Adenocarcinoma of the lung pathophysiology: Difference between revisions

Jump to navigation Jump to search
No edit summary
No edit summary
Line 38: Line 38:
*  
*  
*  
*  
 
*Underlying [[lung]] disease such as [[Chronic obstructive pulmonary disease|COPD]], [[idiopathic pulmonary fibrosis]] and [[tuberculosis]] may exacerbate also trigger the process.
*Individual susceptibility, active [[smoking]], [[radon]] exposure, exposure to high pollution levels, [[asbestos]] exposure, occupational or environmental exposure to particular agents or [[Carcinogen|carcinogens]] contribute to the development of adenocarcinoma of the [[lung]]. [[Hydrocarbon|Hydrocarbons]] cause damage to the [[DNA]] and form DNA adducts. Benzo-A-pyrine has effects on inducing [[P53 (protein)|p53]] mutations and affects [[Signaling pathway|molecular signaling pathways]] such as [[AKT]].
*The “multiple hit theory” for adenocarcinoma of the [[lung]] states that genetic [[reproduction]] is hindered due to the cumulative effect of several toxic insults. Underlying [[lung]] disease such as [[Chronic obstructive pulmonary disease|COPD]], [[idiopathic pulmonary fibrosis]] and [[tuberculosis]] may exacerbate also trigger the process.
*Mutations involving several [[Oncogene|oncogenes]] may lead to the development of adenocarcinoma of the lung. These are as follows:
**Mutations of [[APOBEC1|APOBEC protein]]
==Genetics==
==Genetics==



Revision as of 15:41, 26 February 2019

Adenocarcinoma of the Lung Microchapters

Home

Patient Information

Overview

Historical Perspective

Classification

Pathophysiology

Causes

Differentiating Adenocarcinoma of the Lung from other Diseases

Epidemiology and Demographics

Risk Factors

Screening

Natural History, Complications and Prognosis

Diagnosis

Diagnostic Study of Choice

Staging

History and Symptoms

Physical Examination

Laboratory Findings

Electrocardiogram

X Ray

Echocardiography and Ultrasound

CT

MRI

Other Imaging Findings

Other Diagnostic Studies

Treatment

Medical Therapy

Intervention

Surgery

Primary Prevention

Secondary Prevention

Cost-Effectiveness of Therapy

Future or Investigational Therapies

Case Studies

Case #1

Adenocarcinoma of the lung pathophysiology On the Web

Most recent articles

Most cited articles

Review articles

CME Programs

Powerpoint slides

Images

American Roentgen Ray Society Images of Adenocarcinoma of the lung pathophysiology

All Images
X-rays
Echo & Ultrasound
CT Images
MRI

Ongoing Trials at Clinical Trials.gov

US National Guidelines Clearinghouse

NICE Guidance

FDA on Adenocarcinoma of the lung pathophysiology

CDC on Adenocarcinoma of the lung pathophysiology

Adenocarcinoma of the lung pathophysiology in the news

Blogs on Adenocarcinoma of the lung pathophysiology

Directions to Hospitals Treating Adenocarcinoma of the lung

Risk calculators and risk factors for Adenocarcinoma of the lung pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Trusha Tank, M.D.[2], Shanshan Cen, M.D. [3], Sudarshana Datta, MD [4]

Overview

Adenocarcinoma is the most common type of lung cancer found in non-smokers and is usually seen as a peripheral lesion in the lungs. In past several years many genetic and environmental factors has been identified as a causative factor for lung cancer. Individual susceptibility, active smoking, radon exposure, exposure to high pollution levels, asbestos exposure, occupational or environmental exposure to particular agents or carcinogens contribute to the development of adenocarcinoma of the lung. Hydrocarbons cause damage to the DNA and form DNA adducts. Benzo-A-pyrine has effects on inducing p53 mutations and affects molecular signaling pathways such as AKT. Genes involved in the pathogenesis of adenocarcinoma of the lung include EGFR, HER2, KRAS, ALK, and BRAF. On gross pathology, peripheral multifocal lesions are characteristic findings in patients with adenocarcinoma of the lung. On microscopic histopathological analysis, nuclear atypia, eccentrically placed nuclei, abundant cytoplasm, and conspicuous nucleoli are characteristic findings of adenocarcinoma of the lung.

