Lung tumours

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Lung tumours comes to pathology to get diagnosed. This article basically deals with core biopsies. Pulmonary cytopathology is dealt with in the pulmonary cytopathology article.

An introduction to lung pathology is found in the pulmonary pathology article.

Lung tumours overview

Schematic overview of lung cancer (clinical)

 
 
 
 
 
 
 
 
Lung cancer
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary
 
 
 
 
 
 
 
Metastatic
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NSCLC
 
 
 
SCLC
 
 
 
 
 
 
 
 
 
 
 
  • NSCLC = non-small cell lung cancer.
  • SCLS = small cell lung cancer.

Basic pathologic approach to lung cancer

 
 
 
 
 
 
Lung cancer
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adenocarcinoma
 
Squamous
cell carcinoma
 
SCLC
 
LCLC
  • LCLC = large cell lung cancer.
  • SCLS = small cell lung cancer.

Notes:

  • Most lung cancer fits into one of the above categories.
  • All types may be metastatic. Pathologists usually don't have to sort this out, as the clinican often knows whether a given lesion is metastatic (when correlated with radiology).
  • Lung cancers may have a mixed morphology, e.g. SCLS may have squamous component.[1]
  • Categorization as non-small cell lung cancer (NSCLC) should be avoided, as treatment is now somewhat dependent on subcategorization.[2]

Major types (primary)

Mnemonic ASSL:

Epidemiology

  • Adenocarcinoma is the most common (primary lung cancer).[3]
  • Adenocarcinoma is the non-smoker tumour - SCLC and squamous are more strongly associated with smoking.

Distribution

  • Distribution - think about the location of letters in mnemonic ASSL.
    • Adenocarcinoma is usually periperal, i.e. smaller airways.
    • Squamous cell carcinoma and small cell carcinoma are typically central.

Management of primary lung cancer

Management is currently determined by categorization into:

  • Small cell cancer.
  • Non-small cell cancer (includes adenocarcinoma, squamous cell carcinoma, large cell carcinoma).

Microscopic features overview

Adenocarcinoma

  • Glands or cytoplasm with mucin.

Squamous cell carcinoma

  • Distinct cell borders with intercellular bridges.
  • Eosinophilic cytoplasm.

Small cell carcinoma

IHC

There is a great review paper by Jagirdar.[4]

Small cell carcinoma

  • CD56 +ve - sensitive.[5]
  • CK7 -ve, CK20 -ve.

Note:

  • CD56 - cytoplasmic.[6]

Squamous cell carcinoma

  • CK7 -ve, CK20 -ve.
  • HMWK +ve.
  • Usually TTF-1 -ve.[7]

Primary vs. secondary

  • TTF-1 is considered useful.[4]
    • 75% +ve adenocarcinoma
    • 11% +ve SSC
    • 50% +ve large cell carcinoma
    • 0% +ve mesothelioma
    • significant rates of +ve in some metastatic tumours -- see article by Jagirdar.

Note:

Neuroendocrine tumours

Main article: Neuroendocrine tumours

Overview

Classification

The grouping can be divided into four types:[11]

  • Small cell carcinoma.
  • Large cell neuroendocrine carcinoma.
  • Typical carcinoid.
  • Atypical carcinoid.

Cytologic features

Cytologic features useful for differentiation:

  • Small cell carcinoma: necrosis, scant cytoplasm, mitoses.
  • Typical carcinoid: often more cytoplasm, no necrosis, low mitotic rate (MIB-1: scant staining).
  • Atypical carcinoid: higher mitotic rate/MIB-1 than typical carcinoid,[12] no necrosis.

Notes:[11]

  • Large cell and small cell tumours behave in a similar fashion; large cell can be considered a morphological variant of small cell.
  • 9/10 of carcinoids are typical and usually have a good prognosis, i.e. do not metastasize.
    • Central location (vis-a-vis peripheral location) tends favours typical carcinoid over atypical carcinoid.

Malignant tumours

Adenocarcinoma of the lung

  • AKA lung adenocarcinoma.

