The pathologic evaluation of lymph nodes (LNs) for metastatic disease plays an important role in the surgical staging of nearly all solid-organ malignancies. Nodal tissue is evaluated by pathology either as part of an en bloc resection or as separate, anatomically distinct specimens. In either case, the specimen is grossly examined and LNs are dissected and submitted for histologic examination via a variety of nonstandardized methods. The surgical pathology report typically includes both the total LN count (LNC), as well as the number of positive LNs, and has developed into a critical aspect of planning cancer treatment protocols. According to the 8th edition of the AJCC Cancer Staging Manual, the pathologic node staging (pN) of 29 of the approximately 70 solid-organ staging systems use LNCs in some form and, of these, 13 are staged solely on the number of positive LNs.1 LNC has been proposed as a metric to assess adequacy of surgical resection and/or pathologic examination, and thresholds of a minimum LNC have been required for inclusion in a number of clinical trials (ClinicalTrials.gov identifiers: NCT00002706 and NCT00340808).2,3
Interest regarding LNC and clinical outcomes is abundant. The literature is replete with large studies investigating the role of LNC and outcomes, many of which demonstrate improved outcomes with higher LNCs.4–7 However, these studies provide very little information regarding methods of nodal quantitation. Nearly all of the published literature simply cites the “pathology report” as the source of LNC data. In the studies that do give additional information on LNC methods, it is typically limited to a brief description of the tissue-processing technique and a nominal statement that tissue was evaluated by standard microscopy.
The lack of formally described LNC methods in these studies may come as a surprise to most non-pathologists. To the uninitiated, LNs in a specimen could be easily compared with jelly beans in a jar: dump them out and count. However, the actual process involves many factors, each with their own challenges. Multiple studies have attempted to assess LNC variability and have demonstrated a variety of factors, including the patient's anatomy, tumor biology, experience of the gross examiner, and use of fat-clearing solutions.6,8–12 Although many of these studies also identify the pathologist as a significant source of variation, this has not been uniformly true.13 By far, the least investigated aspect of LNC is the actual enumeration process of the pathologist during microscopic review; however, this is the time at which the LNC is determined. To date, a single study has evaluated this aspect and demonstrated significant interpathologist variability.14 However, the study was somewhat limited in the number of pathologists (N=10), and the heterogeneity of their practice setting (2 departments). In order to further assess whether LNC represents a scientifically meaningful number, we conducted the largest and most diverse study of LNC by pathologists.
We would like to thank the International Society of Gynecological Pathologists and the British Association of Gynaecological Pathologists for the distribution of the survey to their members. We are indebted to the gynecologic oncology and radiation oncology faculty at the University of Michigan for their thoughtful input into the manuscript.
The authors have disclosed that they have no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors.
Results of the pilot study were previously presented as an abstract at the United States & Canadian Academy of Pathology 2017 Annual Meeting; March 4–10, 2017; San Antonio, Texas.
McDonald JR, Renehan AG, O'Dwyer ST, Haboubi NY. Lymph node harvest in colon and rectal cancer: current considerations. World J Gastrointest Surg 2012;4:9–19.
Fleming ND, Soliman PT, Westin SN et al.. Impact of lymph node ratio and adjuvant therapy in node-positive endometrioid endometrial cancer. Int J Gynecol Cancer 2015;25:1437–1444.
Alagkiozidis I, Weedon J, Grossman A et al.. Extent of lymph node dissection and overall survival in patients with uterine carcinosarcoma, papillary serous and endometrioid adenocarcinoma: a retrospective cohort study. Int J Surg 2015;24:9–13.
Willaert W, Mareel M, Van De Putte D et al.. Lymphatic spread, nodal count and the extent of lymphadenectomy in cancer of the colon. Cancer Treat Rev 2014;40:405–413.
Lykke J, Roikjaer O, Jess Pfor the Danish Colorectal Cancer Group. The relation between lymph node status and survival in stage I-III colon cancer: results from a prospective nationwide cohort study. Colorectal Dis 2013;15:559–565.
Lanowska M, Vasiljeva J, Chiantera V et al.. Implication of the examining pathologist to meet the oncologic standard of lymph node count after laparoscopic lymphadenectomy. Oncology 2010;79:161–167.
Nash GM, Row D, Weiss A et al.. A predictive model for lymph node yield in colon cancer resection specimens. Ann Surg 2011;253:318–322.
Chapman B, Paquette C, Tooke C et al.. Impact of Schwartz enhanced visualization solution on staging colorectal cancer and clinicopathological features associated with lymph node count. Dis Colon Rectum 2013;56:1028–1035.
Berg M, Guriby M, Nordgard O et al.. Influence of microsatellite instability and KRAS and BRAF mutations on lymph node harvest in stage I-III colon cancers. Mol Med 2013;19:286–293.
da Costa DW, van Dekken H, Witte BI et al.. Lymph node yield in colon cancer: individuals can make the difference. Dig Surg 2015;32:269–274.
Forde GK, Carlson JW, Downey GO et al.. A quality process study of lymph node evaluation in endometrial cancer. Int J Gynecol Pathol 2011;30:335–339.
Parkash V, Bifulco C, Feinn R et al.. To count and how to count, that is the question: interobserver and intraobserver variability among pathologists in lymph node counting. Am J Clin Pathol 2010;134:42–49.
Plummer M. JAGS: A Program for Analysis of Bayesian Graphical Models Using Gibbs Sampling. Available at: https://www.r-project.org/conferences/DSC-2003/Proceedings/Plummer.pdf. Accessed March 14, 2018.
Johnson PM, Malatjalian D, Porter GA. Adequacy of nodal harvest in colorectal cancer: a consecutive cohort study. J Gastrointest Surg 2002;6:883–890.
Ostadi MA, Harnish JL, Stegienko S, Urbach DR. Factors affecting the number of lymph nodes retrieved in colorectal cancer specimens. Surg Endosc 2007;21:2142–2146.
Evans MD, Barton K, Rees A et al.. The impact of surgeon and pathologist on lymph node retrieval in colorectal cancer and its impact on survival for patients with Dukes' stage B disease. Colorectal Dis 2008;10:157–164.
Rieger NA, Barnett FS, Moore JW et al.. Quality of pathology reporting impacts on lymph node yield in colon cancer. J Clin Oncol 2007;25:463–464.
Euscher ED, Bassett R, Malpica A. Lymph node counts in endometrial cancer: expectations versus reality. Am J Surg Pathol 2011;35:913–918.
Bakkum-Gamez JN, Mariani A, Dowdy SC et al.. The impact of surgical guidelines and periodic quality assessment on the staging of endometrial cancer. Gynecol Oncol 2011;123:58–64.
Smith DC, Macdonald OK, Lee CM, Gaffney DK. Survival impact of lymph node dissection in endometrial adenocarcinoma: a Surveillance, Epidemiology, and End Results analysis. Int J Gynecol Cancer 2008;18:255–261.
Markl B. Stage migration vs immunology: the lymph node count story in colon cancer. World J Gastroenterol 2015;21:12218–12233.
Johnson PM, Porter GA, Ricciardi R, Baxter NN. Increasing negative lymph node count is independently associated with improved long-term survival in stage IIIB and IIIC colon cancer. J Clin Oncol 2006;24:3570–3575.
Moorcraft SY, Marriott C, Peckitt C et al.. Patients' willingness to participate in clinical trials and their views on aspects of cancer research: results of a prospective patient survey. Trials 2016;17:17.