EXTRAORDINARY CASE REPORT
Generalized Basaloid Follicular Hamartoma Syndrome: A Case Report and Review of the Literature Priyanka Gumaste, BA,* Arisa E. Ortiz, MD,†‡ Amit Patel, MD,§ Jonathan Baron, MD,¶ Ronald Harris, MD, MBA,§ and Ronald Barr, MDk
Abstract: Basaloid follicular hamartoma (BFH) is a rare, generally benign lesion of importance because of its clinical and histopathological similarity to infundibulocystic basal cell carcinoma. Autosomal dominant generalized BFH syndrome is 1 of the 5 clinical forms of BFH that has been described in the literature. We report a case of BFH syndrome in a 47-year-old Hispanic female who presented with an increasing number of small 1- to 2-mm tan to brown smooth facial papules, few palmar pits, and cobblestoning of the tongue. Her mother had similar lesions on her face. A biopsy of one of the patient’s facial lesions confirmed the diagnosis of BFH. Of note, this patient later presented with rapid growth of one of her facial lesions, and a subsequent biopsy confirmed the development of a basal cell carcinoma arising within one of her BFH lesions. Although BFH is classically stable for years and does not require immediate surgical removal, our case highlights the importance of continual monitoring of these patients, given the potential for malignant transformation of these lesions.
CASE REPORT A 47-year-old Hispanic female presented to our clinic with an increasing number of “basal cell carcinomas” (BCCs) of the face. The patient had a history of numerous BCCs that were previously excised. Over the past 5 years, she developed hundreds of these lesions on her face. She had a history of excessive tanning and multiple blistering sunburns. She denied a history of skeletal abnormalities including jaw cysts. Her mother also had a history of multiple BCCs, breast cancer, and undiagnosed kidney masses. Physical examination revealed numerous 1- to 2-mm tan to brown smooth papules scattered over the entire face (Fig. 1), few palmar pits, and cobblestoning of the tongue. Histopathology of one of the facial lesions showed a bland basaloid proliferation arranged in anastomosing columns and cords with small infundibular pigmented cysts, scant stroma, and minimal palisading or clefting (Fig. 2). The diagnosis of generalized BFH was made. Given the number of lesions present in our patient and her
Key Word: basaloid follicular hamartoma (Am J Dermatopathol 2015;37:e37–e40)
INTRODUCTION Basaloid follicular hamartoma (BFH) is a generally benign superficial, folliculocentric basaloid proliferation. BFH has varying clinical presentations. Autosomal dominant, generalized basaloid follicular hamartoma syndrome (BFHS) is 1 of the 5 clinical forms of BFH that has been described in the literature.1–4 Patients with BFHS commonly present at birth or in early childhood with numerous small skin-colored papules across the face, neck, and trunk. Palmoplantar pitting, alopecia, hypohidrosis and hypotrichosis are other commonly associated features.1 Herein, we report a case of familial BFHS along with a review of literature. From the *Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ; †Department of Dermatology, Dermatology Cosmetic and Laser Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA; ‡Department of Medicine-Division of Dermatology, UC San Diego, San Diego, CA; §Department of Dermatology, UC Irvine, Irvine, CA; ¶RBGB Dermatology, Santa Ana, CA; and kLaguna Pathology Medical Group, Laguna Beach, CA. All authors participated in the drafting of the manuscript and critical revision of the manuscript for important intellectual content. Presented at the CalDerm Society Annual Meeting, September 20–22, 2013, Santa Barbara Fess Parker’s Double Tree Hotel. The authors declare no conflicts of interest. Reprints: Arisa E. Ortiz, MD, UC San Diego, 8899 University Center Lane 350, San Diego, CA 92122 (e-mail: [email protected]). Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
Am J Dermatopathol Volume 37, Number 3, March 2015
FIGURE 1. Numerous 1- to 2-mm tan to brown smooth papules scattered over the entire face. www.amjdermatopathology.com |
e37
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Gumaste et al
Am J Dermatopathol Volume 37, Number 3, March 2015 family history, this likely represents BFHS (Table 1). Of note, this patient later presented with rapid growth of one of her facial lesions, and a biopsy confirmed the development of a BCC arising within one of her BFH lesions (Fig. 3). She subsequently underwent Mohs micrographic surgery and was started on topical tazarotene as prophylaxis. She is monitored periodically for malignant transformation of her BFH lesions, sparing unnecessary surgery.
