Does nodal micrometastasis impact outcome in biliary cancer?

The prognosis of biliary cancer is poor, largely because of the high proportion of patients in whom lymph-node metastasis has already occurred by the time of presentation and a poor response to nonsurgical therapies. Preoperative staging of nodal status is an important part of the assessment of treatment options but might be misleading; computed tomography has poor sensitivity, whereas endoscopic ultrasonography is valuable in the evaluation of the extent of cancer invasion as well as the involvement of regional lymph nodes. These imaging techniques only detect macroscopic changes. Lymph nodes that appear normal macroscopically, and even microscopically using conventional histopathological staining, might harbor microscopic deposits of tumor cells. The significance of these micrometastases has not previously been elucidated wrote Dr Michael Silva of the Department of Transplantation and Hepatobiliary and Pancreatic Surgery, Churchill Hospital, Headington, UK in the December issue of Nature Reviews Clinical Oncology.

The Union for International Cancer Control has advocated the use of the term micrometastasis for deposits of 2 mm or less in size. To differentiate shed tumor cells with limited metastatic potential from true micrometastasis, recent studies have classified metastatic tumor cells by size into 'micrometastasis' (≥0.2 mm diameter) and 'isolated tumor cells' (<0.2 mm diameter). The potential aggressiveness of a micrometastasis is dependent on poorly explored parameters including cell number and location. This classification has not been validated in terms of prognostic value.

While the majority of studies have shown a worse prognosis in association with the presence of nodal micrometastasis, others have shown no impact on survival. It is of note that, overall, the incidence of detected micrometastasis seems to be similar among these studies, although most involved small patient cohorts ranging from 25 to 70 patients. There is a further lack of consensus on the number of lymph nodes that should be analyzed in staging bile duct cancer. The American Joint Committee on Cancer (AJCC) staging manual states that histologic examination of at least three lymph nodes is required for adequate N-stage determination for extrahepatic bile duct cancer; this recommendation has not been validated. In a recent study from the Memorial Sloan–Kettering Cancer Center, the estimated optimal total lymph node count for proximal cholangiocarcinoma (seven) differed from that of distal cholangiocarcinoma (eleven); this suggests that the current AJCC recommendations are at risk of under-staging these tumors.

The debate about the prognostic significance of regional lymph-node micrometastasis in patients with node-negative biliary cancer has recently been revisited by Yonemori and colleagues who conducted a single-center, retrospective analysis of archival, formalin-fixed, paraffin-embedded lymph nodes from patients who had undergone curative resection for biliary cancer with regional lymphadenectomy. Of the 243 patients, 92 (38%) showed regional lymph-node metastases with hematoxylin and eosin (H&E) staining. It should be noted that this was also a heterogeneous group, including patients with carcinoma of gall bladder, proximal and distal bile duct, and ampulla.

A total of 1,421 lymph nodes from 151 patients with biliary cancer, that were classed as negative for tumor with conventional H&E staining, were re-examined using immunohistochemical methods. Micrometastases were classified as small (≤0.2 mm diameter) and large (>0.2 mm diameter) and were diagnosed in 49 (3%) regional lymph nodes from 33 (22%) patients. These micrometastases were small in 23 patients (15%) and large in 10 (7%). In these patients, the 3-year and 5-year survival of 46% and 15%, respectively, was significantly worse than in patients negative for micrometastasis (68% and 57%, respectively; P = 0.005). Both small and large micrometastases had a negative impact on survival. The authors published their results in the Annals of Surgery.

It might be helpful to consider under what circumstances knowledge of the micrometastasis status of the patient might usefully influence treatment. Certainly, it allows more accurate staging and prognosis, but does not influence the decision to operate (or what operation to perform) since the information is only available postoperatively (and intraoperative analysis would not be feasible with current technology). One might speculate that this cohort of patients with histopathology-node-negative, micrometastasis-positive disease might be the subset of patients that would benefit from a very aggressive strategy of adjuvant therapy. Currently, there is no direct evidence to support this hypothesis.