsy is often required for a definitive diagnosis
Pulmonary tuberculosis Cough longer than 2 to 3 weeks, discolored or bloody sputum, night sweats, weight loss, loss of appetite, and/or pleuritic chest pain Chest x-ray: primary disease commonly presents as middle and lower lung zone infiltrates, ipsilateral adenopathy, atelectasis from airway compression, and pleural effusion can be seen, reactivation-type (post-primary) pulmonary TB usually involves apical and/or posterior segment of right upper lobe, apicoposterior segment of left upper lobe, or superior segment of either lower lobe, with or without cavitation, as disease progresses it spreads to other segments/lobes; sputum smear: positive for acid-fast bacilli (AFB), sputum may be spontaneously expectorated or induced, and at least 3 specimens should be collected (minimum 8 hours apart, including an early morning specimen, which is the best way to detect Mycobacterium tuberculosis), organisms other than M. tuberculosis, especially on-tuberculous mycobacteria (e.g., M. kansasii and M. avium , may be positive for AFB stain; nucleic acid amplification tests (NAAT): positive for M. tuberculosis DNA or RNA amplification tests for rapid diagnosis, may be used on sputum or any sterile body fluid
Non-Hodgkin's lymphoma (NHL) Aggressive NHL may present with fever, drenching night sweats, malaise, weight loss, cough, shortness of breath, abdominal discomfort, headache, change in mental status, dizziness, ataxia, pleural effusion, lymphadenopathy, pallor, purpura, jaundice, hepatomegaly, splenomegaly, skin nodules, and abnormal neurological examination, low-grade NHL patients often minimally symptomatic or asymptomatic CT chest: frequently anterior mediastinum, can determine if mass is cystic or solid and whether it contains calcium or fat, contrast enhancement provides information concerning vascularisation of the mass and relationship to adjacent structures; FBC with differential: shows thrombocytopenia, pancytopenia; Blood smear: shows nucleated red blood cells, giant platelets; lymph node biopsy with immunohistochemistry: shows characteristic cells, preferably obtain excisional or core biopsy to provide information on lymph node architecture; mediastinoscopy: used to sample mediastinal nodes
Hodgkin's lymphoma Predominantly a disease of young adults; most patients present with a several-month history of persistent adenopathy, most commonly of the cervical chain Plain chest x-ray: typically shows mediastinal mass/large mediastinal adenopathy; PET scan: involved sites appear fluorodeoxyglucose (FDG)-avid (bright) with PET imaging; lymph node biopsy with immunohistochemistry: the Hodgkin's cell can be a characteristic Reed-Sternberg cell, or one of its variants, such as the lacunar cell in the nodular sclerosis subtype; in nodular lymphocyte-predominant Hodgkin's lymphoma, the characteristic cell is the lymphocytic and histiocytic (L&H) cell, also referred to as a popcorn cell
Thymoma/thymic carcinoma Approximately 30% of patients with thymoma are asymptomatic at the time of diagnosis; may also present with cough, chest pain, signs of upper airway congestion, superior vena cava syndrome, dysphagia, or hoarseness; may have features of paraneoplastic syndromes associated with thymoma including myasthenia gravis, polymyositis, lupus erythematosus, rheumatoid arthritis, thyroiditis, and Sjogren's syndrome; about 30% of patients have symptoms suggestive of myasthenia gravis (e.g., ptosis, double vision) Plain chest x-ray: in 50% of the patients, thymomas are detected by chance with plain-film chest radiography; CT chest: 90% occur in anterior mediastinum; Positron emission tomography (PET): may be of value in determining malignancy and extramediastinal involvement; pre-operative biopsy: indicated if there are atypical features or if imaging suggests invasive tumor and patient is under consideration for induction therapy
Bronchogenic cyst Usually diagnosed in infancy and childhood, although 50% are diagnosed after 15 years of age; Approximately 50% of patients are asymptomatic; in adults, chest pain (often pleuritic) and dysphagia (due to esophageal compression) are the most common symptoms; may also feature recurrent cough and chest infection/pneumonia, superior vena cava syndrome, tracheal compression, and pneumothorax Two-view chest radiography: typically shows a sharply demarcated spherical mass of variable size, most commonly located in the middle mediastinum around the carina, can appear as a solid tumor or show air-fluid level if cyst is infected or contains secretions; CT chest: frequently middle mediastinum, typically at level of the mediastinum, calcifications may also be seen; MRI: frequently middle mediastinum, typically at level of the mediastinum, T2-weighted images show a homogeneous mass of moderate-to-bright intensity, on T1-weighted images, lesions may vary in intensity depending on protein content of the cyst
Tracheal tumors Common symptoms include dyspnea, cough, hemoptysis, wheeze, and stridor; less commonly, hoarseness and dysphagia may be present Plain chest radiographs are generally insensitive for detection of tracheal tumors, clues that may indicate the presence of a tracheal tumour include abnormal calcification, tracheal narrowing, post-obstructive pneumonia, and/or atelectasis; helical CT enables accurate calculation of tumor volumes and can help differentiate mucosal lesions from submucosal lesions; MRI can be useful in assessing extension into surrounding tissue and vascular anatomy; bronchoscopy allows direct visualisation, opportunity for biopsy, and potential for laser treatment
Thyroid mass Symptoms and signs depend on size of mass; may be visible/palpable as lump on anterior aspect of neck; may present with dysphagia, hoarseness, difficulty breathing, and pain in neck or throat; may also be signs and symptoms of hyper- or hypothyroidism depending on the nature of the mass Laboratory testing should include thyroid function panel, with TSH, free T4, free T3; I-123 thyroid scan is ordered for patients with overt or subclinical hyperthyroidism a hyperfunctioning (hot) nodule is almost always benign, most nodules are hypofunctioning (cold) (most of these are benign, but malignant nodules are also cold); ultrasound and doppler can be used to define dimensions of thyroid nodules and solid/cystic component(s), features suspicious of malignancy include microcalcifications, a more tall-than-wide shape, hypervascularity, marked hypoechogenicity, or irregular margins, it can also guide fine-needle aspiration, which can reveal malignant cells or cyst fluid; CT neck can evaluate cervical lymph nodes in cases of medullary thyroid cancer, and extension of the scan into the chest can help evaluate a retrosternal thyroid mass

Other conditions that can be mistaken for lung cancer including the following:

Differential Diagnosis

Lung cancer must be differentiated from other cavitary lung lesions.

