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Multiple papulonodules on the face and scalp
J AM ACAD DERMATOL VOLUME 70, NUMBER 2
diagnosis is unclear. The examination of distal nail clippings looking for cavitation of the nail plate may help in establishing the diagnosis. Histologic analysis provides the definitive diagnosis of OM. Three distinct histologic features define OM: (1) a fibroepithelial tumor with fibrillary collagen bundles and epithelial invaginations into the dermis proximally and longitudinally-oriented fibroepithelial projections with matrix epithelium lined cavities distally; (2) a tumor derived from the nail matrix with a distinct superficial and deep layer; and (3) a keratogenous nail plate with cavitations. Immunohistochemical testing is not necessary in typical cases, but CD341 and anticytokeratin AE1/AE3 antibody with CD99e and epithelial membrane antigen staining can help distinguish histologic variants of OM from other lesions, especially if the nail plate was separated from the tumor during excision. The pathophysiology of OM is unknown. However, an animal study found that an aberrant expression of cadherins, namely B-cadherin, may be involved in pathogenesis of OM. Complete surgical excision of the tumor is the recommended treatment. To date, there are no reported cases of recurrence after complete excision, leading to the notion that it is a benign lesion. Some authors, however, note that they cannot exclude the possibility of malignancy. For this series the recommended choices are: 6, e; 7, d; 8, a; 9, d. BIBLIOGRAPHY Baran R, Kint A. Onychomatrixoma: filamentous tufted tumour in the matrix of a funnel-shaped nail: a new entity (report of three cases). Br J Dermatol 1992;126:510-5. Burchette JL, Pham TT, Higgins SP, Cook JL, Soler AP. Expression of cadherin/catenin cellecell adhesion molecules in a onychomatricoma. Int J Surg Pathol 2008;16:349-53. De Bengoa RB, Gates J, Iglesias ME, Martinex BA. Rare toenail onychomatricoma: surgical resolution of five cases. Dermatol Surg 2011;37:709-11. Fayol J, Baran R, Perrin C, Labrousse F. Onychomatricoma with misleading features. Acta Derm Venereol 2000;80:370-2. Miteva M, Cadore de Farias D, Zaiac M, Romanelli P, Tosti A. Nail clipping diagnosis of onychomatricoma. Arch Dermatol 2011; 147:1117-8. Perrin C, Baran R, Balaguer T, Chignon-Sicard B, Cannata GE, Petrella T, et al. Onychomatricoma: new clinical and histological features. A review of 19 tumors. Am J Dermatopathol 2010;32:1-8. Perrin C, Baran R, Pisani A, Ortonne JP, Michiels JF. The onychomatricoma: additional histologic criteria and immunohistochemical study. Am J Dermatopathol 2002;24:199-203. Perrin C, Goettmann S, Baran R. Onychomatricoma: clinical and histopathologic findings in 12 cases. J Am Acad Dermatol 1998;39:560-4. Piraccini BM, Antonucci A, Rech G, Starace M, Misciali C, Tosti A. Onychomatricoma: first description in a child. Pediatr Dermatol 2007;24:46-8.
JAAD grand rounds 397
Rashid RM, Swan J. Onychomatricoma: benign sporadic nail lesion or much more? Dermatol Online J 2006;12:4. Soto R, Wortsman X, Corredoira Y. Onychomatricoma: clinical and sonographic findings. Arch Dermatol 2009;145:1461-2. Tosti A, Piraccini BM, Calderoni O, Fanti PA, Cameli N, Varotti E. Onychomatricoma: a report of three cases, including the first recognized in a colored man. Eur J Dermatol 2000;10: 604-6.
