SkIndia Quiz 27: Rhinophyma and numerous facial papule and nodules in a 39-year-old woman.

A 39-year-old female presented with numerous papulonodular lesions over face appearing since the age of 7 years. These had been asymptomatic and relatively stable in size and number until 3-4 years back when she noticed a coalescence of lesions over her mid face/nasal bridge and progressive enlargement of her nose. Her medical history was unremarkable. Her 23-year-old daughter had also beginning to develop similar lesions over the face since the age of 17 years. Her parents, one male sibling, two sons, and another daughter were reportedly healthy. Physical examination showed rhinophyma-like enlarged nose and innumerable, 2-10 mm sized, skin-colored, smooth surfaced, papules, and nodules involving the whole face [Figure 1]. The glabella, periocular, nasal bridge, alae nasi, nasolabial folds, perilabial and chin were involved predominately. Her daughter also had few lesions of similar morphology over the nose and nasolabial folds. The findings of hematoxylin and eosin stained histology sections of a nodular lesion are shown in Figures 2 and 3.

Figure 1

Rhinophyma and innumerable skin-colored, smooth surfaced, papulo-nodular lesions over the whole face, predominately involving the nasal bridge, alae nasi, and nasolabial folds

Figure 2

Multiple, well-circumscribed nests, lobules and cords separated by fibrous stroma. Calcification of cystic material (thick arrow), and primitive hair shaft-like structures (thin arrow) are seen (H and E, ×10)

Figure 3

Well-circumscribed nests of palisading basaloid cells, without pleomorphism, cellular atypia or mitosis are seen and suggest well-differentiated trichoepitheliomas (H and E, ×40)

ANSWER

Diagnosis: Brooke–Spiegler syndrome: Multiple familial trichoepithelioma

Microscopic findings

Histopathology shows multiple circumscribed lobules and cords of palisading basaloid cells separated by fibrous stroma [Figures 2 and 3]. There is no pleomorphism, cellular atypia or mitosis. Presence of calcified cystic material and primitive hair shaft-like structures suggests well differentiated trichoepitheliomas.

DISCUSSION

Brooke–Spiegler syndrome (familial cylindromatosis, multiple familial trichoepithelioma, turban tumor syndrome), an autosomal dominant condition, is characterized by multiple trichepitheliomas, spiradenomas, or cylindromas with or without overlapping features. There is no racial or gender predilection and its exact prevalence remains unknown. Once considered separate entities both multiple familial trichoepithelioma and Brooke-Spiegler syndrome have the same gene mutations and are now considered phenotypic variants. The mutations in the CYLD gene (cylindromatosis oncogene, mapped to 16q12-q13), the product of which functions as a deubiquitinating enzyme, negatively regulates the nuclear factor kappa B (NFĸ-B) that is responsible for the development of epidermal appendages and oncogensis.[1] On the other hand, the genetic mutation for multiple familial trichoepithelioma is mapped to a locus on chromosome 9p21, while genetic mutations in sporadic trichoepitheliomas have been mapped to PTCH, which is also involved in nevoid basal cell syndrome.[23] It is possible that mutations in the genes regulating proliferation and differentiation of putative stem cells of the pilosebaceous-apocrine unit lead to different combinations of adenexal tumors or neoplasms with features of pilosebaceous differentiation (trichoepithelioma, basal cell carcinomas [BCCs]) or apocrine differentiation (spiroadenoma, spiroadenocylindroma).[4] In addition, involvement of a defective tumor suppressive gene located on chromosome 16q too has been suggested. However, other yet to be identified genes may also be responsible for phenotypes not associated with CYLD or PTCH mutations as no firm genotype-phenotype correlations could be demonstrated in a few cases.[35]

Clinically, skin-colored, small, coalescing papules and nodules start appearing in childhood/puberty, and gradually increase in number and size for several years before stabilizing. Nearly 50% of the lesions occur over face typically concentrating around forehead, nasolabial folds and upper lip. Although rhinophyma is principally associated with end stage rosacea, significant cosmetic disfigurement, even to an extent of leonine facies, may occur in Brooke-Spiegler syndrome. Although concurrent occurrence of trichoepitheliomas, cylindromas and spiradenoms/spiradenocylindromas is not unusual, it has been considered sporadic occurrence and unrelated to Brooke–Spiegler syndrome.[67] Malignant transformation to BCC may happen decades later presenting with ulceration, inflammation, or necrosis and these patients are also at increased risk of adenomas and adenocarcinomas of the salivary glands warranting a long term follow up.[8]

Diagnosis is mainly clinicopathologic and BCC remains the major histologic differential. Primitive hair structures, cornified cysts, cribriform pattern, and stromal fibrosis are pathognomic of trichoepithelioma. In addition, fibroblastic stroma in trichoepithelioma will stain positive for CD34 and not in BCC, which may sometimes be difficult to differentiate histologically. Many other genetic syndromes presenting with multiple facial lesions; BCCs (Gorlin's syndrome), trichilemmomas (Cowden syndrome), and perifollicular fibroma (Brit–Hogg–Dube syndrome), sebaceous neoplasia and keratoacanthoma (Muir–Torre syndrome), or colloid milia, and syringomas require differentiation clinically and histologically. Solitary lesions can be excised and for others split skin graft, photodynamic therapy, flattening of the lesions by dermabrasion, electrodessication cryosurgery or LASER (argon, CO2, erbium, ND: Yag plus, CO2) therapy have been used with variable results. Recurrences are common and repeated procedure(s) may be necessary for cosmetic improvement. Partial response to topical imiquimod (5%) has been reported. Sodium salicylate and prostaglandin A1 that inhibit NFĸ-B activity and restore growth control are experimental therapies for cylindromas.[9]

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.