Causes of

lung cavities

Differentiating Features Differentiating radiological findings Diagnosis

confirmation

  • CXR and CT demonstrates cavities in the upper lobe of the lung
  • Sputum smear positive for acid-fast bacilli and nucleic acid amplification tests (NAAT) is used on sputum or any sterile fluid for rapid diagnosis and is positive for mycobacteria.
  • Any age group
  • Acute, fulminant life threating complication of prior infection
  • >100.4 °F fever, with hemodynamic instability
  • Worsening pneumonia-like symptoms
  • CBC is positive for causative organism
  • Children and elderly are at risk
  • Empyema appears lenticular in shape and has a thin wall with smooth luminal margins
  • Pulmonary nodules with cavities and infiltrates are a frequent manifestation on CXR
  • Elderly females of 40-50 age group
  • Manifestation of rheumatoid arthritis
  • Presents with other systemic symptoms including symmetric arthritis of the small joints of the hands and feet with morning stiffness are common manifestations
  • Pulmonary nodules with cavitation are located in the upper lobe (Caplan syndrome) on X-ray
  • On CXR bilateral adenopathy and coarse reticular opacities are seen
  • CT of the chest demonstrates extensive hilar and mediastinal adenopathy
  • Additional findings on CT include fibrosis (honeycomb, linear, or associated with bronchial distortion), pleural thickening, and ground-glass opacities.[7]
  • Common appearance on CT is patchy consolidation,often accompanied by ground-glass opacities and nodules.[11]
  • Exclusively afflicts smokers, with a peak age of onset of between 20 and 40 years
  • Clinical presentation varies, but symptoms generally include months of dry cough, fever, night sweats, and weight loss
  • Skin is involved in 80% of the cases, scaly erythematous rash is typical
  • Thin-walled cystic cavities are the usual radiographic manifestation, observed in over 50% of patients by either CXR or CT scans.[13]
  • Biopsy of the lung

PBC USG

There are no ultrasound findings associated with primary biliary cirrhosis. However, the ultrasound is mandatory for liver and biliary tree for all cholestatic patients for the differentiation of intrahepatic from extrahepatic cholestasis.

  • The ultrasound findings may include:[14]
    • Cholestasis
    • Abdominal lymphadenopathy

Ultrasound examination of the liver and biliary tree is obligatory in all cholestatic patients in order to differentiate intrahepatic from extrahepatic . When the biliary system appears normal and serum AMA are present, no further radiologic workup is necessary. , particularly in the hilar region of the liver, is seen in 80% of patients with PBC

PBC CT

  • Findings on CT scan suggestive of advanced primary biliary cirrhosis include:[15]
    • Small heterogeneously attenuating liver
    • Varices
    • Splenomegaly
    • Lymphadenopathy
  • Findings on CT scan suggestive of less advanced disease include:
    • Enlarged or normal size liver
    • Smooth contour liver
    • Little atrophy
    • Lacelike fibrosis
    • Regenerative nodules
    • Varices
    • Ascites
    • Lymphadenopathy

Synonoms

  • Solitary hyperplastic nodule
  • Hepatic hamartoma
  • Focal cirrhosis
  • Hamartomatous cholangiohepatoma
  • Hepatic pseudotumor

Historical Perspective

  • In early 1900s,Focal nodular hyperplasia was first described.
  • Between 1918-1982,96.625 autopsy studies were conducted out of which 8 percent of nonhemangiomatous lesions were focal nodular hyperplasia.
  • In 1994,Working party of the world congresses of gastroenterology suggested a standardized terminology of nodular hepatic lesions that placed Focal noduldar carcinoma in the group of regenerative nodules, as opposed to dysplastic or neoplastic nodules.[16]

Differentiating Focal nodular hyperplasia from Other diseases

Focal nodular hyperplasia must be differentiated from:

Abbreviations: RUQ= Right upper quadrant of the abdomen, LUQ= Left upper quadrant, LLQ= Left lower quadrant, RLQ= Right lower quadrant, LFT= Liver function test, SIRS= Systemic inflammatory response syndrome, ERCP= Endoscopic retrograde cholangiopancreatography, IV= Intravenous, N= Normal, AMA= Anti mitochondrial antibodies, LDH= Lactate dehydrogenase, GI= Gastrointestinal, CXR= Chest X ray, IgA= Immunoglobulin A, IgG= Immunoglobulin G, IgM= Immunoglobulin M, CT= Computed tomography, PMN= Polymorphonuclear cells, ESR= Erythrocyte sedimentation rate, CRP= C-reactive protein, TS= Transferrin saturation, SF= Serum Ferritin, SMA= Superior mesenteric artery, SMV= Superior mesenteric vein, ECG= Electrocardiogram

Disease Clinical manifestations Diagnosis Comments
Symptoms Signs
Abdominal Pain Fever Rigors and chills Nausea or vomiting Jaundice Constipation Diarrhea Weight loss GI bleeding Hypo-

tension

Guarding Rebound Tenderness Bowel sounds Lab Findings Imaging
Focal nodular hyperplasia Diffuse ± ± + + Normal
  • Open biopsy if diagnosis can not be established
Hepatocellular carcinoma/Metastasis RUQ + + + + + + + + +
  • Normal
  • Hyperactive if obstruction present

Other symptoms:

Cholangiocarcinoma RUQ + + + + + Normal
  • Predisposes to pancreatic cancer
Pancreatic carcinoma MidEpigastric + + + + + Normal

Skin manifestations may include:

Disease Abdominal Pain Fever Rigors and chills Nausea or vomiting Jaundice Constipation Diarrhea Weight loss GI bleeding Hypo-

tension

Guarding Rebound Tenderness Bowel sounds Lab Findings Imaging Comments
Gallbladder cancer Midepigastric + + + + Normal
Liver hemangioma Intermittent RUQ + + Normal
  • Abnormal LFTs
Liver abscess RUQ + + + + Normal
  • US
  • CT
Cirrhosis RUQ+Bloating + + + + Normal US
  • Stigmata of liver disease
  • Cruveilhier- Baumgarten murmur
Inflammatory lesions RUQ ± + + Normal US
  • Nodular,shrunken or coarse liver
  • Stigmata of liver disease


Focal Nodular Hyperplasia

FNH is typically benign, and usually no treatment is needed. Hemangiomas are the most common and are entirely benign. Treatment is unnecessary unless their expansion causes symptoms

Focal nodular hyperplasia (FNH) is a non-malignant hepatic tumor that is not of vascular origin. In one autopsy series of 96,625 patients, 8 percent of non-hemangiomatous lesions were FNH, representing 66 percent of all benign non-hemangiomatous lesions seen between 1918 and 1982 [1]. In large retrospective studies of patients referred for ultrasound and multidetector computed tomography, the prevalence of focal nodular hyperplasia was 0.2 percent and 1.6 percent, respectively [2,3].