Multiple papulonodules on the face and scalp Sharon R. Kim, MD, Adam Rees, MD, Mohsin R. Mir, MD, Paul M. Rodriguez-Waitkins, MD, and Sylvia Hsu, MD Houston, Texas A 61-year-old white woman presented with a 20-year history of multiple, asymptomatic papulonodular lesions on her face and scalp. She was otherwise healthy. She denied any significant family history. The physical examination revealed a well appearing female with multiple skin-colored, dome-shaped papules on her face and several pink nodules on her scalp (Fig 9). Biopsy specimens from the mid forehead (Fig 10) and frontal scalp (Fig 11) were obtained for histopathologic examination. 10. Which of the following syndromes is the most likely diagnosis? a. Bazex b. Rombo c. BrookeeSpiegler d. Reed e. Cowden 11. What is the most common mutated gene in this syndrome? a. CYLD b. PTEN c. APC d. STK11 e. Fumarate hydratase 12. What is the function of the most commonly mutated gene? a. Protooncogene b. Tumor suppressor c. Stimulatory G-protein alfa subunit d. Calcium-binding messenger protein e. Transcription factor 13. What is the inheritance pattern of this syndrome? a. Autosomal dominant b. Autosomal recessive c. X-linked dominant d. X-linked recessive e. Mitochondrial
398 JAAD grand rounds
14. This patient is at risk for which of the following complications? a. Vermiculate atrophoderma b. Follicular atrophoderma c. Hypohidrosis d. Hypotrichosis e. Malignant transformation to cylindrocarcinoma For this series, the recommended choices are: 10, c; 11, a; 12, b; 13, a; 14, e. Discussion BrookeeSpiegler syndrome (BSS) is a rare autosomal dominant disorder that results in cutaneous adnexal tumors, such as cylindromas, spiradenomas, and trichoepitheliomas. BSS is most commonly caused by mutations of the cylindromatosis (CYLD) tumor suppressor gene. CYLD is a negative regulator of the nuclear factor (NF)-kB signal transduction pathway. NF-kB is antiapoptotic, mutations in CYLD therefore result in increased resistance to apoptosis. In BSS, this antiapoptotic effect localizes to the folliculo-sebaceous-apocrine unit, resulting in adnexal neoplasms. Spontaneous mutations have been described in patients with a negative family history. Patients present in the second or third decade of life with adnexal neoplasms of the face and scalp that
J AM ACAD DERMATOL
FEBRUARY 2014
increase in number and size over the years. Women are affected more commonly than men. Spiradenomas usually present as a solitary nodule on the face. Cylindromas are papulonodules located on the scalp that may coalesce to form ‘‘turban tumors’’ and result in hair loss. Rarely, cylindromas undergo malignant transformation to cylindrocarcinoma. Trichoepitheliomas are skin-colored papules most commonly located on the central face. Other syndromes associated with multiple trichoepitheliomas include Rombo syndrome and Bazex syndrome. Other tumors associated with BSS include basal cell adenoma of the parotid gland, trichoblastoma, nevus sebaceous, and follicular cyst. The diagnosis of BSS is based on the identification of characteristic clinical and histopathologic skin findings. The key histologic finding in cylindromas is a dermal proliferation of basaloid cells in a ‘‘jigsaw puzzle’’ pattern. Spiradenomas are well circumscribed dermal or subcutaneous nodules composed of basaloid cells admixed with hyaline droplets and lymphocytes. Trichoepitheliomas have dermal aggregates of basaloid cells within a fibrous stroma. Treatment options for BSS include wide local excision, dermabrasion, electrodessication, cryotherapy, radiotherapy, CO2 laser ablation, and topical applications of sodium salicylate and prostaglandin A1. The proposed mechanism of action of the latter is inhibition of NK-kB activity. Because of the high recurrence rate and potential for malignant transformation, it is recommended that BSS patients undergo close follow-up.
BIBLIOGRAPHY Almeida S, Maillard C, Itin P, Hohl D, Huber M. Five new CYLD mutations in skin appendage tumors and evidence that aspartic acid 681 in CYLD is essential for deubiquitinase activity. J Invest Dermatol 2008;128:587-93. Brummelkamp TR, Nijman SM, Dirac AM, Bernards R. Loss of cylindromatosis tumour suppressor inhibits apoptosis by activating NF-kappaB. Nature 2003;424:797-801.
