Histopathology of Lung Cancer

A definite diagnosis of lung cancer involves the assessment of a lung biopsy (sample of lung tumor detected by imaging methods) under the microscope. The histopathology process in lung cancer diagnosis may include morphological characterization, immunohistochemistry (IHC) and often, molecular or genetic tests (biomarker tests). Patients with metastatic disease are recommended to receive programmed cell death ligand 1 (PD-L1) testing for therapy potential use of immunotherapy.

Pathologists observe and run several tests on the biopsy and record their observations in a biopsy or histopathology report. This report contains some medical terms but we have included explanations to help you understand what you will expect in it.

Upon detecting a suspected lung cancer case, the oncologist or surgeon sends a sample of abnormal tissue to the pathologists for histopathology assessment. The lung biopsy may come in the form of

• Tiny tissue samples from a needle or bronchial biopsy
• Whole tumor from surgical resection
• Cytology-type specimen (e.g., sputum or mucus) from effusion fluid or from needle aspirates

Any biopsy samples can be used in histopathology assessment as long as sufficient tumor cells are in the sample. If the sample is mishandled or improperly processed, loss of material can occur, resulting in insufficient material for a full, comprehensive diagnosis.

The initial step of tissue handling and processing involves

• Slicing of tissue block into thin sections
• Preservation of tissue sections
• Fixing tissue sections onto slides for microscopic analysis
• Basic staining of tissue section for easier visualization under the microscope

The pathologist would first determine the tumor cell morphology (or appearance) based on the cell characteristics seen by eyes under the microscope. A small cell lung cancer (SCLC) tumor can be easily distinguished from a non-small cell lung cancer (NSCLC) tumor based on the cell morphology.

Thereafter, the NSCLC cases are further classified into specific subtypes like

• Adenocarcinoma
• Squamous cell carcinoma
• NSCLC-NOS (not otherwise specified)

NSCLC-NOS is a diagnostic term for neither adenocarcinoma nor squamous cell carcinoma.

Adenocarcinoma and squamous cell carcinoma have distinctive morphological characteristics. However, the NSCLC-NOS cells lack adenocarcinoma and squamous cell carcinoma morphological characteristics.

An additional test, like immunohistochemistry (IHC), is needed to distinguish the subtypes accurately based on the specific molecular patterns on NSCLC-NOS cells. In IHC, scientists have identified and established the specific patterns for different lung cancer subtypes.

Based on the distinct patterns of IHC markers, NSCLC-NOS cases can be accurately classified as adenocarcinoma or squamous cell carcinoma. If a case lacks both morphologic characteristics and IHC evidence of adenocarcinoma and squamous cell carcinoma, it may be classified as a “null” immunophenotype and may sometimes be suggested as the large cell carcinoma.

Small cell lung cancer. Patients are to undergo treatment based on the two-stage system (limited or extensive stage).

Non-small cell lung cancer (mainly adenocarcinoma and squamous cell carcinoma). To identify actionable targets, molecular testing is recommended for every patient with metastatic or advanced NSCLC. For newly diagnosed patients, doctors would first recommend testing for

• EGFR – on either tissue or blood, taking 1-2 weeks
• ALK – on tissue via IHC or FISH (fluorescence in-situ testing)

Besides EGFR mutation and ALK rearrangement, other actionable targets for NSCLC include

• DDR2 (discoidin domain receptor 2)
• PI3KCA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)
• FGFR1 (fibroblastic growth factor receptor 1)
• AKT1 (RAC-alpha serine/threonine-protein kinase)
• Programmed death-ligand 1, PD-L1 by immunohistochemistry (IHC) or newer methods

Other NSCLC subtypes. Other subtypes without actionable targets can be treated by systemic therapy like chemotherapy or immunotherapy.

Related: Genetics Of Lung Cancer and How To Test Them

The diagnosis of lung cancer presents several formidable challenges, primarily revolving around the critical factor of time and the judicious utilization of limited tissue samples.

1. Time is a paramount concern in cancer diagnosis – early detection and swift diagnosis lead to less aggressive treatments and improved survival rates
2. Pathologists must be meticulous in minimizing tissue usage during each diagnostic test, all while anticipating subsequent phases of diagnosis. Striking the right balance is crucial. On one hand, they must prioritize patient safety, cautiously deliberating on the use of invasive biopsy techniques, ensuring minimal harm while extracting a sufficient amount of tumor tissue. On the other hand, the lung tumor biopsy is often conducted using only the naked eye, which adds an element of subjectivity and challenge to the procedure. Subsequently, during microscopic assessment, it becomes imperative to extract fewer tumor cells from a biopsy sample that may be intermingled with normal cells to ensure there is enough material for comprehensive laboratory tests.

The histopathology diagnosis of lung cancer is a complex and time-sensitive process involving the careful analysis of tissue samples. The challenges include the need for swift and accurate diagnosis, the judicious use of limited tissue samples, and the inherent subjectivity in some aspects of the process. Despite these challenges, accurate histopathology assessments are vital in tailoring effective treatment strategies and ultimately improving the outcomes and survival rates for lung cancer patients.