EUS-FNA and biomarkers for the staging of non-small cell lung cancer

Background

Non-small cell carcinoma of the lung (NSCLC) is the most common cause of cancer death in the United States [1], with more than 160,000 annual deaths [2]. The American Joint Committee on Cancer TNM system is the current staging system for lung cancer, and its goal is to classify patients into groups based on the extent of disease. This system relies heavily on the pathologic evaluation of the primary tumor (T), regional nodes (N) and distant metastases (M). Lymph nodes in the mediastinum are the most common sites of metastases. Recent advances in molecular diagnostics has great potential to increase the accuracy of detection of both primary tumors and metastatic lymph nodes by enabling detection of very small numbers of cancer cells (”micrometastases”) using minimally invasive sampling techniques such as image-guided fine needle aspiration (FNA).

Mediastinal lymph nodes evaluation is a critical component of staging NSCLC patients. Lymph nodes larger than 1 cm in diameter by CT are presumed to contain metastatic disease. However, when compared with surgical pathology, CT misses mediastinal lymph node metastases (false negative) in approximately 13 % of patients and incorrectly suggests it (false positive) in approximately 50 % [3]. Because of this limitation, mediastinoscopy has, for years, been accepted as the ”gold standard” for mediastinal staging. Mediastinoscopy requires general anesthesia and specialized expertise to perform safely, and therefore is not universally employed.

Recently, positron emission tomography (PET) has emerged as a non-invasive method for evaluating cancer stage. Recent studies suggest that the sensitivity and specificity of PET may be in excess of 80 - 90 % [4] [5]. Because PET relies on the accumulation of a radioactive tracer in proportion to cellular metabolic activity, its ability to detect microscopic tumor deposits and distinguish between inflammation and cancer is limited. Moreover, PET and CT scan cannot make a tissue diagnosis.

The presence or absence of mediastinal lymph node metastases has been classically dependent on histological analysis alone. However, survival statistics indicate clearly that reliance on histology is inadequate. Following presumably curative surgical resection, the five-year survival rate for patients with pathologic stage I disease (no histologic evidence of lymph node metastases) is only 62 %. For patients with metastatic disease identified in hilar lymph nodes but not mediastinal lymph nodes (stage II), the five-year survival rate falls to only 42 % [6]. These figures clearly suggest that histological evaluation of mediastinal lymph nodes may miss metastatic disease in a large proportion of patients with NSCLC. Studies have shown that serial sectioning and immunohistochemical staining increase the sensitivity of detection of metastatic disease, and that the presence of metastatic disease detected in this fashion is associated with worse survival [7] [8] [9]. Although serial sectioning provides the ability to detect clinically significant metastatic disease, it is extremely time-consuming and expensive and is thus is not practical performed on routine basis.

Standard therapies for patients with NSCLC include surgery, chemotherapy and radiation therapy, depending on the stage of disease. Surgery is considered most appropriate for patients in whom disease is confined to the lung and hilar lymph nodes (stages I and II). For patients with metastatic disease to mediastinal lymph nodes (stage III), the benefit of surgery as primary therapy is questionable and combined chemo-radiotherapy may be most appropriate [10]. Better preoperative staging would reduce the rate of unnecessary surgical exploration and morbidity.

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