J AM ACAD DERMATOL
JAAD grand rounds 399
VOLUME 70, NUMBER 2
Kazakov DV, Soukup R, Mukensnabl P, Boudova L, Michal M. Brooke-Spiegler syndrome: report of a case with combined lesions containing cylindromatous, spiradenomatous, trichoblastomatous, and sebaceous differentiation. Am J Dermatopathol 2005;27:27-33. Lakhani SR. Putting the brakes on cylindromatosis? N Engl J Med 2004;32:187-8. Ponti G, Nasti S, Losi L, Pastorino L, Pollio A, Benassi L, et al. Brooke-Spiegler syndrome: report of two cases not associated
with a mutation in the CYLD and PTCH tumor-suppressor genes. J Cutan Pathol 2012;39:366-71. Rallan D, Harland CC. Brooke-Spiegler syndrome: treatment with laser ablation. Clin Exp Dermatol 2005;30:355-7. Sima R, Vanecek T, Kacerovska D, Trubac P, Cribier B, Rutten A, et al. Brooke-Spiegler syndrome: report of 10 patients from 8 families with novel germline mutations: evidence of diverse somatic mutations in the same patient regardless of tumor type. Diagn Mol Pathol 2010;19:83-91.
CORRECTIONS Tinklepaugh AJ, Wilson BB. Pityriasis folliculorum: A novel therapy for a diagnostically challenging condition. J Am Acad Dermatol 2013;69:e276-7. In the article above, the author order appeared incorrectly. The first author is Adam J. Tinklepaugh, MD, and the second author is Barbara B. Wilson, MD. The correction has been made to the online version of the article. Elewski BE, Rich P, Pollak R, Pariser DM, Watanabe S, Senda H, et al. Efinaconazole 10% solution in the treatment of toenail onychomycosis: Two phase III multicenter, randomized, double-blind studies. J Am Acad Dermatol 2013;68:600-8. In the article above, there was an error in Fig 1. The total number of patients who completed treatment with efinaconazole and vehicle in Study 2 should have read N ¼ 498 (85.4%) and N ¼ 160 (79.2%), respectively. The correction has been made to the online version of the article.
diagnosis is unclear. The examination of distal nail clippings looking for cavitation of the nail plate may help in establishing the diagnosis. Histologic analysis provides the definitive diagnosis of OM. Three distinct histologic features define OM: (1) a fibroepithelial tumor with fibrillary collagen bundles and epithelial invaginations into the dermis proximally and longitudinally-oriented fibroepithelial projections with matrix epithelium lined cavities distally; (2) a tumor derived from the nail matrix with a distinct superficial and deep layer; and (3) a keratogenous nail plate with cavitations. Immunohistochemical testing is not necessary in typical cases, but CD341 and anticytokeratin AE1/AE3 antibody with CD99e and epithelial membrane antigen staining can help distinguish histologic variants of OM from other lesions, especially if the nail plate was separated from the tumor during excision. The pathophysiology of OM is unknown. However, an animal study found that an aberrant expression of cadherins, namely B-cadherin, may be involved in pathogenesis of OM. Complete surgical excision of the tumor is the recommended treatment. To date, there are no reported cases of recurrence after complete excision, leading to the notion that it is a benign lesion. Some authors, however, note that they cannot exclude the possibility of malignancy. For this series the recommended choices are: 6, e; 7, d; 8, a; 9, d. BIBLIOGRAPHY Baran R, Kint A. Onychomatrixoma: filamentous tufted tumour in the matrix of a funnel-shaped nail: a new entity (report of three cases). Br J Dermatol 1992;126:510-5. Burchette JL, Pham TT, Higgins SP, Cook JL, Soler AP. Expression of cadherin/catenin cellecell adhesion molecules in a onychomatricoma. Int J Surg Pathol 2008;16:349-53. De Bengoa RB, Gates J, Iglesias ME, Martinex BA. Rare toenail onychomatricoma: surgical resolution of five cases. Dermatol Surg 2011;37:709-11. Fayol J, Baran R, Perrin C, Labrousse F. Onychomatricoma with misleading features. Acta Derm Venereol 2000;80:370-2. Miteva M, Cadore de Farias D, Zaiac M, Romanelli P, Tosti A. Nail clipping diagnosis of onychomatricoma. Arch Dermatol 2011; 147:1117-8. Perrin C, Baran R, Balaguer T, Chignon-Sicard B, Cannata GE, Petrella T, et al. Onychomatricoma: new clinical and histological features. A review of 19 tumors. Am J Dermatopathol 2010;32:1-8. Perrin C, Baran R, Pisani A, Ortonne JP, Michiels JF. The onychomatricoma: additional histologic criteria and immunohistochemical study. Am J Dermatopathol 2002;24:199-203. Perrin C, Goettmann S, Baran R. Onychomatricoma: clinical and histopathologic findings in 12 cases. J Am Acad Dermatol 1998;39:560-4. Piraccini BM, Antonucci A, Rech G, Starace M, Misciali C, Tosti A. Onychomatricoma: first description in a child. Pediatr Dermatol 2007;24:46-8.