FNH is seen in both sexes and throughout the age spectrum, although it is found predominantly in women (in a ratio of 8 or 9:1) between the ages of 20 and 50 years [4]. FNH comprises up to 2 percent of liver tumors in children [5].

This topic review will focus on the pathogenesis, clinical manifestations and management of FNH. An approach to patients presenting with a focal liver lesion is discussed separately. (See "Solid liver lesions: Differential diagnosis and evaluation".)


PATHOGENESIS — FNH has various labels: solitary hyperplastic nodule, hepatic hamartoma, focal cirrhosis, hamartomatous cholangiohepatoma, and hepatic pseudotumor. This profusion of terms epitomizes the confusion surrounding our understanding of the pathogenesis of the many conditions in which nodules of benign appearing hepatocytes are found. The International Working Party of the World Congresses of Gastroenterology proposed a standardized nomenclature in 1994, which placed FNH in the group of regenerative nodules, as opposed to dysplastic or neoplastic nodules [6]. This fits well with our current understanding of the pathogenesis of FNH. The contention that this lesion is non-neoplastic has been bolstered by the reported polyclonal origin of the hepatocytes [7], although this is disputed by others [8].

Previously considered to be a hamartoma, a neoplasm, a response to ischemia or other injury, or a focal area of regeneration, FNH is now generally accepted to be a hyperplastic (regenerative) response to hyperperfusion by the characteristic anomalous arteries found in the center of these nodules [4,9,10]. Whether vascular injury is also involved is less clear, but FNH is occasionally supplied primarily by portal venous blood due to thrombosis of the anomalous central artery [11].

The association of FNH with hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease [12]) and hepatic hemangiomas strengthens the hypothesis that FNH is a congenital vascular anomaly. Two pathology studies found cavernous hemangiomas in 6.5 and 2.3 percent of patients with FNH [13,14] and an imaging study, using ultrasound and dynamic CT, found that 23 percent of FNH patients had associated hemangiomas [15]. Multiple FNH lesions have also been noted in association with hemihypertrophy and vascular malformations (Klippel-Trénaunay-Weber syndrome) [16]. FNH with similar clinical and radiographic features has been documented in identical twins supporting a role of congenital vascular anomalies in its pathogenesis and a possible genetic predisposition to the disease [17].

PATHOLOGY — FNH is most often solitary (80 to 95 percent), and usually less than 5 cm in diameter. Only 3 percent are larger than 10 cm, although FNH as large as 19 cm have been reported [1,13,18]. It has a sharp margin with no capsule and may be pedunculated. The characteristic finding is the presence of a central stellate scar (picture 1) containing an inappropriately large artery with multiple branches radiating through the fibrous septa to the periphery. These branches divide the mass into multiple small nodules or cords of normal appearing hepatocytes (picture 2). The scar-like tissues within FNH nodules are composed of abnormally large portal tracts including large feeding arteries, portal veins, and bile ducts [10].

The arteries drain into adjacent hepatic veins. This radiating, branching pattern produces the spoke and wheel image typically seen on angiography. Although normal bile ducts are absent, bile ductules derived from hepatocyte metaplasia are usually prominent, traveling along the fibrous septa (picture 3). Sinusoids and Kupffer cells are typically present, distinguishing it from hepatocellular adenoma (HA), which usually lacks bile ducts and Kupffer cells [1,13,14,18,19]. The minimal microscopic criteria for the diagnosis of classical FNH are nodular architecture, abnormal vessels, and proliferation of bile ductules [13]. Lymphocyte infiltration, canalicular bile plugs, copper deposition, and feathery degeneration of hepatocytes may suggest cholestasis and/or inactive cirrhosis. Irregular intimal fibrosis or hypertrophy of the media may be seen in large arteries and veins, at times even occluding the lumen [13,14,19]. When present, portal veins are dilated and/or stenotic [10].

Non-classical variants — Non-classical forms of FNH lack either the typical nodular architecture or vascular malformations, but always contain bile ductular proliferation. They almost always lack the characteristic central scar [13]. Three variants have been recognized:

●The most common of these, the telangiectatic type, often presents with multiple FNH. In addition to the lack of a central scar, the mass is characterized by the absence of nodular architecture and the presence of single, quite regular plates of hepatocytes separated by sinusoids fed directly by anomalous arteries [13,20]. The risk of bleeding appears to be similar to the risk observed in patients with a hepatic adenoma [21].


●A mixed hyperplastic and adenomatous form may be difficult to distinguish from HA due to its subtle vascular and bile ductular findings [13,20].


●A third histologic variant consisting of FNH with cytologic atypia resembling dysplasia of large cell type has been proposed [13].


A comprehensive pathological study of 305 lesions failed to identify a macroscopic central stellate scar in 50 percent and noted non-classical histology in 20 percent of the lesions, most showing a telangiectatic variant [13]. The surprisingly high number of lesions without a central scar was almost exclusively due to the large number of masses that had non-classical histology. Ninety-five percent of those with non-classical histology did not have a scar, whereas only 18 percent of those with classical histology lacked a scar [13]. The overall prevalence and clinical significance of these variants remains to be determined.

