Are You Confident of the Diagnosis?
What you should be alert for in the history
The clinical appearance of hidradenoma papilliferum (HP) is nonspecific, but the location and patient gender are very characteristic. HP is a rare, benign cutaneous adnexal tumor that occurs almost exclusively in the anogenital region of women. The most common location is the labia majora, followed by the labia minora. Patients may present with a history of a slow growing nodule, or HP may be an incidental finding on a routine gynecologic exam. The tumor is usually asymptomatic unless erosion or ulceration is present. Reported symptoms in association with HP include pain, pruritus, bleeding and discharge.
Characteristic findings on physical examination
Physical examination reveals a dermal nodule with normal to erythematous overlying skin. HP may have a bluish hue due to the Tyndall effect. The lesion is generally smaller than 15mm (range of 3-80mm) with a mean of 6mm in diameter. On palpation, HP is well-circumscribed, firm and freely mobile. Erosion or ulceration is reported in 10-33% of cases, and if present, lesions tend to be more symptomatic.
Expected results of diagnostic studies
Histology reveals a well-circumscribed dermal nodule without connection to the epidermis or much inflammation unless ulceration is present. Classically, HP has a “maze-like” or “arborizing” architecture with a combination of solid and cystic areas comprised of tubular glandular structures and papillary projections lined by two layers of columnar or cuboidal secretory epithelium with apical snouts (
Figure 1, Figure 2). A myoepithelial cell layer can be highlighted below the secretory epithelium with an anti-smooth muscle actin.
The presence of a myoepithelial layer helps distinguish an HP from an adenocarcinoma, which typically lacks a myoepithelial layer. The histologic differential diagnosis includes syringocystadenoma papilliferum and tubular apocrine adenoma. In general, the diagnosis can be reached due to the location of the tumor, female gender, lack of a lymphoplasmacytic infiltrate or epidermal connection.
In difficult cases, immunohistochemical evaluation for the presence of estrogen and progesterone receptors can be used to verify the diagnosis.
Laboratory tests and imaging studies are of no value in the evaluation of HP.
The findings on physical examination are not diagnostic. The differential diagnosis includes Bartholin’s cyst, epidermal inclusion cyst, mucous cyst, hemorrhoid and primary or metastatic malignancy. The location, age and gender of the patient may raise the clinical suspicion for HP, but a definitive diagnosis requires a biopsy.
Who is at Risk for Developing this Disease?
Caucasian woman, in the fourth to sixth decade of life (age range of 20-90), are at the greatest risk for developing these tumors.
What is the Cause of the Disease?
HP originates from anogenital mammary-like glands or modified apocrine glands elsewhere in the body.
Research on the pathophysiology of these tumors has demonstrated the presence of estrogen and progesterone receptors. Hormonal stimulation may play a role in the pathogenesis and explain the female predominance and development after puberty. Recent research has suggested that mutations in genes encoding PI3K-AKT and MAPK may be the cause of have a role in the development of anogenital HP.***
Systemic Implications and Complications
Hidradenoma papilliferum is a benign tumor but, although extremely rare, malignant transformation to adenosquamous carcinoma and adenocarcinoma has been reported. Various subtypes of human papilloma virus (HPV) including high-risk variants have been identified in HP. HPV is not felt to have a causal role in pathogenesis, but HPV, especially high-risk variants, may play a role in malignant transformation. For this reason, complete excision of these lesions is recommended.
Conservative excision is curative.
Optimal Therapeutic Approach for this Disease
While the diagnosis can be suspected based on the location, age and gender of the patient, definitive diagnosis requires a biopsy. Once the diagnosis is established, local excision is recommended to remove any remaining HP.
Explain to the patient that HP is a benign neoplasm, but growth of the lesion can lead to ulceration and symptoms of tenderness, itching and bleeding. Although malignant transformation is exceedingly rare, it has been reported. For these reasons, the recommended treatment is conservative excision to remove the entire tumor. After surgery, patients should be instructed to follow up for any sign of recurrence.
