A 79-year-old white man with an extensive history of nonmelanoma skin cancer presents for a routine skin examination. During his visit, he asks to have a groin rash checked. For 1 to 2 years, he has been using over-the-counter and prescription antifungal and antibiotic creams for a presumed “jock itch.” Recently, he has developed more discomfort and reports episodic, profuse bleeding from the area. Examination reveals a large erythematous, eroded plaque on the posterior right scrotum extending anteriorly to the right upper thigh. A nodule is present within the plaque. The left scrotum is minimally involved, and there is no adenopathy.
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Paget disease is a rare cutaneous adenocarcinoma that is thought to originate from cutaneous apocrine glands. The disease was originally described by, and named for, Sir James Paget. In 1874, Paget described cutaneous changes of erythema, excoriations, itching, and nipple discharge associated with an underlying carcinoma of the breast.1 Subsequently, Paget disease has been described in other anatomic sites, as well; thus, it is classified as either mammary or extramammary based on the anatomic location.
In 1889, Crocker described the first case of extramammary Paget disease (EMPD) affecting the penis and scrotum, associated with an underlying bladder cancer.1 Since then, EMPD has been further classified into primary or secondary disease, depending upon the presence or lack of a coexistent urogynecologic or gastrointestinal malignancy.1,2
Typically affecting older individuals, EMPD is more common in patients aged 60 to 80 years, with a peak incidence in patients aged 65 years.1,2 Postmenopausal white women are affected most often.
Originating primarily from cutaneous apocrine glands, EMPD principally affects areas with a high apocrine gland concentration, including the axillae, anus, and genital skin.1,3-5 In women, the vulva is most commonly affected and accounts for nearly 65% of all cases of EMPD. In men, the penoscrotal junction, scrotum, and inguinal areas are most commonly affected.1,2,4,6 Despite the perineal and genital predominance, EMPD has infrequently been reported in the umbilicus, as well as on the eyelid, ear, and cheek.3,4
EMPD may be asymptomatic or cause variable degrees of burning or pruritus.1,3 As these are nonspecific symptoms, EMPD is usually not suspected early in its course and is treated empirically as eczema, intertrigo, psoriasis, or a fungal infection.2,3,6 However, EMPD is unresponsive to any of these conventional therapies.
Similarly, the initial lesions of EMPD mimic the various dermatitides mentioned, but with time, develop into an erythematous, ulcerated, or eczematous plaque; fine scale may be present.1,6 Although growth is slow, EMPD tends to be multifocal, with subclinical extension to surrounding tissues.
Persistence of symptoms or lesions, and therapeutic failure, should alert the clinician that the original diagnosis is incorrect and further studies are necessary. Appropriate cultures will exclude infectious etiologies. However, a skin biopsy is necessary to make the diagnosis of EMPD. Unfortunately, the correct diagnosis is usually delayed by 3 years or more.3,6
Biopsy specimen analysis should include routine as well as immunohistochemical staining.1-3 The malignant Paget cells are large, round, atypical intraepithelial cells with pale-staining vacuolated cytoplasm and large nuclei. Abundant mucin is responsible for the large cytoplasmic vacuoles and is easily recognized with routine histochemical stains.1-3,6
Specific immunohistochemical stains help to differentiate between primary and secondary EMPD and exclude the other potential diagnoses, such as Bowen disease (squamous cell carcinoma in situ), Langerhans cell histiocytosis, and amelanotic melanoma.1
Stains for CK7 and CK20 are used to categorize EMPD. Results of staining for primary EMPD are usually positive for CK7 and negative for CK20, whereas results for secondary EMPD are usually positive for both CK7 and CK20.6 Stain results used to identify potential conditions are negative in EMPD and include p63, S100, melan-A, CD1a, and HMB-45.1-3,5,6
Primary EMPD is more common than secondary EMPD; however, it has the potential to become an invasive adenocarcinoma, possibly metastasizing to nearby lymph nodes or even distant organs.
