J Pathol Transl Med.  2015 Jul;49(4):310-317. 10.4132/jptm.2015.05.13.

Analysis of Histologic Features Suspecting Anaplastic Lymphoma Kinase (ALK)-Expressing Pulmonary Adenocarcinoma

  • 1Department of Pathology, Soonchunhyang University Seoul Hospital, Soonchunhyang University College of Medicine, Seoul, Korea.
  • 2Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. hanjho@skku.edu
  • 3Department of Pathology, Gwangmyeong Sungae Hospital, Gwangmyeong, Korea.


Since 2007 when anaplastic lymphoma kinase (ALK) rearrangements were discovered in non-small cell lung cancer, the ALK gene has received attention due to ALK-targeted therapy, and a notable treatment advantage has been observed in patients harboring the EML4/ALK translocation. However, using ALK-fluorescence in situ hybridization (FISH) as the standard method has demerits such as high cost, a time-consuming process, dependency on interpretation skill, and tissue preparation. We analyzed the histologic findings which could complement the limitation of ALK-FISH test for pulmonary adenocarcinoma.
Two hundred five cases of ALK-positive and 101 of ALK-negative pulmonary adenocarcinoma from January 2007 to May 2013 were enrolled in this study. The histologic findings and ALK immunohistochemistry results were reviewed and compared with the results of ALK-FISH and EGFR/KRAS mutation status.
Acinar, cribriform, and solid growth patterns, extracellular and intracellular mucin production, and presence of signet-ring-cell element, and psammoma body were significantly more often present in ALK-positive cancer. In addition, the presence of goblet cell-like cells and presence of nuclear inclusion and groove resembling papillary thyroid carcinoma were common in the ALK-positive group.
The above histologic parameters can be helpful in predicting ALK rearranged pulmonary adenocarcinoma, leading to rapid FISH analysis and timely treatment.


Lung; Adenocarcinoma; Anaplastic large cell lymphoma kinase; Anaplastic lymphoma kinase; in situ hybridization, fluorescence

MeSH Terms

Carcinoma, Non-Small-Cell Lung
Complement System Proteins
In Situ Hybridization
In Situ Hybridization, Fluorescence
Intranuclear Inclusion Bodies
Thyroid Neoplasms
Complement System Proteins


  • Fig. 1. Fluorescence in situ hybridization (FISH) of anaplastic lymphoma kinase (ALK)-rearranged pulmonary adenocarcinoma. Rearranged tumor nuclei show split signals (arrows) of 3´ (orange color) and 5´ (green color) ends of the gene hybridized using a dualcolor ALK break-apart FISH probe (Vysis LSI ALK Dual Color, Break Apart Rearrangement Probe, Abbott Molecular).

  • Fig. 2. Histologic features of anaplastic lymphoma kinase (ALK)-rearranged pulmonary adenocarcinoma. (A) ALK-rearranged tumors show variable growth patterns. At low magnification, the tumor shows solid, acinar, and papillary growth patterns. (B) Cribriform and micropapillary patterns are more frequent in ALK-positive pulmonary adenocarcinoma. (C) Tumors have frequent extracellular and intracellular mucin production. (D) Solid growth is frequently found to contain signet-ring-cells. (E) A few psammoma bodies are noted in the background of mixed tumor and extracellular mucin. (F) Some tumors contain goblet cell-like cells. (G) Intranuclear inclusion and nuclear groove resembling papillary thyroid carcinoma are frequently found. (H) On the biopsied specimen from the patient showing dramatic response to ALK-targeted therapy before ALK-fluorescence in situ hybridization, many signet-ring-cells are found. (I) Tumor cells in Fig. 2H show 3+ ALK-immunohistochemistry score.

Cited by  1 articles

Non-small Cell Lung Cancer with Concomitant EGFR, KRAS, and ALK Mutation: Clinicopathologic Features of 12 Cases
Taebum Lee, Boram Lee, Yoon-La Choi, Joungho Han, Myung-Ju Ahn, Sang-Won Um
J Pathol Transl Med. 2016;50(3):197-203.    doi: 10.4132/jptm.2016.03.09.


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