General

Treatment:

  • Lung adenocarcinoma may be treated with EGFR inhibitors (e.g. gefitinib (Iressa), erlotinib (Tarceva)).[13]

Patients that receive EGFR inhibitors classically are:[14]

  • Non-smokers.
  • Female.
  • Asian. (???)

Microscopic

Features:

  • Nuclear atypia.
  • Eccentrically placed nuclei.
  • Abundant cytoplasm - classically with mucin vacuoles.

Negatives:

  • Lack of intercellular bridges.

Patterns:[15]

  • Lepidic.
  • Acinar.
  • Papillary.
  • Solid.

DDx:

Classification

Classification based on extent:[15]

  1. Adenocarcinoma in situ (AIS) - previously known as BAC.
    • Subtypes: nonmucinous, mucinous, mixed mucinous/nonmucinous.
  2. Minimally invasive adenocarcinoma (MIA).
    • Lepidic growth with upto 5 mm of invasion.
    • Subtypes: nonmucinous (most common), mucinous, mixed mucinous/nonmucinous.
  3. Invasive adenocarcinoma:
    • Subtypes: micropapillary, mucinous (previously mucinous BAC), colloid, fetal, enteric.

IHC

  • CK7 +ve.
  • TTF-1 +ve.
  • CK20 -ve.

Molecular

Bronchioloalveolar carcinoma

Abbreviated BAC.

The term is no longer used in the new classification;[20] it is now "adenocarcinoma in situ" - see lung adenocarcinoma.

Squamous cell carcinoma of the lung

General

  • Strong association with smoking.
  • May be treated with surgery.

Microscopic

Features:

  • Central nucleus.
  • Dense appearing cytoplasm, usu. eosinophilic.
  • +/-Small nucleolus.

DDx:

Small cell carcinoma of the lung

General

  • Strong association with smoking.
  • Typically treated with chemotherapy.

Microscopic

Features:

  • Stippled chromatin.
  • High NC ratio, scant basophilic cytoplasm.
  • Typically small cells ~2x RBC diameter.
  • +/-Nuclear moulding.
  • No nucleolus.
  • Necrosis.
  • Mitoses.

DDx:

Malignant mesothelioma

Should not be confused with benign multicystic mesothelioma.
  • AKA mesothelioma.

General

  • Prognosis sucks.

Locations:

  • Lung.
  • Primary peritoneal.

Epidemiology:

  • Strong association with asbestos exposure.

Conditions associated with asbestos exposure (mnemonic PALM):[21]


Possible association with asbestos exposure:

Microscopic

Features:[23]

  • Infiltrative atypical cells - key feature.
    • +/-Epithelioid cells - may be cytologically bland, i.e. benign appearing.
      • Variable architecture: sheets, microglandular, tubulopapillary.
      • +/-Psammoma bodies.
    • +/-Spindle cells.
  • +/-Ferruginous body - strongly supportive.[24]
    • Looks like a (twirling) baton - segemented appearance, brown colour.
    • Thin (asbestos) fiber in the core.

Note:

  • Asbestos body is not strictly speaking a synonym for ferruginous body.

DDx:[25]

Image:

Subtypes

List of subtypes - mnemonic BEDS:[25][23]

  • Biphasic mesothelioma.
    • 10%+ of epithelioid & 10%+ sarcomatoid.
  • Epithelioid mesothelioma.
  • Desmoplastic mesothelioma.
    • Should be 50%+ dense tissue with storiform pattern & atypical cells.
  • Sarcomatoid mesothelioma.

Stains

  • PASD -ve.
  • Mucicarmine -ve.
    • Typically +ve in adenocarcinoma.

IHC

  • Several panel exists - no agreed upon best panel.[26]
    • Usually two carcinoma markers + two mesothelial markers.

Panel:[26]

  • Mesothelial markers:
    • Calretinin.
    • WT-1.
    • D2-40.
    • CK5/6.
  • Carcinoma markers:
    • CEA (monoclonal and polyclonal).
    • TTF-1.
    • Ber-EP4.
    • MOC-31.