DIAGNOSIS — The diagnosis of FNH is usually made by demonstrating its characteristic features on imaging tests and excluding other lesions. The latter can typically be accomplished by assessment of the context in which FNH is detected and by obtaining specific radiologic and laboratory testing (table 1). The differential diagnosis includes hepatic adenoma, hepatocellular carcinoma, fibrolamellar carcinoma, cirrhosis, large regenerative nodules, hemangioma, and hypervascular metastases. (See "Solid liver lesions: Differential diagnosis and evaluation".)

Symptoms — The majority of reports have found that symptoms or signs directly attributable to FNH are infrequent. Two-thirds to three-fourths of patients are identified incidentally [18], with the mass noted at the time of surgery, on an abdominal imaging study, or at autopsy. Unlike hepatic adenomas, FNH rarely presents with acute onset of hemorrhage, necrosis, or infarction [22,23].

However, symptomatic presentations have been described. In one series, for example, abdominal discomfort or a palpable liver mass was observed in 25 percent of 41 patients [24]. Another series that included 168 patients found that 60 percent had abdominal pain and 4 percent had an abdominal mass [13]. The high number of symptomatic patients in the second report probably reflects selection bias since all of the patients were identified from pathology specimens obtained at the time of surgical resection [13].

Laboratory tests — Liver tests are most often normal although minor elevations in aspartate and alanine aminotransferase, alkaline phosphatase and gamma glutamyl transpeptidase levels may be seen [13,14,24]. The alpha-fetoprotein is normal.

Imaging tests — A confident diagnosis can usually be made through a combination of imaging modalities; tissue diagnosis is usually not required.

Ultrasonography — Although often first identified on ultrasound examination, FNH is variably hyper, hypo, or isoechoic [24] and US is able to identify the central scar in only 20 percent of cases [25]. The ultrasound characteristics are difficult to distinguish from an adenoma or malignant lesions. Power Doppler ultrasound may help differentiate the arterial flow in FNH from the venous flow in HA [24,26,27].

Contrast-enhanced ultrasonography — Several reports have described improved characterization of focal liver lesions using contrast-enhanced ultrasonography compared with standard ultrasonography [28-30]. While the approach is not approved in the United States, it is available in other countries. Test characteristics compared with other imaging modalities remain incompletely defined, although emerging data suggest its ability for differentiation among solid liver lesions is comparable with MRI [31]. (See "Contrast-enhanced ultrasound for the evaluation of liver lesions".)

CT scan — A properly timed dynamic, triphasic, helical CT scan performed without contrast, and with contrast during the hepatic arterial and portal venous phases, will often be highly suggestive of the diagnosis [32,33]. The lesion may be hypo or isodense on non-contrast imaging with the central scar identified in one-third of patients. The lesion becomes hyperdense during the hepatic arterial phase due to the arterial origin of its blood supply (image 1). FNH is generally isodense during the portal venous phase, although the central scar may become hyperdense as contrast diffuses into the scar. While characteristic of FNH, a central scar may be present in the fibrolamellar variant of HCC. (See "Epidemiology, clinical manifestations, diagnosis, and treatment of fibrolamellar carcinoma", section on 'Imaging'.)

MRI — There may be little to distinguish FNH from normal liver on standard MRI, since it is composed of the same elements as normal liver. An isointense lesion is noted on T1-weighted images, while an isointense to slightly hyperintense mass appears on T2-weighted images (image 2 and image 3) [34]. The scar typically shows high signal intensity on T2-weighted images due to vessels or edema in the scar (image 3) [35]. Gadolinium infusion produces rapid enhancement of the FNH mass due to its arterial blood supply, producing a hyperintense lesion on early films (image 2). On delayed images it becomes more isointense with respect to normal liver. The central scar enhances on delayed imaging as contrast gradually diffuses into the fibrous center of the mass [36-39]. In one study, gadolinium enhanced MRI had a sensitivity and specificity of 70 and 98 percent, respectively [24].

A relatively new MR contrast agent has been introduced into clinical use. Unlike currently used gadolinium-based contrast agents for MRI, this agent, a Gd-BOPTA chelate of Gadobenate Dimeglumine, has a dual route of elimination, through both renal and hepatobiliary excretion (image 4). Thus, it can be useful for distinguishing hepatic adenomas from focal nodular hyperplasia. (See "Solid liver lesions: Differential diagnosis and evaluation".)

Angiography — Although angiography may reveal the diagnostic "spoked wheel" appearance of FNH, its use is rarely indicated [32,40,41].

ROLE OF ORAL CONTRACEPTIVES — FNH was first described in the early 1900s, long before the advent of oral contraceptives (OCPs). It is seen in men and children who do not use OCPs and its incidence remained steady after the introduction of OCPs in 1960, in sharp contrast to the dramatic rise in the incidence of HA with the widespread use of OCPs. Thus use of OCPs is not required for the development of FNH [42-44].

On the other hand, FNH may be responsive to estrogens [11]. Patients taking OCPs tend to have larger, more vascular tumors, have more symptoms, and reports of hemorrhage or rupture in patients with FNH have all occurred in patients taking OCPs [45-48]. However, the magnitude of the risk associated with OCPs is uncertain. In a study of 216 women with FNH, use of OCPs did not appear to influence the size or number of FNH lesions or size changes (which were rare) during follow-up for an average of two years [49]. A case control trial comparing 23 women with histologically confirmed FNH to 94 controls estimated the odds ratio of OCP use to be 2.8 (95% CI, 0.8 to 9.4) for those who had ever used OCPs and 4.5 (95% CI, 1.2 to 16.9) for those who had ≥3 years of use [50].

We generally do not insist that oral contraceptives and other estrogen containing preparations should be discontinued. However, it is reasonable to obtain a follow-up imaging study in 6 to 12 months in women who continue taking these drugs.

MANAGEMENT — The natural history of FNH is one of stability and lack of complications. Lesions generally do not change over time, although they occasionally become smaller [49,51-54]. However, as mentioned above, enlargement of FNH in the setting of OCPs and during pregnancy have been reported [55]. There is no evidence for malignant transformation of FNH [13,24,56,57].

