Abstract

Paget disease is an intraepithelial neoplastic proliferation, commonly occurring in the breast and apocrine-rich areas, often associated with an underlying internal malignancy. Extramammary Paget disease (EMPD) of the oral cavity is exceedingly rare, with only eight reported cases, four of which were associated with an underlying internal malignancy. Here, we report a case of oral EMPD involving the buccal mucosa and gingiva of an 81-year-old male with no known underlying internal malignancy. The Paget cells were positive for CK7, CK20, CAM5.2, and androgen receptor, but negative for SOX10 and p63. The immunophenotype, association with internal malignancies, and treatment approaches for oral EMPD are reviewed.

INTRODUCTION

Paget disease was first described in 1874 as intraepidermal infiltration of neoplastic cells in the setting of underlying mammary ductal carcinoma.1, 2 Extramammary Paget disease (EMPD) was subsequently described,3, 4 and unlike mammary Paget disease, is more frequently observed in the absence of underlying internal malignancy (so-called primary EMPD) than in association with an underlying internal malignancy (secondary EMPD).5 EMPD predominantly affects the skin that bears apocrine glands; EMPD affecting skin or mucosa devoid of apocrine glands is rare.6 Primary EMPD of the oral mucosa is rare, with four reported cases; two with in situ involvement of salivary ducts7, 8 and two without.9, 10Secondary EMPD of the oral mucosa associated with an underlying malignancy is rare, with four reported cases (Table 1).

The rarity, origin, prognosis, and best therapy for oral EMPD, especially primary EMPD, are not well understood. The condition is often misdiagnosed clinically as lichen planus10 or fungal infection, leading to a delay in treatment. Herein, we report a case of primary oral EMPD and review the relevant literature.

CASE REPORT

An 81-year-old male with a history of oral lichen planus presented to a community oral and maxillofacial surgeon with lacy white patches and underlying erythema involving the left buccal mucosa and left lateral gingiva. Treatment for lichen planus, including topical tacrolimus, triamcinolone, clobetasol, betamethasone, and subsequent intralesional triamcinolone, proved ineffective. Two weeks after administration of intralesional triamcinolone, a punch biopsy of the left buccal mucosa was performed.

The biopsy specimen showed enlarged hyperchromatic cells arranged singly and in clusters within the epithelium, concentrated along the basal layer and haphazardly spreading upward to reach the epithelial surface (Figure 1). Immunohistochemistry for CK7, cytokeratin CAM5.2, and androgen receptor (AR) were strongly positive in the Paget cells, while CK20, epithelial membrane antigen, and carcinoembryonic antigen (polyclonal) were only weakly positive. The cells were negative for SOX10, p63, mucicarmine, GCDFP-15, and NKX3.1 (performed because of a reported history of prostate cancer) (Figures 1 and S1). The superficial keratinized layers of the epithelium were infiltrated by candida pseudohyphae, highlighted by a periodic acid–Schiff histochemical stain (Figure S1G). A lichenoid lymphoplasmacytic infiltrate was present in the subepithelial lamina propria adjacent to the lesional epithelium. No underlying invasive or in situ malignancy was identified during clinical follow-up (6 months post-diagnosis).

DISCUSSION

EMPD involving apocrine-poor skin and mucosal sites is a rare diagnosis, and oral EMPD is exceptionally rare. For this reason, oral EMPD may be misdiagnosed clinically as a lichenoid lesion7, 8, 10 or fungal infection,7, 11 and biopsy may not be obtained until lesions fail to respond to multiple lines of therapy. In the case described here, the patient was previously treated for suspected lichen planus with multiple topical and intralesional therapies before a biopsy was obtained, highlighting the importance of considering Paget disease in the differential diagnosis of lesions nonresponsive to conventional therapy. Early recognition is important because of the association with underlying internal malignancy, difficulty in obtaining negative margins, and recurrence.

