Serum cytokeratin 19 fragment 21‐1 and carcinoembryonic antigen combination assay as a biomarker of tumour progression and treatment response in extramammary Paget disease

Abstract

Summary Background Extramammary Paget disease (EMPD) is a rare intraepithelial adenocarcinoma affecting the genitals and axillary regions. As metastasis of these tumours is itself rare, solid disease management strategies have not been established. Serum carcinoembryonic antigen (CEA) and cytokeratin 19 fragment 21‐1 (CYFRA 21‐1) levels have been identified as candidate biomarkers for tumour progression in EMPD. Objectives To determine the accuracy of and the correlation between these markers in patients with EMPD. Methods Serum CEA and CYFRA 21‐1 levels were examined in 30 patients with EMPD treated at Keio University Hospital, and compared against clinical information. Both assays were performed at the time of diagnosis, during the postoperative observation period, and following systemic treatment in those with confirmed metastasis. Serum levels were then correlated with tumour progression status and treatment responses. Results Normal levels for both assays were observed in all 11 patients with primary localized disease (100%). In patients with metastatic disease the CEA positivity rate was 79% (15 of 19 patients), with a rate of 63% (12 of 19 patients) for CYFRA 21‐1. Changes in CEA and CYFRA 21‐1 levels were statistically independent; however, using a combined view, elevated levels of either marker improved the positivity rate to 95% (18 of 19 patients). Use of both markers also correlated well with treatment responses. Conclusions The combination of CEA and CYFRA 21‐1 is useful for predicting metastasis and treatment response in patients with EMPD, especially in those who only have elevation of a single marker. What's already known about this topic? Serum levels of carcinoembryonic antigen (CEA) and cytokine 19 fragment 21‐1 (CYFRA 21‐1) have been shown to be elevated in patients with extramammary Paget disease (EMPD). Elevation of serum CEA levels is associated with tumour progression of EMPD. A single small study reported that serum CYFRA 21‐1 levels are elevated in patients with EMPD with lymph node metastasis. What does this study add? Serum CEA and CYFRA 21‐1 were present in 79% and 63% of 19 cases of metastatic EMPD, respectively. Elevations of CEA and CYFRA 21‐1 were statistically independent. CEA and CYFRA 21‐1 combination assays were positive in 95% of cases of metastatic EMPD. What is the translational message? Combination assays with CEA and CYFRA 21‐1 are useful for monitoring treatment response in patients with metastatic EMPD, particularly in those with elevation of either marker.

Serum biomarkers in extramammary Paget disease

“…Studies of CYFRA expression levels in EMPD by Nakamura et al . provide further diagnostic information reporting no elevation in serum CYFRA levels or CEA in patients with primary invasive EMPD, but a significant increase of both markers in patients with evidence of nodal and distant organ metastatic progression . Collectively, the reports by Mijiddorj et al .…”

“…In the current issue of the BJD , two studies highlight potential biomarkers for EMPD; levels of serum cell‐free (cf)DNA) and a combination of serum cytokeratin 19 fragment 21‐1 (CYFRA) and serum carcinoembryonic antigen (CEA) . cfDNA is currently being studied in a range of fields from prenatal diagnosis of trisomy disorders, to its role as a diagnostic, prognostic and predictive biomarker in a host of cancer settings and refers to all nonencapsulated DNA in the bloodstream.…”

“…CYFRA on the other hand is a fragment of cytokeratin 19, which forms an integral part of the epithelial cytoskeleton, whereas CEA is a cell surface glycoprotein. CYFRA and CEA are both found to be elevated in the serum of patients with a range of solid organ malignancies …”

“…and Nakamura et al . further show changes in cfDNA, CYFRA and CEA levels correlate with the response of metastatic EMPD to chemotherapy, suggesting the additional value of these markers as prognostic biomarkers for EMPD therapeutic response . Larger cohort studies of a combination of these three serum markers are therefore warranted to promote and facilitate EMPD diagnosis, disease prognosis and act as a relatively noninvasive monitoring tool for response to systemic therapy.…”

Combined serum carcinoembryonic antigen and cytokeratin 19 fragment levels provide a sensitive biomarker for lymph node metastasis in extramammary Paget’s disease

“…The findings of the present study demonstrated that the combination of CEA and CYFRA levels had higher sensitivity for detecting LN metastasis of extramammary Paget’s disease than each of the other biomarkers evaluated alone. While this study was under review process, a similar study was published 11 . The differences between the two studies were the target (lesion) of the tumor and the validation of multiple tumor markers.…”