Patients who are suspected of having FNH based upon the evaluation described above should be managed conservatively [24,35,49,51,52,54,58,59]. If a diagnosis remains unclear, a liver biopsy may be helpful, but may also be misleading since only resection will be definitive [60]. Follow-up studies at three and six months will often be sufficient to confirm the stability of the lesion and its benign nature, after which no long-term follow-up is required routinely. Surgery should be reserved for the rare, very symptomatic FNH lesion, and the highly suspicious lesion, which has eluded diagnosis by all other modalities.

We generally do not insist that oral contraceptives and other estrogen containing preparations should be discontinued. However, it is reasonable to obtain a follow-up imaging study in 6 to 12 months in women who continue taking these drugs. Small FNH do not appear to pose a significant risk to a successful pregnancy [49,61], although close observation is strongly recommended and resection may be prudent for large (>8 cm) FNH.

SUMMARY AND RECOMMENDATIONS

●Focal nodular hyperplasia (FNH) is a non-malignant hepatic tumor that is not of vascular origin. It is now generally accepted to be a hyperplastic (regenerative) response to hyperperfusion by the characteristic anomalous arteries found in the center of these nodules. (See 'Pathogenesis' above.)


●FNH is most often solitary (80 to 95 percent) and usually less than 5 cm in diameter. Only 3 percent are larger than 10 cm. (See 'Pathology' above.)


●The majority of reports have found that symptoms or signs directly attributable to FNH are infrequent. (See 'Symptoms' above.)


●The diagnosis of FNH is usually made by demonstrating its characteristic features on imaging tests and excluding other lesions. The latter can typically be accomplished by assessing the context in which FNH is detected and by obtaining specific radiologic and laboratory testing (table 1). (See 'Diagnosis' above and "Solid liver lesions: Differential diagnosis and evaluation".)


●The natural history of FNH is one of stability and a lack of complications. Thus, we suggest that patients who are suspected of having FNH based upon the evaluation described above be managed conservatively (Grade 2B). (See 'Management' above.)


●FNH may be responsive to exogenous estrogens. We generally do not insist that oral contraceptives and other estrogen-containing preparations should be discontinued. However, it is reasonable to obtain a follow-up imaging study in 6 to 12 months in women who continue taking these drugs. (See 'Role of oral contraceptives' above.)