The majority of mammary Paget disease is associated with an underlying internal malignancy.12-16 In contrast, the majority of EMPD is primary, with a minority of cases associated with internal malignancy.17 In the oral cavity, four cases of primary EMPD have been reported. The first case involved the hard palate, gingiva, and buccal mucosa with intraepithelial spread to salivary ducts.7 The second case involved oral mucosa and perioral skin without involvement of underlying ducts.9 A third case involved the hard palate with intraepithelial spread to salivary ducts and minor salivary glands, complicated by recurrence at 19 months.8 A fourth case involved the buccal mucosa alone.10 An equal number of cases of secondary oral EMPD have been reported. The first case involved the tongue and was associated with a contiguous minor salivary gland adenocarcinoma that metastasized to regional lymph nodes and the liver.18 The second case involved the tongue, buccal mucosa, palate, and pharynx, including widespread intraductal carcinoma of salivary ducts.11 There was an underlying poorly differentiated carcinoma with rare mucin production and a hyaline matrix, that metastasized to cervical lymph nodes and lung. A third case involved the floor of the mouth and was associated with salivary gland carcinoma and concurrent invasive squamous cell carcinoma, complicated by lymph node metastasis.19 A fourth case was reported in association with submandibular gland salivary duct carcinoma and multiple lung metastases.20 Finally, a case of perioral EMPD associated with oral adenocarcinoma was recently reported, although neither immunohistochemical results, oral mucosal involvement, nor the histologic type of underlying adenocarcinoma was reported.21Secondary EMPD of nearby mucosal sites has infrequently been reported.22, 23

Secondary EMPD portends a poor clinical outcome6, 24 necessitating an extensive search for an underlying malignancy. Immunohistochemistry for CK7, CK20, and GCDFP-15 has been proposed to differentiate primary and secondary EMPD, as primary EMPD is often CK7+, CK20−, and GCDFP-15+.25-28 The reported phenotype of two cases of primary oral EMPD was CK7+ and CK20−, with a third case of CK7+ with unknown CK20.8-10 Conversely, a case of secondary oral EMPD was CK7+.19 As many salivary gland tumors are CK7+, the utility of CK7 and CK20 immunohistochemistry in predicting underlying internal malignancy remains uncertain.29, 30 The current case was CK7+ and CK20+, an immunophenotype associated with urothelial carcinoma and colorectal carcinoma, among others.27 The patient did have a reported history of prostate cancer, but immunohistochemistry for NKX3.1 was negative. Positivity for NKX3.1, however, has been observed in primary genitourinary EMPD, and therefore, may be a pitfall in the diagnosis of metastatic prostate cancer.31 In the cases where GCDFP-15 immunohistochemistry was performed, one case of primary EMPD and two cases of secondary EMPD were positive, with two cases of primary EMPD negative, including the current case,8, 9, 19, 20 an ultimately nonspecific immunophenotype, highlighting the need for better immunohistochemical markers. Recently, immunohistochemistry for trichorhinophalangeal syndrome type 1 (TRPS1) was reported to distinguish primary and secondary EMPD with high sensitivity and specificity.28, 32

The current case strongly expresses AR, which is commonly seen in EMPD and thought to suggest an apocrine orgin,33-38 though the absence of apocrine glands in the oral mucosa raises questions as to the origin of oral EMPD. AR may be a therapeutic target, as androgen stimulation promotes growth in an animal model of EMPD,39 and blockade has shown clinical benefit in metastatic EMPD.40, 41 Androgen blockade is under investigation as a therapy for salivary duct carcinoma42-47 and merits investigation in oral EMPD. Fortunately, primary oral EMPD has a good prognosis; all patients were alive at the time of publication,7-10 including one patient treated with oral thalidomide alone.9

This case report highlights several clinical and diagnostic challenges of oral EMPD. Oral EMPD may be misdiagnosed as lichen planus or fungal infection; clinical suspicion should be high in cases that fail to respond to treatment. Oral EMPD is frequently associated with underlying salivary gland malignancy, which should be carefully sought. Finally, while the optimal treatment remains to be determined, excisions should strive for negative margins through the careful surgical planning and topical and anti-androgen therapies may be used for unresectable cases.