Fredrick L. Kiechle, MD, PhD
Q. As a hospital coagulation laboratory director, I would like advice on how laboratories need to prepare for the change in United States Pharmacopeia potency of heparin that is taking place, before the new, less potent lots of heparin come into patient use. Does the laboratory need to repeat a full validation of the heparin sensitivity of the APTT to verify the target ranges? When we validate new lots of APTT reagent, we collect specimens from patients receiving heparin in our hospital and we perform anti-Xa levels. But if we need to validate our target ranges for the new lot of heparin, presumably we would not wait until the heparin is already in use. Should we spike normal plasmas with the new lot of heparin to determine target APTT ranges?
A. Current and former members of the CAP Coagulation Resource Committee have shared their thoughts and contacted coagulation reagent manufacturers and other organizations. I will summarize our consensus:
1. The approximately 10 percent decrease in unfractionated heparin USP potency will not affect APTT-based therapeutic ranges, since prolongation of clotting times is dependent upon circulating heparin activity and other biological variables but is not a direct measurement of pharmaceutical potency.
2. Our major concern was how manufacturers calibrate heparin activity assays (anti-Xa). Feedback from Stago, Siemens, and Aniara/Hyphen confirms they use calibrators derived from the WHO 5th international heparin standard and not based on USP. Thus, current as well as future APTT therapeutic heparin ranges correlated with these manufacturers’ anti-Xa kits (therapeutic range 0.3–0.7 U/mL) derived from plasma samples from patients receiving heparin infusions should not be affected by the change in potency.
Instrumentation Laboratory offers two chromogenic heparin activity kits (sold through Beckman Coulter in the United States). HemosIL Heparin does not include heparin calibrators, so users calibrate with heparin obtained from their respective pharmacies, and they will be affected by the change in potency. HemosIL Liquid Heparin does include heparin calibration material (sold separately) traceable to the WHO international standard. Laboratories performing heparin activity testing are encouraged to contact their suppliers to determine if the change in heparin USP potency will affect their test results.
3. Heparin dosing nomograms: We are taking a wait-and-see approach, in collaboration with pharmacy departments, to see if there are delays in time to achieve a therapeutic APTT after initial bolus and infusion rates. It will take a while to identify a significant trend. We currently do not anticipate a need to adjust dosing nomograms, given the variable and low bioavailability of unfractionated heparin, imprecision in APTT measurements, and poor correlations between APTT and anti-Xa activities when establishing APTT reagent lotspecific therapeutic ranges. Clinicians who use ACTs to monitor higher heparin concentrations for cardiopulmonary bypass and cardiac catheterization procedures are also potentially affected by the change in heparin potency.
We will continue to monitor the situation and provide updates as needed.
Charles S. Eby, MD
Associate Professor, Division of Laboratory and
Genomic Medicine Department of Pathology
School of Medicine
Chair, CAP Coagulation
Q. Despite diligent searching and the use of O-fix, we continue to have occasional colorectal resections for carcinoma in which we find fewer than 12 negative mesenteric or perirectal lymph nodes. Rather than signifying understaging because of incompetence or laziness on the part of the pathologist or pathology assistant, could finding fewer than 12 lymph nodes in these cases be an indication of impaired cellular immunity on the part of the patient? Could that be the reason this group of patients has a statistically higher rate of recurrence relative to colorectal carcinoma patients in whom 12 or more negative lymph nodes are recovered? Should we expect to recover fewer lymph nodes from patients who have undergone neoadjuvant therapy before resection?