DISCUSSION
BFH was first described in 1969 by Brown et al5 as multiple papules in the nasolabial folds in association with myasthenia gravis and diffuse alopecia and was later termed BFH in 1985 by Mehregan and Baker.6 It can be localized or generalized, acquired, or inherited. Localized subtypes are more common and tend to be sporadic whereas generalized subtypes are usually congenital.7 Five clinical forms of BFH have been noted: (1) solitary or multiple papules,7 (2) a localized plaque with alopecia, (3) a localized linear or unilateral papule or plaque,6 (4) a generalized dominantly inherited familial type without associated disorders,1 or (5) generalized papules associated with alopecia and myasthenia gravis.5 Although BFH can have varying clinical presentations, all types present with common histopathological features and have an increased risk of BCC, which tend to arise de novo.8 Our patient presented with autosomal dominant generalized BFHS, which is a rare type of generalized BFH. Wheeler et al1 first described BFHS in 2000 after evaluating 18 members of a North Carolina family. Most BFHS lesions are 1- to 2-mm smooth skin-colored papules that present at birth or in early childhood and occur on the face and scalp, but have also been noted on the neck, axillae, shoulders, and pubic regions. Milder forms, however, may go unnoticed as patients can present with just a few facial papules and milia. Other common physical examination findings include palmoplantar pitting, alopecia, hypohidrosis, and hypotrichosis. Less common and possibly unrelated cutaneous findings in these patients include atopic dermatitis, keratosis pilaris, lichen striatus, acrochordons, acanthosis nigricans–like changes, dermatosis papulosa nigra, acne vulgaris, café au lait spots, punctate palmar keratosis, and steatocystoma multiplex.1,4 Our patient presented with several clinical findings such as multiple facial papules, palmar pitting, and cobblestoning of the tongue that can also be present in Cowden syndrome, an autosomal dominant disorder characterized by multiple hamartomas derived from all 3 embryonic germ cell layers and high risk of breast and thyroid cancer. The cardinal feature of Cowden syndrome includes the presence of numerous facial trichilemmomas, which are hamartomas of the infundibulum of the hair follicles, which can be distinguished from BFH on histology.9 FIGURE 2. A, Histopathology of biopsied lesion (·5 magnification, hematoxylin–eosin stain). Basaloid masses with peripheral palisading and clefting seen in BCC on the left adjacent to a more bland basaloid proliferation seen in BFH. B, Histopathology of biopsied lesion (·20 magnification, hematoxylin– eosin stain). Higher power of the transition between a classic basaloid proliferation seen in BCC on the left adjacent to a more
bland basaloid proliferation arranged in anastomosing columns or cords with scant stroma and minimal palisading or clefting seen in BFH. C, Histopathology of biopsied lesion (·40 magnification, hematoxylin–eosin stain). Higher power of bland basaloid proliferation arranged in anastomosing columns or cords with small infundibular pigmented cysts, scant stroma, and minimal palisading or clefting.
