Papules on the mid-face

Case #1Brooke-Spiegler syndrome is an autosomal dominant disease causing cutaneous adnexal tumors. Patients present with small, skin-colored papules distributed in the head and neck region. Lesions initially present in late childhood or early adulthood and increase in size and number....

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Case #1

Brooke-Spiegler syndrome is an autosomal dominant disease causing cutaneous adnexal tumors. Patients present with small, skin-colored papules distributed in the head and neck region. Lesions initially present in late childhood or early adulthood and increase in size and number. Girls and women are affected twice as commonly as boys and men.¹

These tumors are typically benign cylindromas, trichoepitheliomas, and spiradenomas, but patients can also develop parotid basal cell adenomas, milia, organoid nevi, and basal cell carcinomas.¹ Cylindromas and spiradenomas are tumors of the apocrine and eccrine sweat glands, respectively, and trichoepitheliomas are tumors of the hair follicle. Brooke-Spiegler syndrome overlaps clinically with multiple familial trichoepithelioma and familial cylindromatosis, all of which are dominantly inherited disorders that cause benign adnexal tumors, and share a common defect in the CYLD gene. Although multiple familial trichoepithelioma is characterized by trichoepitheliomas and familial cylindromatosis is characterized by cylindromas, Brooke-Spiegler syndrome is characterized by cylindromas, spiradenomas, and trichoepitheliomas, as well as follicular cysts and milia. Considering the rare nature of Brooke-Spiegler syndrome, the incidence and prevalence of the disease is unknown.

Although adnexal tumors are typically benign, each class also has a rare but malignant form. It is critical that benign tumors are monitored, as their malignant counterparts have poor outcomes.² Malignant transformation of cylindromas and spiradenomas into carcinomas and sarcomas can occur as part of Brooke-Spiegler syndrome, whereas trichoepitheliomas can give rise to basal cell carcinomas. In rare cases, cylindromas transform into malignant cylindrocarcinomas, which grow rapidly while discoloring, ulcerating, and bleeding. Special consideration must be given to spiradenomas, due to the potential of malignantly transformed spiradenomas to metastasize.¹ Specifically, enlargement, color changes, and pain warrant evaluation for malignant spiradenocarcinoma.² Additionally, patients with Brooke-Spiegler syndrome can also develop adenocarcinoma of the salivary glands.³

Cylindromas are pink, firm, rubbery tumors predominantly found on the scalp, whereas trichoepitheliomas occur on the nose and upper lips, and in the nasolabial folds. Extensive development of cylindromas on the scalp are called “turban tumors,” and these are associated with alopecia, or hair loss.¹

Histologically, cylindromas are characterized by islands of tumor cells in the dermis that are arranged in close proximity to one another in a “cobble stoning” manner on a background of hyalinized stroma; stain results are positive for periodic acid-Schiff and are type IV collagen reactive.² Each island has large, central cells with pale nuclei, surrounded by smaller palisading peripheral cells with dark basophilic nuclei. Malignant forms of cylindromas—cylindrocarcinomas—will lose the characteristic jigsaw pattern and island arrangement with focal necrosis.² Spiradenomas are multilobular, sharply demarcated growths found in the deep dermis and subcutis, often with a fibrous capsule.² The lobules are basophilic and have cords of epithelial cells that consist mostly of nuclei and little cytoplasm. Cystic structures may also form in the lobules. Malignant spiradenocarcinomas exhibit increased mitotic rates, necrosis, atypia, and pleomorphism; they also show loss of lobular growth pattern.²

Brooke-Spiegler syndrome, multiple familial trichoepithelioma, and familial cylindromatosis arise from mutations in the CYLD gene on chromosome 16q12-q13, which normally deubiquinates target proteins and negatively regulates nuclear factor κB (NF-κB) activation. Wild-type CYLD promotes apoptosis through regulation of NF-κB, preventing uncontrolled cellular proliferation. In Brooke-Spiegler syndrome, the mutated CYLD gene is unable to suppress NF-κB activity, which subsequently results in uncontrolled growth and, ultimately, development of adnexal neoplasms. NF-κB is an inducible transcription factor with roles in inflammation and oncogenesis, and activation of NF-κB has been associated with a variety of neoplasms.^3,4

