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Lumpers and Splitters: The Debate Continues.

To the Editor:

In a 2009 Q&A, Glenn Braunstein said that in the field of human chorionic gonadotropin (hCG),

"... there are 'lumpers' and 'splitters.' Lumpers want a single test that measures all of the hCG-related molecular variants, ideally in equimolar quantities. This would be the only test they would use to diagnose and monitor pregnancy, gestational and nongestational trophoblastic disease, and hCG (or variant)-producing nontrophoblastic tumors. As the tumor grows, the markers rise, as it shrinks, the markers fall. The splitters want to have separate assays that are highly specific for the different variants because the type of variant or the ratios of some the variants to each other may provide some additional diagnostic information, such as the differentiation of benign or malignant trophoblastic disease" (1).

I was reminded of this quote when I read a recent article by Mc-Cash et al. (2). The authors reported a decrease in false-positive pregnancy results in patients with cancer by using an intact hCG assay (the splitter philosophy). In their study, intact hCG reduced the number of false-positive pregnancy test results from 13 to 1, a 92% reduction, corresponding to a reduction in the false-positive rate from 38% to 3% (2). Indeed, this is a logical approach in a cancer center. Because intact hCG predominates in early pregnancy and tumors can produce exclusively hCG[beta] (3), the use of an assay that detects only intact hCG would eliminate the detection of hCG variants.

However, although use of an assay that detects exclusively intact hCG is attractive, caution must be used. Intact hCG assays will not detect free hCG[beta], which is exclusively produced by numerous non-trophoblastic tumors (3). For this reason, most institutions use an hCG assay that recognizes intact hCG and hCG[beta] (referred to as total [beta] assays) so that a single assay can be used as both a tumor marker and a screen for pregnancy (the lumper philosophy). If intact-only hCG assays are used, they need to be clearly labeled "Use only to detect pregnancy," and a separate assay that recognizes total hCG[beta] must be available as a tumor marker.

It should be noted that no hCG assay is approved by the Food and Drug Administration as a tumor marker in the US. Use of hCG assays as a tumor marker is off-label. Therefore, if a laboratory offers an hCG assay specifically labeled as a "tumor marker assay," it should be validated as a laboratory-developed test for the detection of tumors.

More importantly, many laboratories incorrectly indicate what forms of hCG their assay recognizes. Cao and Rej reported that in a survey of 296 laboratories, 13% of laboratories that reported "intact hCG" actually measured "total [beta] hCG," and 9% of laboratories that reported "total [beta] hCG" actually measured "intact hCG" (4). Mistakes like this can have serious clinical implications. Laboratories that report "total [beta] hCG" but in fact measured "intact hCG" will be missing cases of tumor-associated hCG.

There is no answer to the lumpers vs splitters debate. As laboratorians, it is imperative that we be familiar with the forms of hCG our assays measure and work with clinicians to ensure they understand the appropriate clinical use for each assay.

Author Contributions: AH authors confirmed they have contributed to the intellectual content of this paper and have met the following 4 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately investigated and resolved.

Authors' Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest:

Employment or Leadership: A.M. Gronowski, Clinical Chemistry, AACC.

Consultant or Advisory Role: A.M. Gronowski, Church and Dwight Co Inc.

Stock Ownership: None declared.

Honoraria: None declared.

Research Funding: None declared.

Expert Testimony: None declared.

Patents: None declared.

Other Remuneration: A.M. Gronowski,

Roche Diagnostics.

Previously published online at DOI: 10.1373/clinchem.2018.294710

References

(1.) Gronowski, AM. Clinical assays for human chorionic gonadotropin: what should we measure and how? ClinChem 2009;55:1900-4.

(2.) McCash SI, Goldfrank DJ, Pessin MS, Ramanathan LV. Reducing false positive pregnancy test results in patients with cancer. Obstet Gynecol 2017;130:825-9.

(3.) Stenman U-H, Alfthan H, Hotakainen K. Human chorionic gonadotropin in cancer. Clin Biochem 2004;37: 549-61.

(4.) Cao ZT, Rej R.Are laboratories reporting serum quantitative hCG results correctly? Clin Chem 2008;54: 761-4.

Ann M. Gronowski *

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO

* Address correspondence to the author at: Washington University School of Medicine Department of Pathology and Immunology

Box 8118, 660 S. Euclid

St. Louis, MO 63110

Fax 314-362-1461

E-mail gronowski@wustl.edu
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Author:Gronowski, Ann M.
Publication:Clinical Chemistry
Article Type:Letter to the editor
Date:Nov 1, 2018
Words:827
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