e38
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| www.amjdermatopathology.com
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Am J Dermatopathol Volume 37, Number 3, March 2015
TABLE 1. Differential Diagnosis for Multiple Facial Papules Angiofibromas/adenoma sebaceum (tuberous sclerosis) BFHS Bazex syndrome Cowden syndrome Gorlin syndrome (Nevoid BCC syndrome) Trichoepitheliomas Steatocystoma multiplex Syringomas
BFHS has been associated with myasthenia gravis,10 cystic fibrosis,11 and systemic lupus erythematosus.12 Assorted systemic disease, such as hypertension..breast cancer, have also been reported in these patients, although it is unclear if this association supersedes that found in the general population.1,4 All forms of BFH are of importance because of their clinical and histopathological similarity to infundibulocystic BCC. Unlike BCC, BFH is classically stable for years and does not require immediate surgical removal. Hence, it is important to differentiate BFH from BCC to avoid unnecessary surgical procedures.8 BFH is thought to be an abnormal formation of vellus hair follicles and is limited to locations with preexisting follicles. Histopathological examination of BFH reveals a discrete epithelial proliferation of anastomosing cords and strands of basaloid cells with scant or absent stroma. Clefting between the tumor and stroma is minimal. Horn cysts and pigmentation are often present.13 Infundibulocystic BCC also appears as basaloid cords and strands that destroy hair follicles, but are distinguished from BFH by their destruction in the interfollicular dermis, as well.8 BCC also tends to have more mitotic figures and necrosis than BFH.1 Immunohistochemistry can also be a useful tool in distinguishing BFH from BCC.14 The stroma of all BCCs, including fibroepithelioma of Pinkus, is CD342, whereas BFH
Generalized Basaloid Follicular Hamartoma Syndrome
and other benign follicular tumors are CD34+. BCC is diffusely BER-EP4+, whereas BFH is BER-EP42.15 Although BCC expresses androgen receptors, BFH does not.16 Ki-67-positive staining nuclei are numerous in BCC but low in BFH.17 BCL-2 positive cells are scattered throughout the lobules and cords of BCC but are restricted to the periphery of the trabeculae in BFH.15 CK20+ Merkel cells are more common in BFH, but can rarely occur in BCC.16 The pathogenesis of BFH is linked to a mutation in the patched (PTCH) gene on chromosome 9q23, which is the same gene implicated in nevoid basal cell carcinoma syndrome (Gorlin–Goltz syndrome). However, the expression of the mutation in BFH is not as severe.18 The PTCH gene encodes the receptor for sonic hedgehog (SHH), a signaling protein involved in developmental patterning. The PTCH receptor normally complexes with smoothened (SMO), a transmembrane G-protein receptor. In the absence of SHH, PTCH receptor inactivates SMO and prevents transduction of a downstream signal. Binding of SHH to the PTCH receptor releases inhibition of SMO, upregulating SHH genes involving Gli transcription factors.19 Constitutive signaling leads to increased cell division and abnormal growth. Although this pathway may contribute to BFH formation, further studies are needed to explore the pathogenesis of BFH development. In summary, BFH is a rare, generally benign follicular hamartoma that is diagnosed histopathologically because of its variable clinical presentation. Patients with BFH have a good prognosis. Observation without treatment of BFH is not unreasonable given its stable nature; however, patients often opt for treatment for cosmetic reasons.4,7 Although there are no standardized treatments for BFH, current management includes surgical excision, cryosurgery, laser surgery, and photodynamic therapy for diffuse or extensive lesions.20,21 Surgical excision is preferred for localized lesions because of the small risk of malignant progression of BFH.21 New options for treatment of BFH are emerging. Experimental treatment with 5-aminolevulinic acid–mediated photodynamic therapy has been shown to be safe and effective.20 Oral and topical retinoids have also been successful in cases with increased Gli-1 transcription, seen in BFH associated with autoimmune disease because retinoids decrease Gli-1 transcriptional activity.19 Vismodegib, a new inhibitor of the hedgehog signaling pathway that binds the SMO receptor leading to decreased tumor cell proliferation, may have some role in patients with BFHS. Further studies are needed, however, to evaluate the effectiveness of vismodegib in treating BFHS. Our case highlights the importance of monitoring BFH lesions for malignant transformation to BCC if they are not removed. Rapid changes in size or appearance of these lesions should prompt immediate biopsy. In the absence of concerning features, aggressive treatments such as Mohs micrographic surgery are not indicated.8 REFERENCES
FIGURE 3. Histopathology of biopsied lesion (·20 magnification, hematoxylin–eosin stain). Higher power of a classic basaloid proliferation seen in BCC with peripheral palisading and clefting. Copyright 2014 Wolters Kluwer Health, Inc. All rights reserved.
