CORRESPONDENCE

Re: Axillary Lymph Node Staging in Breast Cancer by 2-Fluoro-2-deoxy-D-glucose–Positron Emission Tomography: Clinical Evaluation and Alternative Management

Hans Torrenga, Jappe Licht, Jacobus J. M. van der Hoeven, Otto S. Hoekstra, Sybren Meijer, Paul J. van Diest

Affiliations of authors: H. Torrenga, S. Meijer (Department of Surgical Oncology), J. Licht, P. J. van Diest (Department of Pathology), J. J. M. van der Hoeven, O. S. Hoekstra (Department of Nuclear Medicine), Vrije Universiteit Medical Center, Amsterdam, The Netherlands.

Correspondence to: Paul J. van Diest, M.D., Ph.D., Department of Pathology, Vrije Universiteit Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands (e-mail: pj.vandiest{at}vumc.nl).

Greco et al. (1) reported that 2-fluoro-2-deoxy-D-glucose–positron emission tomography (FDG–PET) is a reliable and accurate method to predict the axillary status in breast cancers of 1–2 cm in diameter: Histopathology detected axillary lymph node (ALN) metastases in 72 (43%) of 167 patients, and 68 ALN metastases were detected by PET (sensitivity = 94.4%).

To determine the sensitivity of FDG–PET to detect ALN metastases, the histopathologic methodology is crucial. Compared with other PET studies on this subject, a relatively detailed description was provided by Greco et al. (1), who stated, "each lymph node was sectioned into two or three parts, and one or more sections were prepared from each part," and who used only hematoxylin–eosin (H&E) staining. It remains unclear, however, how many sections were taken on average per ALN, which is important information. With step sectioning at regular intervals (e.g., five sections at 250 µm) and immunohistochemistry (e.g., against keratins by using CAM5.2 anti-keratin antibodies), the detection of ALN metastases is markedly increased (2,3). We reported previously (4) a detection difference (i.e., upstaging) of 20% (95% confidence interval [CI] = 11% to 28%) between one section stained with only H&E and five sections examined immunohistochemically. Eight percent of this difference was explained by H&E staining, and 12% was explained by immunohistochemistry. Thus, the less intensive histopathologic method used by Greco et al. is likely to overestimate the accuracy of PET because micrometastases are missed.

Furthermore, as Greco et al. (1) state in their report, the main pitfall in the detection of ALN metastases by PET is the limited spatial resolution and, therefore, the ability to detect metastases of only a few cells. Such small metastases are an important risk factor for axillary recurrence and have an impact on prognosis (5). Consequently, they are generally considered to be an indication for further surgery or adjuvant therapy (6).

PET is clearly able to detect tumors of less than 1 cm in diameter. However, even with very FDG-avid tumors, such as melanoma, this ability decreases with tumors of less than 6 mm in diameter, as reported by the same group (7).

Using video morphometry, we have measured the total tumor load found in the ALNs of 83 patients with positive sentinel nodes. Lymph nodes were subjected to five-level step sectioning at 250-µm intervals and CAM5.2 immunohistochemistry if the initial H&E sections were negative. If all metastatic cells in the different ALNs are considered at one site, which is clearly an optimistic approach, the cumulative frequency distribution of the total ALN tumor load (Table 1Go) suggests that, even at a 3-mm (i.e., 8 mm2) detection limit of PET, the majority of involved sites (55% [95% CI = 44% to 66%]) would have been false negative at imaging.


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Table 1. Cumulative frequency distribution of the total axillary lymph node metastatic tumor load in 83 patients with invasive breast cancer*
 
In conclusion, we think that the sensitivity of 94.4% as described by Greco et al. is overly optimistic because of the histopathologic method used. From the detection limits of PET and histopathology (one cell = approximately 150 µm2), PET may miss a substantial number of patients with involved ALNs that could have been detected by surgical sentinel node-based staging. We admit that most of the metastases missed by PET would be micrometastases, but until it is proven that such metastases are not clinically important, we think that PET scanning cannot safely be used for ALN staging in patients with breast cancer.

REFERENCES

1 Greco M, Crippa F, Agresti R, Seregni E, Gerali A, Giovanazzi R, et al. Axillary lymph node staging in breast cancer by 2-fluoro-2-deoxy-D-glucose–positron emission tomography: clinical evaluation and alternative management. J Natl Cancer Inst 2001;93:630–5.[Abstract/Free Full Text]

2 Torrenga H, Rahusen FD, Borgstein PJ, Meijer S, van Diest P. Immunohistochemical detection of lymph-node metastases [letter]. Lancet 2000;355:144.

3 Cserni G. Metastases in axillary sentinel lymph nodes in breast cancer as detected by intensive histopathological work up. J Clin Pathol 1999;52:922–4.[Abstract]

4 Torrenga H, Rahusen FD, Meijer S, Borgstein PJ, van Diest PJ. Sentinel node in breast cancer: detailed analysis of the yield from step sectioning and immunohistochemistry. J Clin Pathol 2001;54:550–2.[Abstract/Free Full Text]

5 International (Ludwig) Breast Cancer Study Group. Prognostic importance of occult axillary lymph node micrometastases from breast cancers. Lancet 1990;335:1565–8.[Medline]

6 van der Wall E. The sentinel node in breast cancer: implications for adjuvant treatment? Eur J Nucl Med 1999;26(4 Suppl):S17–9.[Medline]

7 Crippa F, Leutner M, Belli F, Gallino F, Greco M, Pilotti S, et al. Which kinds of lymph node metastases can FDG PET detect? A clinical study in melanoma. J Nucl Med 2000;41:1491–4.[Abstract]


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