The differential diagnosis for numerous firm skin-colored papules on the face should include Cowden syndrome, tuberous sclerosis, Birt-Hogg-Dubé syndrome, Robo syndrome, and basaloid follicular hamartoma syndrome.⁵

Benign lesions arising from Brooke-Spiegler syndrome do not need to be treated, except for cosmetic reasons. Treatment of adnexal tumors ranges widely and includes excision, dermabrasion, electrodessication, and cryotherapy, in addition to the use of lasers (CO₂ and argon).¹ Erbium:yttrium aluminum garnet (Er:YAG) laser treatment can be used to ablate trichoepitheliomas but should not be performed on cylindromas, as histologic assessment due to malignant potential is necessary. New lesions can arise with ablative treatments, although it is still favorable for cosmetic purposes, due to minimal scarring.¹

After counseling the patient about monitoring her lesions, 2 lesions under the nose were electrodessicated for cosmetic reasons. The patient was educated on inheritance pattern and disease course and was advised to schedule biannual skin checks.

Case #2

Sarcoidosis is a disease affecting multiple organ systems and characterized by the formation of noncaseating epithelioid granulomas. Although the inciting cause is still unknown, granulomas result from T-cell recognition of antigens by macrophage presentation, triggering a cellular immune response, and lymphocytic and mononuclear phagocytic infiltration.⁶ Disease progression results in a mass effect, causing dysfunction of surrounding tissue. Prevalence of the disease in the United States ranges from 10:100,000 to 40:100,000. The disease typically presents in the third and fourth decades of life, and it is more common in women.⁷

Skin manifestations of the disease are present in up to one in every four patients, most frequently at disease onset. Thus, any granulomatous skin lesions without known cause should be evaluated for systemic sarcoidosis. However, the presence or absence of cutaneous disease has not been found to correlate with prognosis or extent of disease.⁶

Cutaneous sarcoidosis can be present in various forms, including papules, maculopapules, nodules, plaques, subcutaneous nodules, lupus pernio, or infiltrative scars. The most common form is maculopapular.⁸ Skin lesions are divided into specific (granulomatous) or nonspecific (reactive with no granulomas). Papular sarcoidosis presents most commonly around the eyelids and nasolabial folds, and it typically resolves with minimal scarring. Maculopapular lesions are found on the neck and below, and they are associated with acute organ disease. Plaque sarcoidosis is associated with chronic disease, with lesions found on the face and extensor surfaces of the extremities, back, and buttocks.⁷ Lupus pernio presents with coalescing chronic indurated lesions on the face, often with telangiectasias and disfigurement. Local spread can damage the upper airway and nasal cavity. Lupus pernio is often resistant to therapy and is temporally associated with organ involvement.⁷

Other diseases to consider on the differential diagnosis for these lesions include infectious, autoimmune, or foreign-body-related causes. Syphilis, leprosy, and atypical mycobacteria can all present with widespread lesions as well. Autoimmune disorders such as lupus vulgaris, lupus disseminatus faciei, and metastatic Crohn disease can have similar lesions.⁶

Although no diagnostic test exists for sarcoidosis, biopsy confirmation of lymph nodes, skin, or salivary glands with noncaseating granulomas without foreign bodies, and negative tissue culture results, are necessary to exclude other potential etiologies.⁶ Angiotensin-converting enzyme levels are elevated in 60% of patients with sarcoidosis, and can aid in diagnosis.⁹ Sarcoid histology is characterized by distinct, necrosis-free islands of epithelioid cells with giant cells. Epidermal histology in cutaneous lesions shows hyperkeratosis, acanthosis, parakeratosis, and epidermal atrophy, leading to the variety of lesions described. Epidermal atrophy likely results from a reaction to growth of dermal granulomas, as indicated by the presence of a normal zone between the granulomas and the epidermis.¹⁰

