Immunohistochemistry in Subtyping Non-small Cell Lung Cancer
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Coping with lung cancer can be overwhelming, especially since it is a heterogeneous disease with various subtypes. These subtypes are classified based on microscopic appearance and genetic profile. To determine the cause and progression of cancer, a detailed histopathology report that provides comprehensive information is crucial. This report should include specific details on the subtype of the biopsied tumor and actionable genetic targets that can help doctors plan the most effective therapy for each patient. Pathologists use immunohistochemistry (IHC) to subtype tumor cells based on markers, which is an essential part of the diagnostic process.
Immunohistochemistry is a method that uses specialized antibodies to locate and bind specific targets or markers on cells. Fluorescent dyes or other detection tags can recognize these antibodies and produce quantifiable signals.
What are the aims of immunohistochemistry in the histopathology of lung cancer?
Pathologists perform IHC for two reasons:
- When the tumor cells are poorly differentiated morphologically
- To identify whether the biopsy sample is a primary tumor or metastatic (spread from another cancer site)
Histopathology processes in lung cancer diagnosis. Image data from: Medscape
In a histopathology analysis, the pathologist would first examine the tumor cells' morphology (or appearance) based on the cell’s characteristics under a microscope. This analysis can determine whether the tumor is a small cell lung cancer (SCLC) or a non-small cell lung cancer (NSCLC).
However, if the morphological characteristics are too subtle to diagnose NSCLC accurately, the sample will be classified as NSCLC-NOS (not otherwise specified). The sample will undergo an IHC test that uses markers to classify the tumor more accurately. This technique enables the pathologist to gain further insight into the tumor’s characteristics, ultimately resulting in a more accurate diagnosis.
Morphological diagnosis and IHC evidence of adenocarcinoma and squamous cell carcinoma
Adenocarcinoma | Squamous cell carcinoma |
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Taken from: Zheng M. (2016).
Using a panel of IHC markers, the NSCLC-NOS cases can be accurately classified as adenocarcinoma or squamous cell carcinoma. After confirmation by an IHC, large cell carcinoma is diagnosed if the biopsy lacks both:
- Morphologic characteristics of adenocarcinoma and squamous cell carcinoma
- IHC evidence of adenocarcinoma and squamous cell carcinoma
The lung is a frequent target of metastasis. An IHC helps to confirm the biopsy sample as
- A primary tumor OR
- A metastatic tumor
A metastatic tumor usually expresses distinct patterns of markers CK7 and CK20 while lacking the expression of primary lung cancer markers like TTF-1 and NapsinA. It is important to note that these IHC markers are used to distinguish NSCLC subtypes, and they are different from the biomarkers targetable by drugs. For biomarkers used in targeted therapy, see Genetics Of Lung Cancer and How To Test Them.
IHC markers used in subtyping NSCLC and metastatic tumors
Adenocarcinoma | Squamous cell carcinoma | Large cell carcinoma | Metastatic tumor |
|---|---|---|---|
✔ TTF-1 ✔ NapsinA 🗶 p40 🗶 p63 🗶 CK5/6 🗶 CK5 | ✔ p40 ✔ p63 ✔ CK5/6 ✔ CK5 🗶 TTF-1 🗶 NapsinA | 🗶 TTF-1 🗶 NapsinA 🗶 p40 🗶 p63 🗶 CK5/6 🗶 CK5 | ✔ CK7 ✔ CK20 🗶 TTF-1 🗶 NapsinA 🗶 p40 🗶 p63 🗶 CK5/6 🗶 CK5 |
Taken from: Zheng M. (2016).
For the complete list of the 2015 World Health Organizations Classification of Lung Tumors, refer to Travis et. al., The 2015 World Health Organization Classification of Lung Tumors: Impact of Genetic, Clinical and Radiologic Advances Since the 2004 Classification. J Thorac Oncol. 2015 Sep;10(9):1243-1260.
Why is IHC subtyping so important?
Different NSCLC subtypes respond differently to various chemotherapeutic agents. For instance, certain chemotherapy drugs may be more effective against adenocarcinoma than squamous cell carcinoma. For optimal subtype-based treatments, it is important to distinguish between adenocarcinoma, squamous cell carcinoma, and other NSCLC subtypes. Failure to do so may lead to unnecessary drug toxicity and other harmful effects.
Related: Technologies Currently Used in Biomarker Testing for Lung Cancer
Challenges in IHC subtyping?
Several pitfalls can affect the accuracy of IHC in subtyping NSCLC, including:
- The quality of tissue specimen - poor preservation and handling of tissue specimen can affect the reliability of IHC
- Misinterpretation of IHC results - subtle IHC results require highly experienced pathologists to differentiate between specific and non-specific signals
- False positivity or false negativity - IHC tests are not 100% accurate all the time. Various factors, encompassing selection of antibodies and technical errors arising from the IHC process, may produce false-positive or false-negative results.
Although undergoing many tests to detect and diagnose cancer can be quite exhausting and mentally draining, it should be remembered that they are crucial for achieving a better treatment outcome and recovery. Therefore, the best thing to do is to work with healthcare providers and follow their recommendations to ensure the most effective and safe treatment plan for each case.
Read next: Histopathology of Lung Cancer