Malignant potential

Atypical alveolar hyperplasia

  • Abbreviated AAH.
  • AKA atypical adenomatous hyperplasia of the lung.[27]

General

  • Generally considered the precursor lesion to adenocarcinoma in situ.[28]
  • Typically an incidental finding, i.e. asymptomatic.[29]

Microscopic

Features:[29]

  • Enlarged alveolar lining cells with:
    • Hobnail morphology - free (luminal) surface area > attached/basal surface area.
    • Hyperchromasia.
  • Limited extent:
    • <5 mm. †

DDx:

  • Adenocarcinoma in situ.

Note:

Image:

Atypical carcinoid lung tumour

  • AKA atypical carcinoid tumour of the lung.

General

  • Approximately 20% of lung carcinoids.[30]

Microscopic

Features:[31]

  • Nests of cells.
    • Stippled chromatin.
    • Mild-to-moderate amount of cytoplasm.
  • No necrosis/focal necrosis.
  • Moderate mitotic rate (2-10/HPF - definition suffers from HPFitis).

DDx:

IHC

  • MIB-1 moderate staining.

Solitary fibrous tumour of the pleura

See also: Solitary fibrous tumour.

General

  • Common.
  • Benign.
  • Elderly.

Gross/radiology

  • Chest wall.

Microscopic

Features:

  • Spindle cells.
  • Ropy collagen.

Image:

IHC

  • CD34 +ve.

Benign tumours

Pulmonary carcinoid tumourlet

  • AKA carcinoid tumourlet.

General

Microscopic

Features:

  • Nests of cells - classic pattern.
    • Salt and pepper chromatin - key feature.
  • Size criterion: <= 4 mm.[33]

DDx:

Images:

Typical carcinoid lung tumour

  • AKA carcinoid tumour of the lung.

General

  • Approximately 80% of lung carcinoids.[30]

Microscopic

Features:

  • Nests of cells.
    • Stippled chromatin.
    • Moderate cytoplasm.
  • No necrosis.
  • Low mitotic rate.
  • Size criterion: > 4 mm.[33]

DDx:

IHC

  • MIB-1 scant staining.

Clear cell sugar tumour of the lung

  • AKA clear cell sugar tumour.
    • Abbreviated CCST.

General

Microscopic

Features:[34]

  • Sheets or trabeculae.
  • Irregular epithelioid cells with:
    • Focally clear cytoplasm.

Images:

IHC

  • HMB-45 +ve (nuclear & cytoplasmic).