Unusual Clinical Scenarios to Consider in Patient Management
Nonanogenital, or ectopic, hidradenoma papilliferum most commonly occurs in the head and neck region but also has been reported on the arms and trunk. Ectopic HP has an almost equal female to male ratio. HP has been reported in nevus sebaceous and nevus comedonicus. There has not been a report of a malignant transformation in an ectopic HP.
What is the Evidence?
Scurry, J, van der Putte, SC, Pyman, J, Chetty, N, Szabo, R. ” Mammary-like gland adenoma of the vulva: review of 46 cases”. Pathology. vol. 41. 2009. pp. 372-8. (Most recent large case series on HP. The article by Scurry et al detailed evidence for HP being derived from mammary-like glands rather than apocrine glands and proposed that the name of the lesion be changed to mammary-like gland adenoma. The article also discusses the risk of malignant transformation.)
Woodworth, H, Dockerty, MB, Wilson, RB. “Papillary hidradenoma of the vulva: a clinicopathologic study of 69 cases”. Am J Obstet Gynecol. vol. 110. 1971. pp. 501-8. (Largest of the three case series and provided demographics and clinical presentation of HP.)
Meeker, JH, Neubecker, RD, Helwig, EB. ” Hidradenoma papilliferum”. Am J Clin Pathol. vol. 37. 1962. pp. 182-95. (First large case series on HP and provided demographics, clinical presentation with long-term follow-up in 44 of the 65 lesions.)
Kaufman, T, Pawl, N, Soifer, I, Gretson, W, Kleiner, G. ” Cystic papillary hidradenoma of the vulva: Case report and review of the literature”. Gynecologic Oncology. vol. 26. Feb 1987. pp. 240-5. (Detailed the largest reported lesion and the tendency of HP to behave in a benign manner.)
Vazmitel, M, Spagnolo, DV, Nemcova, J, Michal, M, Kazakov, DV. ” Hidradenoma papilliferum with a ductal carcinoma in situ component: case report and review of the literature”. Am J Dermatopathol. vol. 30. 2008. pp. 392-4. (Case report of ductal carcinoma in situ arising in a HP and discusses the development of malignancy in HP and the role HPV may play in pathogenesis.)
Shah, SS, Adelson, M, Mazur, MT. ” Adenocarcinoma in situ arising in vulvar papillary hidradenoma: report of 2 cases”. Int J Gynecol Pathol. vol. 27. 2008 Jul. pp. 453-6. (Case report of HP with malignant transformation consisting of adenocarcinoma in situ. Good review of the literature of malignancy evolving in HP.)
Pelosi, G, Martignoni, G, Bonetti, F. ” Intraductal carcinoma of mammary-type apocrine epithelium arising within a papillary hidradenoma papilliferum of the vulva. Report of a case and review of the literature”. Arch Pathol Lab Med. vol. 115. 1991. pp. 1249-54. (This is the first report that is widely accepted detailing a malignancy arising in an HP.)
Vang, R, Cohen, PR. ” Ectopic hidradenoma papilliferum: a case report and review of the literature”. J Am Acad Dermatol. vol. 41. 1999. pp. 115-8. (A good review of the literature of ectopic HP.)
Fenandez-Aceneri, MJ, Sanchez, TA, Sanchez, MC, Requena, L. ” Ectopic hidradenoma papilliferum; a case report and literature review”. Am J Dermatopathol. vol. 25. 2003. pp. 176-8. (A good review of the literature of ectopic HP and their clinical behavior.)
DV, Mykiskova, I, Kutzner, H. “Hidradenoma papilliferum with oxyphilic metaplasia. A clinicopathological study of 18 cases, including detection of human papillomavirus”. Am J Dermatopathol. vol. 27. 2005. pp. 102-10. (Detailed unusual histologic presentations and discusses the possible role of HPV.)
***Pfarr, N., Sinn, H.-P., Klauschen, F., Flechtenmacher, C., Bockmayr. “Mutations in genes encoding PI3K-AKT and MAPK signaling define anogenital papillary hidradenoma. Genes Chromosom”. Cancer. vol. 55. 2016. pp. 113-119.
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