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Caution in metastatic renal cell carcinoma within lymph nodes: PAX-2 expression is also seen in nodal lymphocytes.

To the Editor.--In their recent article, Ozcan et al (1) describe PAX-2 as a useful marker for diagnosing metastatic renal cell carcinoma (RCC). The study provides excellent support for the utility of PAX-2 in RCC in lymph nodes, which potentially can be used as a panel in determining the primary tumor when working up cases of nodal metastasis of unknown primary tumor.

We wish to point out a very important limitation of PAX-2 that is not highlighted in the published article. PAX-2, belonging to the paired box-containing gene family, is evolutionarily conserved and shares sequence homologies with PAX-5 (BSAP). While PAX-5 is known to be essential for early B-cell differentiation and is hence expressed in lymphocytes, the expression and role of PAX-2 in lymphocytes is not well documented. We wish to express caution since positive staining for PAX-2 is seen within lymphocytes, thus limiting the utility of lymph nodal metastasis workup. PAX-2 expression may be transient within B lymphocytes. Alternatively, because of sequence homology between PAX2 and PAX-5, the commercial antibody used in this study may have cross-reactivity with PAX-5 and hence show positive staining within B cells. The authors use PAX-2 from Invitrogen, Carlsbad, California (clone or catalog information not provided in the article). Many of Invitrogen's polyclonal PAX-2 antibodies are derived against murine PAX-2 (peptide sequences 204-373). While Invitrogen's technical data sheet mentions that there is no cross-reactivity with other PAX family of proteins, published data (2) suggest that peptide sequences 329 through 416 of mPAX-2 are homologous to hPAX-5.

To illustrate this, we present a recent case reviewed in our consultation service. We recently per formed PAX-2 in a lymph node to exclude metastatic RCC. While there was no carcinoma present, the lymphocytes and the confounding vascular lesion (Figures 1 and 2) showed PAX-2 staining. PAX-2 expression profile was described by the same authors in a previous publication, (3) and is also seen in their Figure 4, A, (1) in which PAX-2 expression is seen in metastatic breast carcinoma and within benign lymphocytes.

[FIGURE 1 OMITTED]

[FIGURE 2 OMITTED]

Given that PAX-2 staining is seen in lymphocytes, it is very important to recognize this limitation when evaluating lymph nodes for metastatic lesions, especially in the workup of unknown primary tumors.

LAUREN GILMORE, MD

RAJAN DEWAR, MD, PhD

Department of Pathology

Beth Israel Deaconess Medical Center and Harvard Medical School

Boston, MA 02215

(1.) Ozcan A, Zhai QJ, Javed R, et al. PAX-2 is a helpful marker for diagnosing metastatic renal cell carcinoma: comparison with the renal cell carcinoma marker antigen and kidney-specific cadherin. Arch Pathol Lab Med. 2010;134(8):1121-1129.

(2.) Dorfler P, Busslinger M. C-terminal activating and inhibitory domains determine the transactivation potential of BSAP (Pax-5), Pax-2 and Pax-8. EMBOJ. 1996;15(8):1971-1982.

(3.) Zhai QJ, Ozcan A, Hamilton C, et al. PAX-2 expression in non-neoplastic, primary neoplastic, and metastatic neoplastic tissue: a comprehensive immunohistochemical study. Appl Immunohistochem Mol Morphol. 2010;18(4):323-332.

The authors have no relevant financial interest in the products or companies described in this article.

In Reply.--We are grateful for the authors' interest in our recent publication on the use of PAX-2 as a marker for metastatic renal cell carcinoma. (1) The authors have appropriately pointed out that PAX-2 can be expressed by a subset of lymphocytes, especially B lymphocytes. Therefore, the lymphocyte nuclei may be positive with immunostain for PAX-2.

It has been well known that an antibody often decorates not only the cells of diagnostic interest but also irrelevant cells in the same tissue sections. Some well-known examples include the expression of vimentin in stromal cells, the expression of keratin in a subset of dendritic reticulum cells in lymph nodes, or the expression of S100 protein in a rare lymphoid cell or macrophage in lymph nodes. The diagnostic significance of a positive staining reaction thus depends on correct identification of the cells of diagnostic interest by routine morphology. As pointed out by the authors, PAX-2 expression by lymphoid cells was described in detail in one of our previous publications, (2) which is referenced in the article in discussion. The morphology of these cells, however, is such that they can be quite clearly identified as lymphoid cells, rather than metastatic neoplastic cells. These positively stained lymphoid cells are indeed clearly illustrated in Figure 4 in the article in discussion. (1) This rather obvious diagnostic caveat is applicable for the use of PAX-2 as a marker for metastatic renal cell carcinoma. Nevertheless, this caveat should have been clearly mentioned and discussed as a diagnostic pitfall in the article in discussion. We are grateful that the authors help reiterate this well-known but important diagnostic caveat.

LUAN TRUONG, MD

Department of Pathology

The Methodist Hospital

Houston, TX 77030

AYHAN OZCAN, MD

Department of Pathology

Gulhane Military Medical Academy and School of Medicine

Ankara, Turkey

(1.) Ozcan A, Zhai QJ, Javed R, et al. PAX-2 is a helpful marker for diagnosing metastatic renal cell carcinoma: comparison with the renal cell carcinoma marker antigen and kidney-specific cadherin. Arch Pathol Lab Med. 2010;134(8): 1121-1129.

(2.) Zhai QJ, Ozcan A, Hamilton C, et al. PAX-2 expression in non-neoplastic, primary neoplastic, and metastatic neoplastic tissue: a comprehensive immunohistochemical study. Appl Immunohistochem Mol Morphol. 2010;18(4):323-332.

The authors have no relevant financial interest in the products or companies described in this article.
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Title Annotation:Letters to the Editor
Author:Gilmore, Lauren; Dewar, Rajan
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Letter to the editor
Date:Apr 1, 2011
Words:891
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