Beyond the Basics: Unique Markers May Assist in Morphologic Classification

OncologyLive, August 2012, Volume 13, Issue 8

The presence of specific molecular biomarkers may assist in determining the correct morphologic diagnosis of the particular cancer being examined.

Maurie Markman, MD

Editor-in-Chief of OncologyLive

Senior vice president for Clinical Affairs and National Director for Medical Oncology Cancer Treatment Centers of America, Eastern Regional Medical Center

The role of immunohistochemical markers in assisting the clinical pathologist in the establishment of a specific histological diagnosis of malignant disease is well established. Further, the information provided may be of considerable prognostic significance and indicate a relatively more or less favorable biology associated with the disease process in the individual patient.

Yet while the presence of particular markers on or within tumor cells has long assisted in the selection of specific therapeutic options (eg, estrogen receptor and HER2 status in breast cancer), more recent experience has rather substantially expanded the patient populations and disease entities where such data are of major clinical relevance. Examples include the presence of a KRAS mutation in metastatic colon cancer, a BRAF mutation in metastatic melanoma, and ALK rearrangement in lung cancer.

In an interesting twist on this rapidly evolving story, the presence of specific molecular biomarkers not only may be useful in selecting effective approaches and avoiding ineffective strategies, but also may assist in determining the correct morphologic diagnosis of the particular cancer being examined.

For instance, the important predictive role of the presence of an activating EGFR mutation in defining a population of individuals with non-small cell lung cancer likely to have the greatest opportunity to experience benefit following treatment with a tyrosine kinase inhibitor of EGFR is well-established.1 It also has been recognized that certain clinical features characterize the patient populations most likely to harbor an activating EGFR mutation. These characteristics include female sex, non-smoker, Asian ethic background, and adenocarcinoma morphology.

However, it remained a rather controversial question as to whether such activating mutations actually occur in patients with pure squamous cell carcinoma of the lung. Similar uncertainties existed with regard to the issue of whether KRAS mutations are ever seen in this morphologic type of non-small cell lung cancer.

Study of Driver Oncogenes in Lung Tumors2

Sample size

95 resected squamous cell carcinomas (SQCC) verified by immunohistochemistry

Mutation screening

9EGFR, KRAS, BRAF, PIK3CA, NRAS, AKT1, ERBB2/HER2, and MAP2K1/MEK1 genes, as well as EGFR/KRAS

Mutations found


1 AKT1



16 cases previously identified as EGFR/KRAS-mutant SQCC during clinical genotyping reclassified:

  • 10 (63%) cases as adenocarcinoma SQC
  • 5 (31%) cases as poorly differentiated adenocarcinoma with squamoid morphology
  • 1 (6%) case had no follow-up

Conducted at Memorial-Sloan Kettering Cancer Center

To address this issue directly, investigators at the Memorial Sloan-Kettering Cancer Center in New York City very carefully examined 95 cases of squamous cell lung cancer seen in their program, an analysis that included a comprehensive panel of immunohistochemical biomarkers.2 Of considerable interest, no cases in this relatively large patient population were found with an activating EGFR mutation. In addition, there were no KRAS mutations observed in this group of tumors.

Further, and of greatest relevance to the specific topic being highlighted in this commentary, the researchers re-examined a number of tumors seen in their department over the preceding five years where a diagnosis of EGFR or KRAS mutation-positive squamous cell lung cancer had been provided by the clinical pathology laboratory (n = 15 patients). In each case, the cancers in this limited retrospective sample were reclassified through use of the comprehensive immunohistochemical laboratory panel as being either a mixed (adenosquamous cell cancer) histology or a poorly differentiated adenocarcinoma.

These data, if confirmed by others, support the hypothesis that activating mutations in EGFR do not occur in pure squamous cell lung cancer, and, if such a mutation is observed, the cancer is either of mixed histology or is a poorly differentiated adenocarcinoma whose morphologic features are difficult to define due to its lack of differentiation.

This report adds to the growing literature demonstrating the major clinical utility of molecular testing within the pathology laboratory, not only to define morphology but also to assist the oncologist in optimizing management decisions.


  1. Keedy VL, Temin S, Somerfield MR, et al. American Society of Clinical Oncology provisional clinical option: epidermal growth factor receptor (EGFR) mutation testing for patients with advanced non-small-cell lung cancer considering first-line EGFR tyrosine kinase inhibitor therapy [published online ahead of print April 11, 2011]. J Clin Oncol. 2011; 29(15):2121-2127. doi:10.1200/JCO.2010.31.8923.
  2. Rekhtman N, Paik PK, Arcila ME, et al. Clarifying the spectrum of driver oncogene mutations in biomarker-verified squamous carcinoma of the lung: lack of EGFR/KRAS and presence of PIK3CA/AKT1 mutations [published online ahead of print January 6, 2012]. Clin Cancer Res. 2012;18(4):1167-1176. doi: 10.1158/1078-0432.CCR-11-2109.