See also

References

  1. ↑ Righi L, Volante M, Rapa I, Scagliotti GV, Papotti M (August 2007). "Neuro-endocrine tumours of the lung. A review of relevant pathological and molecular data". Virchows Arch. 451 Suppl 1: S51–9. doi:10.1007/s00428-007-0445-0. PMID 17684766.
  2. ↑ URL: http://www.nature.com/modpathol/journal/v21/n2s/full/3801018a.html. Accessed on: 8 September 2010.
  3. ↑ Lutschg JH (January 2009). "Lung cancer". N. Engl. J. Med. 360 (1): 87-8; author reply 88. doi:10.1056/NEJMc082208. PMID 19118313.
  4. ↑ 4.0 4.1 Jagirdar J (March 2008). "Application of immunohistochemistry to the diagnosis of primary and metastatic carcinoma to the lung". Arch. Pathol. Lab. Med. 132 (3): 384-96. PMID 18318581. http://journals.allenpress.com/jrnlserv/?request=get-abstract&issn=0003-9985&volume=132&page=384.
  5. ↑ Hiroshima K, Iyoda A, Shida T, et al (October 2006). "Distinction of pulmonary large cell neuroendocrine carcinoma from small cell lung carcinoma: a morphological, immunohistochemical, and molecular analysis". Mod. Pathol. 19 (10): 1358-68. doi:10.1038/modpathol.3800659. PMID 16862075.
  6. ↑ URL: http://jcp.bmjjournals.com/content/58/9/978.full. Accessed: 11 February 2010.
  7. ↑ Al-Zahrani IH (July 2008). "The value of immunohistochemical expression of TTF-1, CK7 and CK20 in the diagnosis of primary and secondary lung carcinomas". Saudi Med J 29 (7): 957-61. PMID 18626520.
  8. ↑ Compérat E, Zhang F, Perrotin C, et al. (October 2005). "Variable sensitivity and specificity of TTF-1 antibodies in lung metastatic adenocarcinoma of colorectal origin". Mod. Pathol. 18 (10): 1371–6. doi:10.1038/modpathol.3800422. PMID 15861215. http://www.nature.com/modpathol/journal/v18/n10/full/3800422a.html.
  9. ↑ URL: http://emedicine.medscape.com/article/426400-overview. Accessed on: 20 January 2010.
  10. ↑ Chong S, Lee KS, Chung MJ, Han J, Kwon OJ, Kim TS (2006). "Neuroendocrine tumors of the lung: clinical, pathologic, and imaging findings". Radiographics 26 (1): 41–57; discussion 57–8. doi:10.1148/rg.261055057. PMID 16418242.
  11. ↑ 11.0 11.1 URL: http://www.cancer.org/docroot/CRI/content/CRI_2_4_1X_What_is_lung_carcinoid_tumor_56.asp. Accessed on: 16 February 2011.
  12. ↑ WG. February 2010.
  13. ↑ Sun Y, Ren Y, Fang Z, et al. (October 2010). "Lung adenocarcinoma from East Asian never-smokers is a disease largely defined by targetable oncogenic mutant kinases". J. Clin. Oncol. 28 (30): 4616–20. doi:10.1200/JCO.2010.29.6038. PMID 20855837.
  14. ↑ Job B, Bernheim A, Beau-Faller M, et al. (2010). "Genomic Aberrations in Lung Adenocarcinoma in Never Smokers". PLoS One 5 (12): e15145. doi:10.1371/journal.pone.0015145. PMC 2997777. PMID 21151896. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2997777/.
  15. ↑ 15.0 15.1 Travis WD, Brambilla E, Noguchi M, et al. (February 2011). "International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma". J Thorac Oncol 6 (2): 244–85. doi:10.1097/JTO.0b013e318206a221. PMID 21252716.
  16. ↑ John, T.; Liu, G.; Tsao, MS. (Aug 2009). "Overview of molecular testing in non-small-cell lung cancer: mutational analysis, gene copy number, protein expression and other biomarkers of EGFR for the prediction of response to tyrosine kinase inhibitors.". Oncogene 28 Suppl 1: S14-23. doi:10.1038/onc.2009.197. PMID 19680292.
  17. ↑ Pao, W.; Wang, TY.; Riely, GJ.; Miller, VA.; Pan, Q.; Ladanyi, M.; Zakowski, MF.; Heelan, RT. et al. (Jan 2005). "KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib.". PLoS Med 2 (1): e17. doi:10.1371/journal.pmed.0020017. PMID 15696205.
  18. ↑ Li, Y.; Ye, X.; Liu, J.; Zha, J.; Pei, L. (Jan 2011). "Evaluation of EML4-ALK fusion proteins in non-small cell lung cancer using small molecule inhibitors.". Neoplasia 13 (1): 1-11. PMID 21245935.