Once suspected, evaluation of pulmonary, ocular, neurologic, and cardiac systems is warranted. Baseline chest radiographs and pulmonary function test results should be obtained, in addition to an electrocardiogram, echocardiogram, complete serum chemistry panel, urine analysis, complete blood count, and tuberculosis screening.⁹ Once diagnosis is confirmed, patients undergoing treatment should be seen twice a year; if they do not require treatment, they should be seen once a year. During visits, lesions should be monitored, and systemic symptoms should be evaluated with a focus on respiratory, ocular, and cardiac symptoms. Any abnormal findings warrant further investigation and referral to indicated specialists.⁶

Treatment of cutaneous sarcoidosis focuses on limiting disfigurement and symptoms. Topical therapy includes high potency corticosteroids, often applied with occlusive dressing.⁶ Monthly intralesional injections of triamcinolone (5-10 mg/mL) or chloroquine (50 mg/mL) is also an option. Additionally, procedures such as dermabrasion, excision, and grafting for ulcerative lesions, and plastic surgery for lupus pernio, are available.⁶

Oral therapies are reserved for large, refractory lesions or generalized eruptions. Prednisone, hydroxychloroquine, chloroquine, allopurinol, methotrexate, thalidomide, isotretinoin, and psoralen plus ultraviolet A (PUVA) therapy have all proven to be effective.⁶ Systemic corticosteroids are first-line therapies in these cases and should be tapered to the minimal dose necessary for relapse prevention.⁷ Patients requiring 10 mg of prednisone daily should be considered candidates for corticosteroid-sparing agents. Methotrexate is frequently given for corticosteroid-resistant lesions. Tumor necrosis factor-α (TNF-α) plays a pivotal role in granuloma formation and has led to the use of targeted therapies such as infliximab, a chimeric monoclonal anti-TNF-α antibody, which has shown efficacy in severe cases.⁷

A total of 60% of patients with sarcoidosis have spontaneous resolution within 2 to 5 years, and an additional 10% to 20% of cases will resolve with corticosteroids. The disease can also progress to fibrosis, which is irreversible.⁷ Overall, prognosis of cutaneous manifestations is tied to the degree of systemic disease.⁶

In our case, this patient was evaluated and oral prednisone was initiated, beginning with 20 mg daily and tapering to 5 mg daily over the course of 1 month. Additionally, baseline chest radiograph, pulmonary function test, complete blood count, and chemistry panel results were obtained. A 1-month follow-up was scheduled to evaluate treatment response and discuss results from laboratory and imaging studies.

Omar Merchant, BS, is a medical student and Maura Holcomb, MD, is a dermatology resident at Baylor College of Medicine in Houston.

References

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2. Storm CA, Seykora JT. Cutaneous adnexal neoplasms. Am J Clin Pathol. 2002;118(suppl):S33-S49.
3. Young AL, Kellermayer R, Szigeti R, et al. CYLD mutations underlie Brooke-Spiegler, familial cylindromatosis, and multiple familial trichoepithelioma syndromes. Clin Genet. 2006;70(3):246-249.
4. Blake PW, Toro JR. Update of cylindromatosis gene (CYLD) mutations in Brooke-Spiegler syndrome: novel insights into the role of deubiquitination in cell signaling. Hum Mutat. 2009;30(7):1025-1036.
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8. Mañá J, Marcoval J, Graells J, et al. Cutaneous involvement in sarcoidosis. Relationship to systemic disease. Arch Dermatol. 1997;133(7):882-888.
9. Haimovic A, Sanchez M, Judson MA, Prystowsky S. Sarcoidosis: a comprehensive review and update for the dermatologist: part II. Extracutaneous disease. J Am Acad Dermatol. 2012;66(5):719.e1-719.e10.
10. Okamoto H. Epidermal changes in cutaneous lesions of sarcoidosis. Am J Dermatopathol. 1999;21(3):229-233.