Pathogenesis

Field of injury and field cancerization

Genetics

Molecular pathogenesis of adenocarcinoma of the lung

Mutations TP53, KRAS, EGFR, NF1, BRAF, MET, RIT
Fusions ALK, ROS1, RET
SCNAs Gains: NKX2-1, TERT, EGFR, MET, KRAS, ERBB2, MDM2

Losses: LRP1B, PTPRD, and CDKN2A

Pathway alterations RTK/RAS/RAF

mTOR JAK-STAT DNA repair Cell cycle regulation Epigenetic deregulation

Gross Pathology

  • On gross pathology, peripheral multifocal lesions are characteristic findings in patients with adenocarcinoma of the lung.[19]
  • Adenocarcinoma of the lung may be preceded by morphological changes such as atypical adenomatous hypertrophy (AAH) in peripheral airway cells.
  • AAH is a parenchymal lesion that arises in the alveoli close to terminal and respiratory bronchioles.
  • AAH lesions are small and usually incidental histological findings; however, they may be detected grossly, especially if they are 0.5 cm or larger.
  • AAH is characterized by an alveolar structure lined by rounded, cuboidal, or low columnar cells.
  • The postulated progression of AAH to adenocarcinoma with bronchioloalveolar features, apparent from the increasingly atypical morphology, is supported by morphometric, cyto-fluorometric, and molecular studies.
Gray-tan tumor seen predominantly at the periphery.
Source: Libre pathology

Microscopic Pathology

Micrograph of mucinous adenocarcinoma of the lung, H&E stain.
Source: Libre pathology
Micrograph showing an adenocarcinoma of the lung (acinar pattern), H&E stain.
Source: Libre pathology


On microscopic histopathological analysis, nuclear atypia, eccentrically placed nuclei, abundant cytoplasm, and conspicuous nucleoli are characteristic findings of adenocarcinoma of the lung.

  • Atypical adenomatous hyperplasia (AAH): is the precursor of peripheral adenocarcinomas. It consists of well demarcated columnar or cuboidal cells with the following features:[20][21]
  • As adenocarcinoma is a derivative of mucus producing glands in the lungs, it tends to stain mucin positive.
  • Based on differentiation, the tumor may be:
    • Well differentiated (low grade) : Normal appearance
    • Poorly differentiated (high grade): Abnormal glandular appearance with a positive mucin stain

