Immunostaining Can Help Classify Paget Disease


AMSTERDAM — A panel of immunohistochemical stains, including human epidermal growth factor receptor 2/neu and CDX2, is useful in distinguishing extramammary Paget disease that is limited to the skin versus the subset of secondary extramammary Paget disease that is associated specifically with concurrent or future anogenital cancer, Dr. Jared Abbott said at the 11th World Congress on Cancers of the Skin.

Other investigators have postulated that the triad of cytokeratin 7 (CK7), CK20, and BRST-2 immunohistochemical stains is broadly useful in distinguishing extramammary Paget disease (EMPD) that is limited to the skin—known as primary EMPD—from all forms of secondary extramammary Paget disease, but Dr. Abbott did not find this to be the case in his own large series. Indeed, caution should be exercised in relying upon the triad of immunostains for this purpose, said Dr. Abbott of the Mayo Clinic, Rochester, Minn.

EMPD is an uncommon condition occurring primarily in the elderly, with more women than men affected. It arises as a cutaneous adenocarcinoma with a proclivity for sites rich in apocrine glands. Patients with EMPD often present with a prominent solitary plaque lesion in the anogenital or vulvar region. The lesion is erythematous, eczematous, and often pruritic. The course is often locally aggressive, with frequent recurrences.

The classic histopathologic findings of EMPD consist of clusters of epithelial cells with pagetoid extension throughout the epidermis, often accompanied by a superficial lymphocytic inflammatory infiltrate, he said at the congress, which was sponsored by the Skin Cancer Foundation and Erasmus University.

The distinction between primary and secondary EMPD is clinically important because the prognoses are entirely different. Primary EMPD, which accounts for at least three-quarters of cases, has a good prognosis, whereas secondary EMPD has a very poor prognosis because the skin disorder is often accompanied—or, in the months to come, followed—by a gastrointestinal or genitourinary malignancy. Unfortunately, primary and secondary EMPD can't be differentiated based upon histopathology. “Their [hematoxylin and eosin stains] look exactly alike,” Dr. Abbott explained.

Other investigators have turned to immunohistochemical staining patterns in an effort to make the distinction. It has been reported that primary EMPD is often CK7- and BRST-2 positive and CK20 negative, whereas secondary EMPD is BRST 2 negative, CK20 positive, and equivocal in terms of CK7.

To see if he could verify this finding, and to assess the utility of some newer immunohistochemical stains, Dr. Abbott studied excisional biopsy specimens from 61 Mayo Clinic patients with EMPD. The median age at diagnosis was 73 years, and 44 patients were women. A total of 45 patients had primary EMPD. The 16 with secondary EMPD, as determined during a median 4-year follow-up, consisted of seven patients with anorectal carcinomas, four with prostate cancer, and five with urothelial cell cancer.

All patients in both the primary and secondary EMPD groups were CK7 positive, so that was of no help, he said. In addition, CK20, BRST-2, androgen receptor, and cyclin D1 did not prove to be of much assistance in distinguishing primary from secondary EMPD. (See box.)

In contrast, HER2/neu and CDX2 were quite helpful in separating primary from secondary EMPD involving anorectal malignancy. Five of the seven patients with lower GI cancer stained positive for CDX2, and all seven were HER2/neu negative. Unfortunately, no staining pattern proved useful in identifying patients with prostate or urothelial cell cancer.

The finding that more than two-thirds of patients with primary EMPD were HER2/neu positive, and that the positivity rate was even higher among those with recurrent primary EMPD, raises the intriguing possibility that Herceptin (trastuzumab) might be an effective therapy in these individuals, although that has never been studied, Dr. Abbott said.


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