The malignancies associated with secondary EMPD are typically within an organ or tissue adjacent to the EMPD.1,6 For example, secondary vulvar EMPD is more commonly associated with a primary carcinoma of the vulva, vagina, cervix, uterus, bladder, colon, and rectum.1
Once the diagnosis of EMPD is established, imaging studies and age-appropriate cancer screening should be performed.1,2,4 Examinations to be considered include a pelvic examination, Papanicolaou smear, cystoscopy, and colonoscopy. Suggested imaging studies include computed tomography (CT) studies of the chest, abdomen, and pelvis.4
For patients with invasive disease, a sentinel lymph node (SLN) biopsy should be considered.4,7 If the SLN biopsy results are positive, or if other signs of widespread involvement exist, a positron emission tomography (PET) scan is indicated to determine the extent of the disease.4
Important prognostic indicators include the depth of invasion of the primary lesion, the presence of nodules within the primary lesion, the presence of extracutaneous involvement, clinically enlarged lymph nodes, specific genetic/protein expression profiles, and site of involvement.4 Among these factors, the depth of invasion and presence of extracutaneous involvement appears to have the strongest correlation with a poor outcome.2,4-6
Wide local excision has long been regarded as the standard of care for therapy.2,5,6,8 However, due to subclinical extension and the multifocal nature of EMPD, wide local excision does not ensure a complete cure; recurrent disease is common, affecting 20% to 60% of those surgically treated.2,8,9
Because recurrence following surgery is so high, other treatment methods have been investigated, including imiquimod, a topical immune response modulator that is approved by the US Food and Drug Administration for the treatment of superficial basal cell carcinomas. By stimulating the production of multiple cytokines including tumor necrosis factor-α, interferon-α, and interleukin-12, imiquimod activates both the innate and adaptive immune systems to create an antitumor effect.9 Multiple studies report topical imiquimod 5% cream to be effective for treatment of EMPD.9-11 However, because these favorable results have only been seen in relatively small cohorts, the consensus is that further trials are needed to confirm efficacy and establish treatment guidelines.9-11 Other nonsurgical treatment options have variable success and include topical 5% 5-fluorouracil cream, radiotherapy, laser therapy, and photodynamic therapy.1,2 Regardless of the treatment modality used, recurrence rates are high, so close follow-up for an extended period of time is recommended.1
For the patient in our case, a biopsy revealed the diagnosis to be EMPD; results of CK staining were positive for CK7 and negative for CK20, an immunohistochemistry profile favoring primary EMPD. He had recently had a negative colonoscopy result and imaging PET/CT scan results were negative for intra-abdominal or pelvic lymphadenopathy or tumors. He has been referred to medical and urologic oncology specialists. The medical oncologist has recommended topical imiquimod; however, tumor size may limit its use due to associated adverse effects. At the time of writing, we are awaiting recommendations from the urologic oncologist.
Robert M. Simonds Jr., BS, is a medical student and Julia R. Nunley, MD, is a professor of dermatology and program director of dermatology at the Medical College of Virginia Hospitals of Virginia Commonwealth University in Richmond
- Lopes Filho LL, Lopes IM, Lopes LR, Enokihara MM, Michalany AO, Matsunaga N. Mammary and extramammary Paget’s disease. Ann Bras Dermatol. 2015;90:225-231.
- Haydon N, Ting F, Southwell-Keely J. An important differential: extramammary Paget’s disease. Eplasty. 2015;15:ic16.
- Kang Z, Zhang Q, Zhang Q, et al. Clinical and pathological characteristics of extramammary Paget’s disease: report of 246 Chinese male patients.Int J Clin Exp Pathol. 2015;8:13233-13240.
- Cohen JM, Granter SR, Werchniak AE. Risk stratification in extramammary Paget disease. Clin Exp Dermatol. 2015;40:473-478.
- Carbotta G, Sallustio P, Prestera A, Laforgia R, Lobascio P, Palasciano N. Perineal Paget’s disease: a rare disorder and review of literature. Ann Med Surg (Lond). 2016;9:50-52.
- Bagby CM, MacLennan GT. Extramammary Paget’s disease of the penis and scrotum. J Urol. 2009;182:2908-2909.
- Fujisawa Y, Yoshino K, Kiyohara Y, et al. The role of sentinel lymph node biopsy in the management of invasive extramammary Paget’s disease: multi-center, retrospective study of 151 patients. J Dermatol Sci. 2015;79:38-42.
- Hunter CL, Skinner EC, Lee GK. Reconstruction with pedicled anterolateral thigh flap after wide local excision of penoscrotal extramammary Paget’s disease: a case report and comprehensive literature review. Eplasty. 2015;15:e26.
- Liau MM, Yang SS, Tan KB, Aw CW. Topical imiquimod in the treatment of extramammary Paget’s disease: a 10 year retrospective analysis in an Asian tertiary centre. Dermatol Ther. 2016;29:459-462.
- Baiocchi G, Begnami MD, Fukazawa EM, et al. Conservative management of extramammary paget disease with imiquimod. J Low Genit Tract Dis. 2012;16:59-63.
- Cowan RA, Black DR, Hoang LN, et al. A pilot study of topical imiquimod therapy for the treatment of recurrent extramammary Paget’s disease. Gynecol Oncol. 2016;142:139-143.