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REFERENCES 1.Craig J, Peters R, Edmundson H. Tumors of the Liver and Intrahepatic Bile Ducts, Fasc 26, 2nd ed, DC Armed Forces Institute of Pathology, Washington, DC 1989. p.6. 2.Kaltenbach TE, Engler P, Kratzer W, et al. Prevalence of benign focal liver lesions: ultrasound investigation of 45,319 hospital patients. Abdom Radiol (NY) 2016; 41:25. 3.Horta G, López M, Dotte A, et al. [Benign focal liver lesions detected by computed tomography: Review of 1,184 examinations]. Rev Med Chil 2015; 143:197. 4.Wanless IR, Mawdsley C, Adams R. On the pathogenesis of focal nodular hyperplasia of the liver. Hepatology 1985; 5:1194. 5.Reymond D, Plaschkes J, Lüthy AR, et al. Focal nodular hyperplasia of the liver in children: review of follow-up and outcome. J Pediatr Surg 1995; 30:1590. 6.International Working Party. Terminology of nodular hepatocellular lesions. Hepatology 1995; 22:983. 7.Paradis V, Laurent A, Flejou JF, et al. Evidence for the polyclonal nature of focal nodular hyperplasia of the liver by the study of X-chromosome inactivation. Hepatology 1997; 26:891. 8.Gaffey MJ, Iezzoni JC, Weiss LM. Clonal analysis of focal nodular hyperplasia of the liver. Am J Pathol 1996; 148:1089. 9.Fukukura Y, Nakashima O, Kusaba A, et al. Angioarchitecture and blood circulation in focal nodular hyperplasia of the liver. J Hepatol 1998; 29:470. 10.Kondo F, Nagao T, Sato T, et al. Etiological analysis of focal nodular hyperplasia of the liver, with emphasis on similar abnormal vasculatures to nodular regenerative hyperplasia and idiopathic portal hypertension. Pathol Res Pract 1998; 194:487. 11.Nakanuma Y. Non-neoplastic nodular lesions in the liver. Pathol Int 1995; 45:703. 12.Wanless IR, Gryfe A. Nodular transformation of the liver in hereditary hemorrhagic telangiectasia. Arch Pathol Lab Med 1986; 110:331. 13.Nguyen BN, Fléjou JF, Terris B, et al. Focal nodular hyperplasia of the liver: a comprehensive pathologic study of 305 lesions and recognition of new histologic forms. Am J Surg Pathol 1999; 23:1441. 14.Ishak KG, Rabin L. Benign tumors of the liver. Med Clin North Am 1975; 59:995. 15.Mathieu D, Zafrani ES, Anglade MC, Dhumeaux D. Association of focal nodular hyperplasia and hepatic hemangioma. Gastroenterology 1989; 97:154. 16.Haber M, Reuben A, Burrell M, et al. Multiple focal nodular hyperplasia of the liver associated with hemihypertrophy and vascular malformations. Gastroenterology 1995; 108:1256. 17.Mindikoglu AL, Regev A, Levi JU, et al. Focal nodular hyperplasia in identical twins. Am J Gastroenterol 2005; 100:1616. 18.Goodman ZD. Benign Tumors of the Liver. In: Neoplasms of the Liver, Okuda K, Ishak KD (Eds), Springer, Tokyo 1987. p.105. 19.Klatskin G, Conn H. Neoplasms of the Liver and Intrahepatic Bile Ducts. In: Histopathology of the Liver, Oxford University Press, New York 1993. p.367. 20.Wanless IR, Albrecht S, Bilbao J, et al. Multiple focal nodular hyperplasia of the liver associated with vascular malformations of various organs and neoplasia of the brain: a new syndrome. Mod Pathol 1989; 2:456. 21.Bioulac-Sage P, Rebouissou S, Sa Cunha A, et al. Clinical, morphologic, and molecular features defining so-called telangiectatic focal nodular hyperplasias of the liver. Gastroenterology 2005; 128:1211. 22.Brunt EM, Flye MW. Infarction in focal nodular hyperplasia of the liver. A case report. Am J Clin Pathol 1991; 95:503. 23.Lee MJ, Saini S, Hamm B, et al. Focal nodular hyperplasia of the liver: MR findings in 35 proved cases. AJR Am J Roentgenol 1991; 156:317. 24.Cherqui D, Rahmouni A, Charlotte F, et al. Management of focal nodular hyperplasia and hepatocellular adenoma in young women: a series of 41 patients with clinical, radiological, and pathological correlations. Hepatology 1995; 22:1674. 25.Shamsi K, De Schepper A, Degryse H, Deckers F. Focal nodular hyperplasia of the liver: radiologic findings. Abdom Imaging 1993; 18:32. 26.Bartolozzi C, Lencioni R, Paolicchi A, et al. Differentiation of hepatocellular adenoma and focal nodular hyperplasia of the liver: comparison of power Doppler imaging and conventional color Doppler sonography. Eur Radiol 1997; 7:1410. 27.Wang LY, Wang JH, Lin ZY, et al. Hepatic focal nodular hyperplasia: findings on color Doppler ultrasound. Abdom Imaging 1997; 22:178. 28.Quaia E. The real capabilities of contrast-enhanced ultrasound in the characterization of solid focal liver lesions. Eur Radiol 2011; 21:457. 29.Kang HS, Kim BK, Shim CS. Focal nodular hyperplasia: with a focus on contrast enhanced ultrasound. Korean J Hepatol 2010; 16:414. 30.Bernatik T, Seitz K, Blank W, et al. Unclear focal liver lesions in contrast-enhanced ultrasonography--lessons to be learned from the DEGUM multicenter study for the characterization of liver tumors. Ultraschall Med 2010; 31:577. 31.Seitz K, Bernatik T, Strobel D, et al. Contrast-enhanced ultrasound (CEUS) for the characterization of focal liver lesions in clinical practice (DEGUM Multicenter Trial): CEUS vs. MRI--a prospective comparison in 269 patients. Ultraschall Med 2010; 31:492. 32.Mergo PJ, Ros PR. Benign Lesions of the Liver. In: The Radiologic Clinics of North America, 2, W.B. Saunders, Philadelphia 1998. Vol 36, p.319. 33.Carlson SK, Johnson CD, Bender CE, Welch TJ. CT of focal nodular hyperplasia of the liver. AJR Am J Roentgenol 2000; 174:705. 34.Mattison GR, Glazer GM, Quint LE, et al. MR imaging of hepatic focal nodular hyperplasia: characterization and distinction from primary malignant hepatic tumors. AJR Am J Roentgenol 1987; 148:711. 35.Buetow PC, Pantongrag-Brown L, Buck JL, et al. Focal nodular hyperplasia of the liver: radiologic-pathologic correlation. Radiographics 1996; 16:369. 36.Irie H, Honda H, Kaneko K, et al. MR imaging of focal nodular hyperplasia of the liver: value of contrast-enhanced dynamic study. Radiat Med 1997; 15:29. 37.Mahfouz AE, Hamm B, Taupitz M, Wolf KJ. Hypervascular liver lesions: differentiation of focal nodular hyperplasia from malignant tumors with dynamic gadolinium-enhanced MR imaging. Radiology 1993; 186:133. 38.Rummeny E, Weissleder R, Sironi S, et al. Central scars in primary liver tumors: MR features, specificity, and pathologic correlation. Radiology 1989; 171:323. 39.Mathieu D, Rahmouni A, Anglade MC, et al. Focal nodular hyperplasia of the liver: assessment with contrast-enhanced TurboFLASH MR imaging. Radiology 1991; 180:25. 40.Welch TJ, Sheedy PF 2nd, Johnson CM, et al. Focal nodular hyperplasia and hepatic adenoma: comparison of angiography, CT, US, and scintigraphy. Radiology 1985; 156:593. 41.Rogers JV, Mack LA, Freeny PC, et al. Hepatic focal nodular hyperplasia: angiography, CT, sonography, and scintigraphy. AJR Am J Roentgenol 1981; 137:983. 42.Fechner RE. Benign hepatic lesions and orally administered contraceptives. A report of seven cases and a critical analysis of the literature. Hum Pathol 1977; 8:255. 43.Ishak KG. Hepatic Neoplasms Associated with Contraceptive and Anabolic Steroids in Carcinogenic Hormones. In: Recent Results in Cancer Research, Lingeman CH (Ed), Springer-Verlag, New York 1979. p.73. 44.Geders JM, Haque S, Tesi RJ, et al. A young man with a solitary hepatic mass. Hepatology 1995; 22:655. 45.Nime F, Pickren JW, Vana J, et al. The histology of liver tumors in oral contraceptive users observed during a national survey by the American College of Surgeons Commission on Cancer. Cancer 1979; 44:1481. 46.Aldinger K, Ben-Menachem Y, Whalen G. Focal nodular hyperplasia of the liver associated with high-dosage estrogens. Arch Intern Med 1977; 137:357. 47.Klatskin G. Hepatic tumors: possible relationship to use of oral contraceptives. Gastroenterology 1977; 73:386. 48.Shortell CK, Schwartz SI. Hepatic adenoma and focal nodular hyperplasia. Surg Gynecol Obstet 1991; 173:426. 49.Mathieu D, Kobeiter H, Maison P, et al. Oral contraceptive use and focal nodular hyperplasia of the liver. Gastroenterology 2000; 118:560. 50.Scalori A, Tavani A, Gallus S, et al. Oral contraceptives and the risk of focal nodular hyperplasia of the liver: a case-control study. Am J Obstet Gynecol 2002; 186:195. 51.Weimann A, Ringe B, Klempnauer J, et al. Benign liver tumors: differential diagnosis and indications for surgery. World J Surg 1997; 21:983. 52.Heinemann LA, Weimann A, Gerken G, et al. Modern oral contraceptive use and benign liver tumors: the German Benign Liver Tumor Case-Control Study. Eur J Contracept Reprod Health Care 1998; 3:194. 53.Di Stasi M, Caturelli E, De Sio I, et al. Natural history of focal nodular hyperplasia of the liver: an ultrasound study. J Clin Ultrasound 1996; 24:345. 54.Leconte I, Van Beers BE, Lacrosse M, et al. Focal nodular hyperplasia: natural course observed with CT and MRI. J Comput Assist Tomogr 2000; 24:61. 55.Scott LD, Katz AR, Duke JH, et al. Oral contraceptives, pregnancy, and focal nodular hyperplasia of the liver. JAMA 1984; 251:1461. 56.Wanless IR. Nodular regenerative hyperplasia, dysplasia, and hepatocellular carcinoma. Am J Gastroenterol 1996; 91:836. 57.Rubin RA, Mitchell DG. Evaluation of the solid hepatic mass. Med Clin North Am 1996; 80:907. 58.Belghiti J, Pateron D, Panis Y, et al. Resection of presumed benign liver tumours. Br J Surg 1993; 80:380. 59.De Carlis L, Pirotta V, Rondinara GF, et al. Hepatic adenoma and focal nodular hyperplasia: diagnosis and criteria for treatment. Liver Transpl Surg 1997; 3:160. 60.Fabre A, Audet P, Vilgrain V, et al. Histologic scoring of liver biopsy in focal nodular hyperplasia with atypical presentation. Hepatology 2002; 35:414. 61.Weimann A, Mössinger M, Fronhoff K, et al. Pregnancy in women with observed focal nodular hyperplasia of the liver. Lancet 1998; 351:1251.