1. Wheeler CE Jr, Carroll MA, Groben PA, et al. Autosomal dominantly inherited generalized basaloid follicular hamartoma syndrome: report of a new disease in a North Carolina family. J Am Acad Dermatol. 2000;43: 189–206. 2. Metry D, Guill C. Generalized basaloid follicular hamartoma syndrome. J Am Acad Dermatol. 2001;45:644–646.
www.amjdermatopathology.com |
e39
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Gumaste et al
Am J Dermatopathol Volume 37, Number 3, March 2015
3. Jih DM, Shapiro M, James WD, et al. Familial basaloid follicular hamartoma: lesional characterization and review of the literature. Am J Dermatopathol. 2003;25:130–137. 4. Lee PL, Lourduraj LT, Palko MJ III, et al. Hereditary basaloid follicular hamartoma syndrome. Cutis. 2006;78:42–46. 5. Brown AC, Crounse RG, Winkelmann RK. Generalized hair-follicle hamartoma, associated with alopecia, aminoacidura, and myasthenia gravis. Arch Dermatol. 1969;99:478–493. 6. Mehregan AH, Baker S. Basaloid follicular hamartoma: three cases with localized and systematized unilateral lesions. J Cutan Pathol. 1985;12:55–65. 7. Brownstein MH. Basaloid follicular hamartoma: solitary and multiple types. J Am Acad Dermatol. 1992;27:237–240. 8. Saxena A, Shapiro M, Kasper DA, et al. Basaloid follicular hamartoma: a cautionary tale and review of the literature. Dermatol Surg. 2007;33:1130–1135. 9. Eng C. Will the real Cowden syndrome please stand up: revised diagnostic criteria. J Med Genet. 2000;37:828–830. 10. Weltfriend S, David M, Ginzburg A, et al. Generalized hair follicle hamartoma: the third case report in association with myasthenia gravis. Am J Dermatopathol. 1987;9:428–432. 11. Mascaro JM Jr, Ferrando J, Bombi JA, et al. Congenital generalized follicular hamartoma associated with alopecia and cystic fibrosis in three siblings. Arch Dermatol. 1995;131:454–458. 12. Morton S, Stevens A, Powell RJ. Basaloid follicular hamartoma, total body hair loss and SLE. Lupus. 1998;7:207–209. 13. Mills O, Thomas LB. Basaloid follicular hamartoma. Arch Pathol Lab Med. 2010;134:1215–1219.
14. Jakobiec FA, Zakka FR, Kim N. Basaloid follicular hamartoma of the eyelid. Ophthal Plast Reconstr Surg. 2012;28:e127–e130. 15. Ramos-Ceballos FI, Pashaei S, Kincannon JM, et al. Bcl-2, CD34 and CD10 expression in basaloid follicular hamartoma, vellus hair hamartoma and neurofollicular hamartoma demonstrate full follicular differentiation. J Cutan Pathol. 2008;35:477–483. 16. Katona TM, Ravis SM, Perkins SM, et al. Expression of androgen receptor by fibroepithelioma of Pinkus: evidence supporting classification as a basal cell carcinoma variant? Am J Dermatopathol. 2007;29: 7–12. 17. Naeyaert JM, Pauwels C, Geerts ML, et al. CD-34 and Ki-67 staining patterns of basaloid follicular hamartoma are different from those in fibroepithelioma of Pinkus and other variants of basal cell carcinoma. J Cutan Pathol. 2001;28:538–541. 18. Grachtchouk V, Grachtchouk M, Lowe L, et al. The magnitude of hedgehog signaling activity defines skin tumor phenotype. EMBO J. 2003;22: 2741–2751. 19. Smith KJ, Skelton H. Basaloid follicular hamartomas associated with autoimmune disease: a possible role for retinoids in therapy. J Am Acad Dermatol. 2003;49:1067–1070. 20. Oseroff AR, Shieh S, Frawley NP, et al. Treatment of diffuse basal cell carcinomas and basaloid follicular hamartomas in nevoid basal cell carcinoma syndrome by wide-area 5-aminolevulinic acid photodynamic therapy. Arch Dermatol. 2005;141:60–67. 21. Go JW, Oh HE, Cho HK, et al. A case of basaloid follicular hamartoma. Ann Dermatol. 2010;22:229–231.
