Is positron emission tomography an accurate non-invasive alternative to sentinel lymph node biopsy in breast cancer patients?

Abstract

Breast cancer is the most common malignancy among women, leading to approximately 45 000 deaths per annum in the United States (1). The presence of axillary lymph node metastases has major prognostic implications in breast cancer patients (2,3), and it is an important criterion in determining the need for adjuvant chemotherapy (4). Sentinel lymph node (SLN) biopsy has become routine practice in the surgical treatment of patients with breast cancer because the disease status of the SLNs accurately reflects the status of the remaining axillary lymph nodes (5–7). Hence, patients who present with a negative SLN (no metastases) can be spared from having a more traumatic axillary lymph node dissection (ALND), which has been shown to be associated with substantial shortand long-term sequelae (8,9). Despite the enormous advantages of SLN biopsy over ALND in regard to post-operative complications in nodenegative patients, it would be of great clinical benefit if a reliable non-invasive method to assess lymph node status in breast cancer patients could be found. Positron emission tomography (PET) reflects the biochemical and physiologic processes occurring in the tissues being imaged and has been used in diagnosing a variety of malignancies (10, 11). The most frequently used positron emitting radiopharmaceutical is 18-fluor labeled 2-deoxy-D-glucose (F-FDG), a radioactively labeled glucose analog. The clinical use of F-FDG–PET is based on the premise that cancer cells exhibit a higher glycolytic rate than do non-neoplastic cells. Thus, F-FDG accumulates predominantly in the tumor tissue and can be visualized by a PET camera. Since the first reported visualization of lymph node metastases with F-FDG–PET in a preclinical animal study in 1990 (12), several investigations (13–19) have assessed the accuracy of PET in evaluating the nodal status of patients with breast cancer. These investigations have yielded conflicting results, with some investigators doubting that F-FDG–PET is capable of accurately assessing the nodal status of breast cancer patients (13–16) and others believing that a noninvasive PET scan could replace SLN biopsy at predicting the disease status of the axillary lymph nodes (17–19). In a recent investigation by an Italian group (18), preoperative F-FDG–PET was compared with the histologic findings of ALND in 167 clinically node-negative T1 (tumor size 2cm) and T2 (tumor size >2cm to 5cm) breast cancer patients, the largest patient collective published. F-FDG–PET detected 68 of 72 patients with axillary metastases, resulting in an overall sensitivity for PET of 94%. In the subset of T2 patients, the sensitivity was even higher (98%; 48/49), with only one false-negative finding. Based on these results, the authors claimed that F-FDG–PET can safely predict axillary lymph node status in patients with breast cancer and is a reliable and accurate method to identify patients who can avoid ALND. In the second largest published patient collective (19), preoperative F-FDG–PET was compared with the histologic findings of ALND in 124 pT1–T3 (T3 tumor size >5cm) breast cancer patients. PET scanning correctly identified all 44 patients with axillary lymph node metastases, resulting in an overall sensitivity for PET of 100%. These findings led the investigators of that study to suggest that F-FDG–PET should be considered as the initial test in evaluating axillary lymph nodes in breast cancer patients and that those patients without increased axillary F-FDG-uptake may not require ALND. Other investigations (17,20–23) with smaller patient numbers have reported similar findings, with sensitivities of pre-operative F-FDG–PET at detecting axillary lymph-node metastases ranging from 90% to 100%. In contrast to the above-mentioned investigations, several studies have found that F-FDG–PET has a low sensitivity at detecting SLN or axillary lymph node metastases. Indeed, Avril et al. (14) suggest that F-FDG–PET scanning cannot substitute for histologic analyses of axillary lymph nodes. Their study compared the diagnostic potential of F-FDG–PET with ALND in 41 breast cancer patients and reported an overall sensitivity for PET of 79% (19/24). PET sensitivity in the subset of patients with pT1 tumors was, however, only 33%; four of six patients had false-negative results, and the largest metastasis undetected by F-FDG–PET measured 12 mm in diameter. Kelemen et al. (15) also found low PET sensitivity when they compared F-FDG–PET scanning with the histolopathologic findings of SLN biopsies in clinically node-negative T1 and T2 breast cancer patients. If the SLN biopsies were negative by hematoxylin and eosin (H&E) staining, further biopsy sections were obtained for immunohistochemical (IHC) analyses using polyclonal anticytokeratin (CK) antibodies. Four of five patients with SLN metastases had false-negative F-FDG–PET scans (i.e., F-FDG–PET sensitivity was only 20%), and the missed metastases ranged from a micro-metastasis (defined as a cohesive cluster of malignant cells >0.2 mm to 2.0 mm in diameter), which was identified by IHC only, to macro-metastases up to 11 mm in