Histological Subtypes

  • The IASLC/ATS/ERS lung adenocarcinoma histologic classification system was proposed in the Journal of Thoracic Oncology in 2011.[22]
  • According to this new classification, tumor size ≤3 cm with pure lepidic pattern, but without lymphatic, vascular, pleural invasion or tumor necrosis was defined as adenocarcinoma in situ (AIS).
  • If tumor size ≤3 cm with a lepidic predominant pattern and contained ≤5 mm stromal invasion it was defined as minimally invasive adenocarcinoma (MIA).
  • If tumor had >5 mm stromal invasion it was defined as an invasive adenocarcinoma.
  • Histologically adenocarcinoma is divided in to following subtypes:[23][24][25][26][27][28]
    • Lepidic adenocarcinoma
    • Acinar adenocarcinoma:
      • Acinar pattern comprises infiltrating round to oval glands lined by tumour cells.
      • Irregular-shaped glands.
      • Malignant cells: Hyperchromatic nuclei, fibroblastic stroma.
      • Sometimes the glandular cells and lumina may contain mucin.
    • Papillary adenocarcinoma
      • The papillary pattern is composed of glandular tumour cells growing along fibrovascular cores.
      • Papillae, necrosis, surrounding invasion, cuboidal to columnar epithelial lining, mucinous or non-mucinous.
      • Lung adenocarcinomas with papillary growth show 2 types of papillary architecture:
        • True papillary type: Papillae containing a layered glandular epithelium surrounded by fibrovascular core.
        • Micropapillary type: The papillary tufts lack a central fibrovascular core and extensively shed within alveolar spaces.
    • Micropapillary adenocarcinoma:
      • The papillary tufts lack a central fibrovascular core and extensively shed within alveolar spaces.
      • Micropapillary growth has been associated with an aggressive clinical course compared with traditional papillary adenocarcinoma.
      • Micropapillary adenocarcinoma (MPA) may be often diagnosed at a high stage in nonsmokers, with intralobar satellites.
      • Micropapillary adenocarcinoma frequently metastasizes to the contralateral lung, mediastinal lymph nodes, bone, and adrenal glands, with high mortality.
    • Solid adenocarcinoma
      • Cohesive cell cluster in a nest-like pattern without acinar polarity are the hallmark of the solid growth pattern.
      • Solid adenocarcinoma consists of sheets of tumor cells with abundant cytoplasm and mostly vesicular nuclei with several conspicuous nucleoli.
      • No acinar, papillary, or lepidic patterns are seen and there was no suggestion of mucin in tumor cell cytoplasm
    • Invasive mucinous adenocarcinoma
      • Mixed invasive mucinous: Invasive mucinous adenocarcinoma demonstrates areas with lepidic, acinar, and papillary patterns.
        • Fibrotic focus that contains invasive tumor with a desmoplastic stroma.
        • The tumor consists of columnar cells filled with abundant mucin in the apical cytoplasm and shows small, basally oriented nuclei.
      • Nonmucinous adenocarcinoma
    • Colloid adenocarcinoma:
      • This tumor consists of abundant pools of mucin growing within and distending airspaces.
      • Well differentiated mucinous glandular epithelium along the surface of fibrous septa and within the pools of mucin.
      • Tumor cells may be very inconspicuous.
      • The surface of the fibrous wall may be lined by well-differentiated cuboidal or columnar mucinous epithelium.
    • Fetal adenocarcinoma:
      • Fetal adenocarcinoma consists of malignant glandular cells growing in tubules and papillary structures with endometrioid morphology.
      • Some tumor cells have prominent clear cytoplasm, and squamoid morules are present
    • Enteric adenocarcinoma:
      • Consists of an adenocarcinoma that morphologically resembles colonic adenocarcinoma with back-to-back angulated acinar structures.
      • The tumor cells are cuboidal to columnar with nuclear pseudostratification.
      • The tumor stains strongly for CDX-2.
    • Minimally invasive adenocarcinoma (MIA)
      • Nonmucinous (MIA):
        • This subpleural adenocarcinoma tumor consists primarily of lepidic growth with a small (0.5 cm) central area of invasion.
        • It may present as the lepidic pattern and/or acinar invasion.
      • Mucinous (MIA):
        • Mucinous MIA consists of a tumor showing lepidic growth and a small (0.5 cm) area of invasion.
        • The tumor cells consist of mucinous columnar cells and pale cytoplasm resembling goblet cells growing mostly in a lepidic pattern along the surface of alveolar walls.
        • The tumor invades the areas of stromal fibrosis in an acinar pattern.
        • Low grade differentiation.
    • Preinvasive lesions
      • Atypical adenomatous hyperplasia (AAH): Consists of atypical pneumocytes proliferating along alveolar walls.
        • Non invasive.
        • The slightly atypical pneumocytes are cuboidal and show gaps between the cells.
        • Nuclei are hyperchromatic and may present with nuclear enlargement and multinucleation.
      • Adenocarcinoma in situ (AIS)
        • Nonmucinous (AIS): Tumor grows purely with a lepidic pattern.
          • No foci of invasion or scarring is seen.
          • It shows atypical pneumocytes proliferating along the thickened, but preserved, alveolar walls.
        • Mucinous AIS: Consists of a nodular proliferation of mucinous columnar cells growing in a purely lepidic pattern.
          • Although there is a small central scar, no stromal or vascular invasion is seen.
          • The tumor cells consist of cuboidal to columnar cells with abundant apical mucin and small, basally oriented nuclei.