A. Although the mechanism underlying the association between survival and lymph node number in colorectal cancer patients remains largely unexplained, as summarized in a 2007 editorial,1 accumulating evidence suggests that host response to tumor may be one factor influencing the recovery of lymph nodes from resection specimens. George, et al.,2 found that cases of tumors with increased tumor infiltrating lymphocytes yielded more lymph nodes, suggesting that immune response to the tumor may have an indirect impact on survival. High levels of intratumoral memory and effector T cells, in particular, have been associated with fewer lymph node metastases3 and increased survival. These recent studies suggest that in some patients, the number of negative lymph nodes recovered after careful examination of the specimen may be a surrogate marker for tumor-host immunologically mediated interactions and a reflection of tumor biology. Multiple studies, including pooled analyses,4 have demonstrated a survival advantage with increased numbers of lymph nodes harvested, especially for stage II patients. For instance, Joseph, et al.,5 found that when more than 30 lymph nodes were found, the five-year survival rate was 100 percent, but when less than 30 lymph nodes were found, the survival rate fell to 80 percent. Prandi, et al.,6 found a smaller effect: When zero to seven lymph nodes were recovered, the five-year survival rate was 81 percent, compared with 89 percent when greater than 18 nodes were found. A likely explanation that partially accounts for these results is stage migration: When more lymph nodes are examined, there is a greater likelihood that metastases will be found and the patient will be staged correctly as stage III. However, stage migration does not explain increased survival across entire cohorts, without consideration of stage.
Lymph node harvest is significantly decreased in specimens from patients undergoing neoadjuvant therapy for rectal cancer (from a median of nine lymph nodes in the control group to four per specimen in the neoadjuvant group in one study7), and the size of the nodes detected is also decreased in such cases. At our institution, we have noted that while we are able to retrieve at least 12 lymph nodes from more than 90 percent of colon carcinoma resections, fewer than 25 percent of rectal carcinoma specimens treated with neoadjuvant therapy will yield 12 or more lymph nodes.
The number of lymph nodes recovered from colorectal cancer resection specimens is influenced by multiple factors, some related to the surgeon (surgical nodal dissection technique, length of colon or rectum resected), some related to the pathologist (diligence of examination of the specimen), and some related to the patient (age, obesity,8 and neoadjuvant therapy). Patients older than 78 years are less likely to have 12 or more lymph nodes identified than are younger patients (odds ratio 0.68),9 and left-sided colectomy specimens consistently yield fewer lymph nodes than right-sided colectomy specimens.10
1. Ricciardi R, Baxter NN. Association versus causation versus quality improvement: setting benchmarks for lymph node evaluation in colon cancer. J Natl Cancer Inst. 2007;99:414–415.
2. George S, Primrose J, Talbot R, et al. Will Rogers revisited: prospective observational study of survival of 3592 patients with colorectal cancer according to number of nodes examined by pathologists. Br J Cancer. 2006;95:841–847.
3. Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. [see comment]. Science. 2006;313:1960–1964.
4. Chang GJ, Rodriguez-Bigas MA, Skibber JM, et al. Lymph node evaluation and survival after curative resection of colon cancer: systematic review. [see comment]. [Review] [41 refs]. J Natl Cancer Inst. 2007;99:433–441.
5. Joseph NE, Sigurdson ER, Hanlon AL, et al. Accuracy of determining nodal negativity in colorectal cancer based on the number of nodes retrieved on resection. Ann Surg Oncol. 2003;10:213–218.
6. Prandi M, Lionetto R, Bini A, et al. Prognostic evaluation of stage B colon cancer patients is improved by adequate lymphadenectomy: results of a secondary analysis of a large scale adjuvant trial. Ann Surg. 2002;235:458–463.
7. Wijesuriya RE, Deen KI, Hewavisenthi J, et al. Neoadjuvant therapy for rectal cancer down-stages the tumor but reduces lymph node harvest significantly. Surg Today. 2005;35:442–445.
8. Görög D, Nagy P, Péter A, et al. Influence of obesity on lymph node recovery from rectal resection specimens. Pathol Oncol Res. 2003;9:180–183.
9. Bilimoria KY, Stewart AK, Palis BE, et al. Adequacy and importance of lymph node evaluation for colon cancer in the elderly. J Am Coll Surg. 2008;206:247–254.
10. Bilimoria KY, Palis B, Stewart AK, et al. Impact of tumor location on nodal evaluation for colon cancer. Dis Colon Rectum. 2008;51:154–161.
Kay Washington, MD, PhD
Professor of Pathology
Vanderbilt University Medical Center
Member, CAP Cancer Committee
Dr. Kiechle is medical director of clinical pathology, Memorial Healthcare, Hollywood, Fla.