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| www.amjdermatopathology.com
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Generalized Basaloid Follicular Hamartoma Syndrome: A Case Report and Review of the Literature Priyanka Gumaste, BA,* Arisa E. Ortiz, MD,†‡ Amit Patel, MD,§ Jonathan Baron, MD,¶ Ronald Harris, MD, MBA,§ and Ronald Barr, MDk
Abstract: Basaloid follicular hamartoma (BFH) is a rare, generally benign lesion of importance because of its clinical and histopathological similarity to infundibulocystic basal cell carcinoma. Autosomal dominant generalized BFH syndrome is 1 of the 5 clinical forms of BFH that has been described in the literature. We report a case of BFH syndrome in a 47-year-old Hispanic female who presented with an increasing number of small 1- to 2-mm tan to brown smooth facial papules, few palmar pits, and cobblestoning of the tongue. Her mother had similar lesions on her face. A biopsy of one of the patient’s facial lesions confirmed the diagnosis of BFH. Of note, this patient later presented with rapid growth of one of her facial lesions, and a subsequent biopsy confirmed the development of a basal cell carcinoma arising within one of her BFH lesions. Although BFH is classically stable for years and does not require immediate surgical removal, our case highlights the importance of continual monitoring of these patients, given the potential for malignant transformation of these lesions.
CASE REPORT A 47-year-old Hispanic female presented to our clinic with an increasing number of “basal cell carcinomas” (BCCs) of the face. The patient had a history of numerous BCCs that were previously excised. Over the past 5 years, she developed hundreds of these lesions on her face. She had a history of excessive tanning and multiple blistering sunburns. She denied a history of skeletal abnormalities including jaw cysts. Her mother also had a history of multiple BCCs, breast cancer, and undiagnosed kidney masses. Physical examination revealed numerous 1- to 2-mm tan to brown smooth papules scattered over the entire face (Fig. 1), few palmar pits, and cobblestoning of the tongue. Histopathology of one of the facial lesions showed a bland basaloid proliferation arranged in anastomosing columns and cords with small infundibular pigmented cysts, scant stroma, and minimal palisading or clefting (Fig. 2). The diagnosis of generalized BFH was made. Given the number of lesions present in our patient and her
Key Word: basaloid follicular hamartoma (Am J Dermatopathol 2015;37:e37–e40)
INTRODUCTION Basaloid follicular hamartoma (BFH) is a generally benign superficial, folliculocentric basaloid proliferation. BFH has varying clinical presentations. Autosomal dominant, generalized basaloid follicular hamartoma syndrome (BFHS) is 1 of the 5 clinical forms of BFH that has been described in the literature.1–4 Patients with BFHS commonly present at birth or in early childhood with numerous small skin-colored papules across the face, neck, and trunk. Palmoplantar pitting, alopecia, hypohidrosis and hypotrichosis are other commonly associated features.1 Herein, we report a case of familial BFHS along with a review of literature. From the *Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ; †Department of Dermatology, Dermatology Cosmetic and Laser Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA; ‡Department of Medicine-Division of Dermatology, UC San Diego, San Diego, CA; §Department of Dermatology, UC Irvine, Irvine, CA; ¶RBGB Dermatology, Santa Ana, CA; and kLaguna Pathology Medical Group, Laguna Beach, CA. All authors participated in the drafting of the manuscript and critical revision of the manuscript for important intellectual content. Presented at the CalDerm Society Annual Meeting, September 20–22, 2013, Santa Barbara Fess Parker’s Double Tree Hotel. The authors declare no conflicts of interest. Reprints: Arisa E. Ortiz, MD, UC San Diego, 8899 University Center Lane 350, San Diego, CA 92122 (e-mail: [email protected]). Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
Am J Dermatopathol Volume 37, Number 3, March 2015
FIGURE 1. Numerous 1- to 2-mm tan to brown smooth papules scattered over the entire face. www.amjdermatopathology.com |
e37
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Gumaste et al
Am J Dermatopathol Volume 37, Number 3, March 2015 family history, this likely represents BFHS (Table 1). Of note, this patient later presented with rapid growth of one of her facial lesions, and a biopsy confirmed the development of a BCC arising within one of her BFH lesions (Fig. 3). She subsequently underwent Mohs micrographic surgery and was started on topical tazarotene as prophylaxis. She is monitored periodically for malignant transformation of her BFH lesions, sparing unnecessary surgery.