  19. ↑ Yang, P.; Kulig, K.; Boland, JM.; Erickson-Johnson, MR.; Oliveira, AM.; Wampfler, J.; Jatoi, A.; Deschamps, C. et al. (Jan 2012). "Worse disease-free survival in never-smokers with ALK+ lung adenocarcinoma.". J Thorac Oncol 7 (1): 90-7. doi:10.1097/JTO.0b013e31823c5c32. PMID 22134072.
  20. ↑ Travis, WD.; Brambilla, E.; Noguchi, M.; Nicholson, AG.; Geisinger, K.; Yatabe, Y.; Powell, CA.; Beer, D. et al. (Sep 2011). "International association for the study of lung cancer/American Thoracic Society/European Respiratory Society: international multidisciplinary classification of lung adenocarcinoma: executive summary.". Proc Am Thorac Soc 8 (5): 381-5. doi:10.1513/pats.201107-042ST. PMID 21926387.
  21. ↑ Mitchell, Richard; Kumar, Vinay; Fausto, Nelson; Abbas, Abul K.; Aster, Jon (2011). Pocket Companion to Robbins & Cotran Pathologic Basis of Disease (8th ed.). Elsevier Saunders. pp. 375. ISBN 978-1416054542.
  22. ↑ Reid, A.; Heyworth, J.; de Klerk, N.; Musk, AW. (Nov 2009). "Asbestos exposure and gestational trophoblastic disease: a hypothesis.". Cancer Epidemiol Biomarkers Prev 18 (11): 2895-8. doi:10.1158/1055-9965.EPI-09-0731. PMID 19900938.
  23. ↑ 23.0 23.1 Humphrey, Peter A; Dehner, Louis P; Pfeifer, John D (2008). The Washington Manual of Surgical Pathology (1st ed.). Lippincott Williams & Wilkins. pp. 156. ISBN 978-0781765275.
  24. ↑ URL: http://medical-dictionary.thefreedictionary.com/asbestos+body. Accessed on: 4 November 2011.
  25. ↑ 25.0 25.1 Corson, JM. (Nov 2004). "Pathology of mesothelioma.". Thorac Surg Clin 14 (4): 447-60. doi:10.1016/j.thorsurg.2004.06.007. PMID 15559051.
  26. ↑ 26.0 26.1 Marchevsky AM (March 2008). "Application of immunohistochemistry to the diagnosis of malignant mesothelioma". Arch. Pathol. Lab. Med. 132 (3): 397-401. PMID 18318582. http://journals.allenpress.com/jrnlserv/?request=get-abstract&issn=0003-9985&volume=132&page=397.
  27. ↑ Mori, M.; Rao, SK.; Popper, HH.; Cagle, PT.; Fraire, AE. (Feb 2001). "Atypical adenomatous hyperplasia of the lung: a probable forerunner in the development of adenocarcinoma of the lung.". Mod Pathol 14 (2): 72-84. doi:10.1038/modpathol.3880259. PMID 11235908.
  28. ↑ 28.0 28.1 Sakuma, Y.; Matsukuma, S.; Yoshihara, M.; Nakamura, Y.; Nakayama, H.; Kameda, Y.; Tsuchiya, E.; Miyagi, Y. (Sep 2007). "Epidermal growth factor receptor gene mutations in atypical adenomatous hyperplasias of the lung.". Mod Pathol 20 (9): 967-73. doi:10.1038/modpathol.3800929. PMID 17618248.
  29. ↑ 29.0 29.1 Humphrey, Peter A; Dehner, Louis P; Pfeifer, John D (2008). The Washington Manual of Surgical Pathology (1st ed.). Lippincott Williams & Wilkins. pp. 114. ISBN 978-0781765275.
  30. ↑ 30.0 30.1 Naalsund, A.; Rostad, H.; Strøm, EH.; Lund, MB.; Strand, TE. (Apr 2011). "Carcinoid lung tumors--incidence, treatment and outcomes: a population-based study.". Eur J Cardiothorac Surg 39 (4): 565-9. doi:10.1016/j.ejcts.2010.08.036. PMID 20888248.
  31. ↑ Humphrey, Peter A; Dehner, Louis P; Pfeifer, John D (2008). The Washington Manual of Surgical Pathology (1st ed.). Lippincott Williams & Wilkins. pp. 115. ISBN 978-0781765275.
  32. ↑ Bennett, GL.; Chew, FS. (Mar 1994). "Pulmonary carcinoid tumorlets.". AJR Am J Roentgenol 162 (3): 568. PMID 8109497.
  33. ↑ 33.0 33.1 URL: http://pathhsw5m54.ucsf.edu/case7/image75.html. Accessed on: 23 January 2012.
  34. ↑ 34.0 34.1 34.2 Kim, WJ.; Kim, SR.; Choe, YH.; Lee, KY.; Park, SJ.; Lee, HB.; Chung, MJ.; Jin, GY. et al. (Dec 2008). "Clear cell "sugar" tumor of the lung: a well-enhanced mass with an early washout pattern on dynamic contrast-enhanced computed tomography.". J Korean Med Sci 23 (6): 1121-4. doi:10.3346/jkms.2008.23.6.1121. PMC 2610653. PMID 19119463. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2610653/.
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