JAAD grand rounds 397
Rashid RM, Swan J. Onychomatricoma: benign sporadic nail lesion or much more? Dermatol Online J 2006;12:4. Soto R, Wortsman X, Corredoira Y. Onychomatricoma: clinical and sonographic findings. Arch Dermatol 2009;145:1461-2. Tosti A, Piraccini BM, Calderoni O, Fanti PA, Cameli N, Varotti E. Onychomatricoma: a report of three cases, including the first recognized in a colored man. Eur J Dermatol 2000;10: 604-6.
Multiple papulonodules on the face and scalp Sharon R. Kim, MD, Adam Rees, MD, Mohsin R. Mir, MD, Paul M. Rodriguez-Waitkins, MD, and Sylvia Hsu, MD Houston, Texas A 61-year-old white woman presented with a 20-year history of multiple, asymptomatic papulonodular lesions on her face and scalp. She was otherwise healthy. She denied any significant family history. The physical examination revealed a well appearing female with multiple skin-colored, dome-shaped papules on her face and several pink nodules on her scalp (Fig 9). Biopsy specimens from the mid forehead (Fig 10) and frontal scalp (Fig 11) were obtained for histopathologic examination. 10. Which of the following syndromes is the most likely diagnosis? a. Bazex b. Rombo c. BrookeeSpiegler d. Reed e. Cowden 11. What is the most common mutated gene in this syndrome? a. CYLD b. PTEN c. APC d. STK11 e. Fumarate hydratase 12. What is the function of the most commonly mutated gene? a. Protooncogene b. Tumor suppressor c. Stimulatory G-protein alfa subunit d. Calcium-binding messenger protein e. Transcription factor 13. What is the inheritance pattern of this syndrome? a. Autosomal dominant b. Autosomal recessive c. X-linked dominant d. X-linked recessive e. Mitochondrial
398 JAAD grand rounds
14. This patient is at risk for which of the following complications? a. Vermiculate atrophoderma b. Follicular atrophoderma c. Hypohidrosis d. Hypotrichosis e. Malignant transformation to cylindrocarcinoma For this series, the recommended choices are: 10, c; 11, a; 12, b; 13, a; 14, e. Discussion BrookeeSpiegler syndrome (BSS) is a rare autosomal dominant disorder that results in cutaneous adnexal tumors, such as cylindromas, spiradenomas, and trichoepitheliomas. BSS is most commonly caused by mutations of the cylindromatosis (CYLD) tumor suppressor gene. CYLD is a negative regulator of the nuclear factor (NF)-kB signal transduction pathway. NF-kB is antiapoptotic, mutations in CYLD therefore result in increased resistance to apoptosis. In BSS, this antiapoptotic effect localizes to the folliculo-sebaceous-apocrine unit, resulting in adnexal neoplasms. Spontaneous mutations have been described in patients with a negative family history. Patients present in the second or third decade of life with adnexal neoplasms of the face and scalp that
J AM ACAD DERMATOL
FEBRUARY 2014
increase in number and size over the years. Women are affected more commonly than men. Spiradenomas usually present as a solitary nodule on the face. Cylindromas are papulonodules located on the scalp that may coalesce to form ‘‘turban tumors’’ and result in hair loss. Rarely, cylindromas undergo malignant transformation to cylindrocarcinoma. Trichoepitheliomas are skin-colored papules most commonly located on the central face. Other syndromes associated with multiple trichoepitheliomas include Rombo syndrome and Bazex