References

  1. Travis WD, Travis LB, Devesa SS (January 1995). "Lung cancer". Cancer. 75 (1 Suppl): 191–202. doi:10.1002/1097-0142(19950101)75:1+<191::AID-CNCR2820751307>3.0.CO;2-Y. PMID 8000996.
  2. Mitchell, Richard Sheppard; Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson. "Chapter 13, box on morphology of adenocarcinoma". Robbins Basic Pathology (8th ed.). Philadelphia: Saunders. ISBN 1-4160-2973-7.
  3. Kanwal, Madiha; Ding, Xiao-Ji; Cao, Yi (2017). "Familial risk for lung cancer". Oncology Letters. 13 (2): 535–542. doi:10.3892/ol.2016.5518. ISSN 1792-1074.
  4. Kadara, H.; Scheet, P.; Wistuba, I. I.; Spira, A. E. (2016). "Early Events in the Molecular Pathogenesis of Lung Cancer". Cancer Prevention Research. 9 (7): 518–527. doi:10.1158/1940-6207.CAPR-15-0400. ISSN 1940-6207.
  5. Raso, Maria Gabriela; Wistuba, Ignacio I. (2007). "Molecular Pathogenesis of Early-Stage Non-small Cell Lung Cancer and a Proposal for Tissue Banking to Facilitate Identification of New Biomarkers". Journal of Thoracic Oncology. 2 (7): S128–S135. doi:10.1097/JTO.0b013e318074fe42. ISSN 1556-0864.
  6. Wistuba II, Gazdar AF (2006). "Lung cancer preneoplasia". Annu Rev Pathol. 1: 331–48. doi:10.1146/annurev.pathol.1.110304.100103. PMID 18039118.
  7. Devarakonda, Siddhartha; Morgensztern, Daniel; Govindan, Ramaswamy (2015). "Genomic alterations in lung adenocarcinoma". The Lancet Oncology. 16 (7): e342–e351. doi:10.1016/S1470-2045(15)00077-7. ISSN 1470-2045.
  8. Kadara H, Scheet P, Wistuba II, Spira AE (July 2016). "Early Events in the Molecular Pathogenesis of Lung Cancer". Cancer Prev Res (Phila). 9 (7): 518–27. doi:10.1158/1940-6207.CAPR-15-0400. PMID 27006378.
  9. Auerbach, Oscar; Stout, A. P.; Hammond, E. Cuyler; Garfinkel, Lawrence (1961). "Changes in Bronchial Epithelium in Relation to Cigarette Smoking and in Relation to Lung Cancer". New England Journal of Medicine. 265 (6): 253–267. doi:10.1056/NEJM196108102650601. ISSN 0028-4793.
  10. Stewart, Bernard (2014). World cancer report 2014. Lyon, France Geneva, Switzerland: International Agency for Research on Cancer,Distributed by WHO Press, World Health Organization. ISBN 9283204298.
  11. Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S; et al. (2007). "Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer". Nature. 448 (7153): 561–6. doi:10.1038/nature05945. PMID 17625570.
  12. Davies KD, Le AT, Theodoro MF, Skokan MC, Aisner DL, Berge EM; et al. (2012). "Identifying and targeting ROS1 gene fusions in non-small cell lung cancer". Clin Cancer Res. 18 (17): 4570–9. doi:10.1158/1078-0432.CCR-12-0550. PMC 3703205. PMID 22919003.
  13. Stewart, Bernard (2014). World cancer report 2014. Lyon, France Geneva, Switzerland: International Agency for Research on Cancer,Distributed by WHO Press, World Health Organization. ISBN 9283204298.
  14. Weir, Barbara A.; Woo, Michele S.; Getz, Gad; Perner, Sven; Ding, Li; Beroukhim, Rameen; Lin, William M.; Province, Michael A.; Kraja, Aldi; Johnson, Laura A.; Shah, Kinjal; Sato, Mitsuo; Thomas, Roman K.; Barletta, Justine A.; Borecki, Ingrid B.; Broderick, Stephen; Chang, Andrew C.; Chiang, Derek Y.; Chirieac, Lucian R.; Cho, Jeonghee; Fujii, Yoshitaka; Gazdar, Adi F.; Giordano, Thomas; Greulich, Heidi; Hanna, Megan; Johnson, Bruce E.; Kris, Mark G.; Lash, Alex; Lin, Ling; Lindeman, Neal; Mardis, Elaine R.; McPherson, John D.; Minna, John D.; Morgan, Margaret B.; Nadel, Mark; Orringer, Mark B.; Osborne, John R.; Ozenberger, Brad; Ramos, Alex H.; Robinson, James; Roth, Jack A.; Rusch, Valerie; Sasaki, Hidefumi; Shepherd, Frances; Sougnez, Carrie; Spitz, Margaret R.; Tsao, Ming-Sound; Twomey, David; Verhaak, Roel G. W.; Weinstock, George M.; Wheeler, David A.; Winckler, Wendy; Yoshizawa, Akihiko; Yu, Soyoung; Zakowski, Maureen F.; Zhang, Qunyuan; Beer, David G.; Wistuba, Ignacio I.; Watson, Mark A.; Garraway, Levi A.; Ladanyi, Marc; Travis, William D.; Pao, William; Rubin, Mark A.; Gabriel, Stacey B.; Gibbs, Richard A.; Varmus, Harold E.; Wilson, Richard K.; Lander, Eric S.; Meyerson, Matthew (2007). "Characterizing the cancer genome in lung adenocarcinoma". Nature. 