HCC Differnetial Table

Abbreviations: RUQ= Right upper quadrant of the abdomen, LUQ= Left upper quadrant, LLQ= Left lower quadrant, RLQ= Right lower quadrant, LFT= Liver function test, SIRS= Systemic inflammatory response syndrome, ERCP= Endoscopic retrograde cholangiopancreatography, IV= Intravenous, N= Normal, AMA= Anti mitochondrial antibodies, LDH= Lactate dehydrogenase, GI= Gastrointestinal, CXR= Chest X ray, IgA= Immunoglobulin A, IgG= Immunoglobulin G, IgM= Immunoglobulin M, CT= Computed tomography, PMN= Polymorphonuclear cells, ESR= Erythrocyte sedimentation rate, CRP= C-reactive protein, TS= Transferrin saturation, SF= Serum Ferritin, SMA= Superior mesenteric artery, SMV= Superior mesenteric vein, ECG= Electrocardiogram

Disease Clinical manifestations Diagnosis Comments
Symptoms Signs
Abdominal Pain Fever Rigors and chills Nausea or vomiting Jaundice Constipation Diarrhea Weight loss GI bleeding Hypo-

tension

Guarding Rebound Tenderness Bowel sounds Lab Findings Imaging
Hepatocellular carcinoma/Metastasis RUQ + + + + + + + + +
  • Normal
  • Hyperactive if obstruction present

Other symptoms:

Cholangiocarcinoma RUQ + + + + + Normal
  • Predisposes to pancreatic cancer
Pancreatic carcinoma MidEpigastric + + + + + Normal

Skin manifestations may include:

Focal nodular hyperplasia Diffuse ± ± + + Normal
  • Open biopsy if diagnosis can not be established
Disease Abdominal Pain Fever Rigors and chills Nausea or vomiting Jaundice Constipation Diarrhea Weight loss GI bleeding Hypo-

tension

Guarding Rebound Tenderness Bowel sounds Lab Findings Imaging Comments
Gallbladder cancer Midepigastric + + + + Normal
Liver hemangioma Intermittent RUQ + + Normal
  • Abnormal LFTs
Liver abscess RUQ + + + + Normal
  • US
  • CT
Cirrhosis RUQ+Bloating + + + + Normal US
  • Stigmata of liver disease
  • Cruveilhier- Baumgarten murmur
Inflammatory lesions RUQ ± + + Normal US
  • Nodular,shrunken or coarse liver
  • Stigmata of liver disease

Classification

Historical Perspective

Pathophysiology

Causes

Differentiating Splenic Rupture from Other Diseases

Epidemiology and Demographics

Risk Factors

Screening

Natural History, Complications and Prognosis

Diagnosis

Diagnostic Study of Choice

History and Symptoms

Physical Examination

Laboratory Findings

Electrocardiogram

X-Ray

MRI

Other Imaging Findings

Other Diagnostic Studies

Algorithms

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Major molecular events in the pathogenesis of HCC
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Genomic alterations
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Epigenetic modifications
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Growthfactor pathway alterations
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gene Mutations
 
Gene Amplification
 
 
 
 
 
 
 
DNA methylation micro RNA
 
 
 
 
Micro RNA
 
 
 
 
 
LNC RNA
 
 
 
 
 
 
Major Signaling pathways
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
•TERT promoter
•TP53
•CTNNB1
•AXIN1
•AXIN2
•ATM
•RPS6KA3
•JAK1
•IL6R
•IL6ST
•ARID1
•ARID2
 
•CCND1
•FGF19
•CDKNA2A
•CDKNA2B
•AXIN1
•IRF2
•MET
 
 
 
 
 
 
 
GSTP1
•E-Cadherin
•CDKNA2
•RASSF1A
•SOCS-3
•MIGMT
 
 
 
 
•MiR-155
•Mir-122
•Mir-224
•Mir-21
 
 
 
 
 
•HULC
•HEIH
•Dreh
•MVIH
•HOTAIR
•MDIG
•LINE1
 
 
 
 
 
 
•Wnt/β –catenin
•Tyrosine kinase pathways
EGF
HGF/c-MET
FGF
VEGF
•IGF
•HIF
•TGF β
•Hedgehog
Elderly Male with jaundice from pancreatic cancer, By James Heilman, MD (Own work) [CC BY 3.0 (http://creativecommons.org/licenses/by/3.0)], via Wikimedia Commons [17]

The incidence of HCC has almost tripled since the early 1980s in the United States where it is the fastest rising cause of cancer-related deaths1. According to population based Surveillance Epidemiology and End Results registry data, the overall HCC age adjusted incidence rates for liver and intrahepatic ducts cancer is as high as 8 per 100,000 underling population in 2010 (Fig. 1) of which at least 6 per 100,000 related to HCC. Men are at approximately three times higher risk than women. Asian men (i.e., Chinese, Korean, Filipino, and Japanese) have the highest age-adjusted incidence rates. However, the largest proportional increases have occurred among Hispanics followed by blacks and non-Hispanic whites, whereas the lowest proportional increases have occurred among Asians. In contrast to Asians/Pacific Islanders, HCC incidence rates are reported to be higher among Hispanics born in the United States than among foreign-born Hispanics2. HCC incidence rates have increased in each successive birth cohort born between 1900 and 19593 (Fig. 2). In addition, the age distribution of HCC patients has shifted to younger ages, with the greatest proportional increases among individuals 45–60 years old (Fig. 2). There is a south to north gradient in the incidence and mortality of HCC; Southern states including Texas, Louisiana, and Mississippi have some of the highest HCC incidence rates in the nation (Fig. 3). In one study, Texas Latino and especially South Texas Latinos had the highest age-adjusted HCC incidence rates (as high as 10.6/100,000)4.