syndrome. Other tumors associated with BSS include basal cell adenoma of the parotid gland, trichoblastoma, nevus sebaceous, and follicular cyst. The diagnosis of BSS is based on the identification of characteristic clinical and histopathologic skin findings. The key histologic finding in cylindromas is a dermal proliferation of basaloid cells in a ‘‘jigsaw puzzle’’ pattern. Spiradenomas are well circumscribed dermal or subcutaneous nodules composed of basaloid cells admixed with hyaline droplets and lymphocytes. Trichoepitheliomas have dermal aggregates of basaloid cells within a fibrous stroma. Treatment options for BSS include wide local excision, dermabrasion, electrodessication, cryotherapy, radiotherapy, CO2 laser ablation, and topical applications of sodium salicylate and prostaglandin A1. The proposed mechanism of action of the latter is inhibition of NK-kB activity. Because of the high recurrence rate and potential for malignant transformation, it is recommended that BSS patients undergo close follow-up.
BIBLIOGRAPHY Almeida S, Maillard C, Itin P, Hohl D, Huber M. Five new CYLD mutations in skin appendage tumors and evidence that aspartic acid 681 in CYLD is essential for deubiquitinase activity. J Invest Dermatol 2008;128:587-93. Brummelkamp TR, Nijman SM, Dirac AM, Bernards R. Loss of cylindromatosis tumour suppressor inhibits apoptosis by activating NF-kappaB. Nature 2003;424:797-801.
J AM ACAD DERMATOL
JAAD grand rounds 399
VOLUME 70, NUMBER 2
Kazakov DV, Soukup R, Mukensnabl P, Boudova L, Michal M. Brooke-Spiegler syndrome: report of a case with combined lesions containing cylindromatous, spiradenomatous, trichoblastomatous, and sebaceous differentiation. Am J Dermatopathol 2005;27:27-33. Lakhani SR. Putting the brakes on cylindromatosis? N Engl J Med 2004;32:187-8. Ponti G, Nasti S, Losi L, Pastorino L, Pollio A, Benassi L, et al. Brooke-Spiegler syndrome: report of two cases not associated
with a mutation in the CYLD and PTCH tumor-suppressor genes. J Cutan Pathol 2012;39:366-71. Rallan D, Harland CC. Brooke-Spiegler syndrome: treatment with laser ablation. Clin Exp Dermatol 2005;30:355-7. Sima R, Vanecek T, Kacerovska D, Trubac P, Cribier B, Rutten A, et al. Brooke-Spiegler syndrome: report of 10 patients from 8 families with novel germline mutations: evidence of diverse somatic mutations in the same patient regardless of tumor type. Diagn Mol Pathol 2010;19:83-91.
CORRECTIONS Tinklepaugh AJ, Wilson BB. Pityriasis folliculorum: A novel therapy for a diagnostically challenging condition. J Am Acad Dermatol 2013;69:e276-7. In the article above, the author order appeared incorrectly. The first author is Adam J. Tinklepaugh, MD, and the second author is Barbara B. Wilson, MD. The correction has been made to the online version of the article. Elewski BE, Rich P, Pollak R, Pariser DM, Watanabe S, Senda H, et al. Efinaconazole 10% solution in the treatment of toenail onychomycosis: Two phase III multicenter, randomized, double-blind studies. J Am Acad Dermatol 2013;68:600-8. In the article above, there was an error in Fig 1. The total number of patients who completed treatment with efinaconazole and vehicle in Study 2 should have read N ¼ 498 (85.4%) and N ¼ 160 (79.2%), respectively. The correction has been made to the online version of the article.