450 (7171): 893–898. doi:10.1038/nature06358. ISSN 0028-0836.
  15. Rodenhuis S, Slebos RJ, Boot AJ, Evers SG, Mooi WJ, Wagenaar SS, van Bodegom PC, Bos JL (October 1988). "Incidence and possible clinical significance of K-ras oncogene activation in adenocarcinoma of the human lung". Cancer Res. 48 (20): 5738–41. PMID 3048648.
  16. Imielinski M, Berger AH, Hammerman PS, Hernandez B, Pugh TJ, Hodis E, Cho J, Suh J, Capelletti M, Sivachenko A, Sougnez C, Auclair D, Lawrence MS, Stojanov P, Cibulskis K, Choi K, de Waal L, Sharifnia T, Brooks A, Greulich H, Banerji S, Zander T, Seidel D, Leenders F, Ansén S, Ludwig C, Engel-Riedel W, Stoelben E, Wolf J, Goparju C, Thompson K, Winckler W, Kwiatkowski D, Johnson BE, Jänne PA, Miller VA, Pao W, Travis WD, Pass HI, Gabriel SB, Lander ES, Thomas RK, Garraway LA, Getz G, Meyerson M (September 2012). "Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing". Cell. 150 (6): 1107–20. doi:10.1016/j.cell.2012.08.029. PMC 3557932. PMID 22980975.
  17. Hurlin, Peter J.; Huang, Jie (2006). "The MAX-interacting transcription factor network". Seminars in Cancer Biology. 16 (4): 265–274. doi:10.1016/j.semcancer.2006.07.009. ISSN 1044-579X.
  18. Devarakonda S, Morgensztern D, Govindan R (July 2015). "Genomic alterations in lung adenocarcinoma". Lancet Oncol. 16 (7): e342–51. doi:10.1016/S1470-2045(15)00077-7. PMID 26149886.
  19. Adenocarcinoma of the lung. Librepathology 2015. http://librepathology.org/wiki/index.php/File:Adenocarcinoma_%283950819000%29.jpg
  20. Kumar, Vinay (2007). Robbins basic pathology. Philadelphia, PA: Saunders/Elsevier. ISBN 1416029737.
  21. Stewart, Bernard (2014). World cancer report 2014. Lyon, France Geneva, Switzerland: International Agency for Research on Cancer,Distributed by WHO Press, World Health Organization. ISBN 9283204298.
  22. . doi:10.3978/j.issn.2072-1439.2014.09.13. Missing or empty |title= (help)
  23. Travis, William (2004). Pathology and genetics of tumours of the lung, pleura, thymus, and heart. Lyon: IARC Press. ISBN 9283224183.
  24. "www.jto.org".
  25. Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger K, Yatabe Y, Ishikawa Y, Wistuba I, Flieder DB, Franklin W, Gazdar A, Hasleton PS, Henderson DW, Kerr KM, Nakatani Y, Petersen I, Roggli V, Thunnissen E, Tsao M (May 2013). "Diagnosis of lung adenocarcinoma in resected specimens: implications of the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification". Arch. Pathol. Lab. Med. 137 (5): 685–705. doi:10.5858/arpa.2012-0264-RA. PMID 22913371.
  26. Iwata H (September 2016). "Adenocarcinoma containing lepidic growth". J Thorac Dis. 8 (9): E1050–E1052. doi:10.21037/jtd.2016.08.78. PMID 27747060.
  27. Jones KD (December 2013). "Whence lepidic?: the history of a Canadian neologism". Arch. Pathol. Lab. Med. 137 (12): 1822–4. doi:10.5858/arpa.2013-0144-HP. PMID 23937575.
  28. Lin, Gengpeng; Xie, Canmao (2017). "PUB070 Acinar-Predominant Pattern Correlates with Poorer Outcome in Invasive Mucinous Adenocarcinoma of the Lung". Journal of Thoracic Oncology. 12 (1): S1489. doi:10.1016/j.jtho.2016.11.2040. ISSN 1556-0864.


Template:WikiDoc Sources