Video codes

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synonym website

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Image

Normal versus Abnormal Barium study of esophagus with varices


Image to the right

C. burnetii, the Q fever causing agent
C. burnetii, the Q fever causing agent

Image and text to the right

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Gallery


References

  1. 1.0 1.1 Chaudhuri MR (1973). "Primary pulmonary cavitating carcinomas". Thorax. 28 (3): 354–66. PMC 470041. PMID 4353362.
  2. Mouroux J, Padovani B, Elkaïm D, Richelme H (1996). "Should cavitated bronchopulmonary cancers be considered a separate entity?". Ann. Thorac. Surg. 61 (2): 530–2. doi:10.1016/0003-4975(95)00973-6. PMID 8572761.
  3. Onn A, Choe DH, Herbst RS, Correa AM, Munden RF, Truong MT, Vaporciyan AA, Isobe T, Gilcrease MZ, Marom EM (2005). "Tumor cavitation in stage I non-small cell lung cancer: epidermal growth factor receptor expression and prediction of poor outcome". Radiology. 237 (1): 342–7. doi:10.1148/radiol.2371041650. PMID 16183941.
  4. 4.0 4.1 Langford CA, Hoffman GS (1999). "Rare diseases.3: Wegener's granulomatosis". Thorax. 54 (7): 629–37. PMC 1745525. PMID 10377211.
  5. Lee KS, Kim TS, Fujimoto K, Moriya H, Watanabe H, Tateishi U, Ashizawa K, Johkoh T, Kim EA, Kwon OJ (2003). "Thoracic manifestation of Wegener's granulomatosis: CT findings in 30 patients". Eur Radiol. 13 (1): 43–51. doi:10.1007/s00330-002-1422-2. PMID 12541109.
  6. Baughman RP, Teirstein AS, Judson MA, Rossman MD, Yeager H, Bresnitz EA, DePalo L, Hunninghake G, Iannuzzi MC, Johns CJ, McLennan G, Moller DR, Newman LS, Rabin DL, Rose C, Rybicki B, Weinberger SE, Terrin ML, Knatterud GL, Cherniak R (2001). "Clinical characteristics of patients in a case control study of sarcoidosis". Am. J. Respir. Crit. Care Med. 164 (10 Pt 1): 1885–9. doi:10.1164/ajrccm.164.10.2104046. PMID 11734441.
  7. Brauner MW, Grenier P, Mompoint D, Lenoir S, de Crémoux H (1989). "Pulmonary sarcoidosis: evaluation with high-resolution CT". Radiology. 172 (2): 467–71. doi:10.1148/radiology.172.2.2748828. PMID 2748828.
  8. Murphy J, Schnyder P, Herold C, Flower C (1998). "Bronchiolitis obliterans organising pneumonia simulating bronchial carcinoma". Eur Radiol. 8 (7): 1165–9. doi:10.1007/s003300050527. PMID 9724431.
  9. 9.0 9.1 Al-Ghanem S, Al-Jahdali H, Bamefleh H, Khan AN (2008). "Bronchiolitis obliterans organizing pneumonia: pathogenesis, clinical features, imaging and therapy review". Ann Thorac Med. 3 (2): 67–75. doi:10.4103/1817-1737.39641. PMC 2700454. PMID 19561910.
  10. Cordier JF, Loire R, Brune J (1989). "Idiopathic bronchiolitis obliterans organizing pneumonia. Definition of characteristic clinical profiles in a series of 16 patients". Chest. 96 (5): 999–1004. PMID 2805873.
  11. Lee KS, Kullnig P, Hartman TE, Müller NL (1994). "Cryptogenic organizing pneumonia: CT findings in 43 patients". AJR Am J Roentgenol. 162 (3): 543–6. doi:10.2214/ajr.162.3.8109493. PMID 8109493.
  12. Suri HS, Yi ES, Nowakowski GS, Vassallo R (2012). "Pulmonary langerhans cell histiocytosis". Orphanet J Rare Dis. 7: 16. doi:10.1186/1750-1172-7-16. PMC 3342091. PMID 22429393.
  13. Moore AD, Godwin JD, Müller NL, Naidich DP, Hammar SP, Buschman DL, Takasugi JE, de Carvalho CR (1989). "Pulmonary histiocytosis X: comparison of radiographic and CT findings". Radiology. 172 (1): 249–54. doi:10.1148/radiology.172.1.2787035. PMID 2787035.
  14. Blachar A, Federle MP, Brancatelli G (2001). "Primary biliary cirrhosis: clinical, pathologic, and helical CT findings in 53 patients". Radiology. 220 (2): 329–36. doi:10.1148/radiology.220.2.r01au36329. PMID 11477233.
  15. Blachar, Arye; Federle, Michael P.; Brancatelli, Giuseppe (2001). "Primary Biliary Cirrhosis: Clinical, Pathologic, and Helical CT Findings in 53 Patients". Radiology. 220 (2): 329–336. doi:10.1148/radiology.220.2.r01au36329. ISSN 0033-8419.
  16. "Terminology of nodular hepatocellular lesions". Hepatology. 22 (3): 983–93. 1995. PMID 7657307.
  17. "File:Jaundice08.jpg - Wikimedia Commons". External link in |title= (help)
  18. 18.0 18.1 18.2 Neuroendocrine tumor of the pancreas. Libre Pathology. http://librepathology.org/wiki/index.php/Neuroendocrine_tumour_of_the_pancreas