DISCUSSION
BFH was first described in 1969 by Brown et al5 as multiple papules in the nasolabial folds in association with myasthenia gravis and diffuse alopecia and was later termed BFH in 1985 by Mehregan and Baker.6 It can be localized or generalized, acquired, or inherited. Localized subtypes are more common and tend to be sporadic whereas generalized subtypes are usually congenital.7 Five clinical forms of BFH have been noted: (1) solitary or multiple papules,7 (2) a localized plaque with alopecia, (3) a localized linear or unilateral papule or plaque,6 (4) a generalized dominantly inherited familial type without associated disorders,1 or (5) generalized papules associated with alopecia and myasthenia gravis.5 Although BFH can have varying clinical presentations, all types present with common histopathological features and have an increased risk of BCC, which tend to arise de novo.8 Our patient presented with autosomal dominant generalized BFHS, which is a rare type of generalized BFH. Wheeler et al1 first described BFHS in 2000 after evaluating 18 members of a North Carolina family. Most BFHS lesions are 1- to 2-mm smooth skin-colored papules that present at birth or in early childhood and occur on the face and scalp, but have also been noted on the neck, axillae, shoulders, and pubic regions. Milder forms, however, may go unnoticed as patients can present with just a few facial papules and milia. Other common physical examination findings include palmoplantar pitting, alopecia, hypohidrosis, and hypotrichosis. Less common and possibly unrelated cutaneous findings in these patients include atopic dermatitis, keratosis pilaris, lichen striatus, acrochordons, acanthosis nigricans–like changes, dermatosis papulosa nigra, acne vulgaris, café au lait spots, punctate palmar keratosis, and steatocystoma multiplex.1,4 Our patient presented with several clinical findings such as multiple facial papules, palmar pitting, and cobblestoning of the tongue that can also be present in Cowden syndrome, an autosomal dominant disorder characterized by multiple hamartomas derived from all 3 embryonic germ cell layers and high risk of breast and thyroid cancer. The cardinal feature of Cowden syndrome includes the presence of numerous facial trichilemmomas, which are hamartomas of the infundibulum of the hair follicles, which can be distinguished from BFH on histology.9 FIGURE 2. A, Histopathology of biopsied lesion (·5 magnification, hematoxylin–eosin stain). Basaloid masses with peripheral palisading and clefting seen in BCC on the left adjacent to a more bland basaloid proliferation seen in BFH. B, Histopathology of biopsied lesion (·20 magnification, hematoxylin– eosin stain). Higher power of the transition between a classic basaloid proliferation seen in BCC on the left adjacent to a more
bland basaloid proliferation arranged in anastomosing columns or cords with scant stroma and minimal palisading or clefting seen in BFH. C, Histopathology of biopsied lesion (·40 magnification, hematoxylin–eosin stain). Higher power of bland basaloid proliferation arranged in anastomosing columns or cords with small infundibular pigmented cysts, scant stroma, and minimal palisading or clefting.
e38
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| www.amjdermatopathology.com
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Am J Dermatopathol Volume 37, Number 3, March 2015
TABLE 1. Differential Diagnosis for Multiple Facial Papules Angiofibromas/adenoma sebaceum (tuberous sclerosis) BFHS Bazex syndrome Cowden syndrome Gorlin syndrome (Nevoid BCC syndrome) Trichoepitheliomas Steatocystoma multiplex Syringomas
BFHS has been associated with myasthenia gravis,10 cystic fibrosis,11 and systemic lupus erythematosus.12 Assorted systemic disease, such as hypertension..breast cancer, have also been reported in these patients, although it is unclear if this association supersedes that found in the general population.1,4 All forms of BFH are of importance because of their clinical and histopathological similarity to infundibulocystic BCC. Unlike BCC, BFH is classically stable for years and does not require immediate surgical removal. Hence, it is important to differentiate BFH from BCC to avoid unnecessary surgical procedures.8 BFH is thought to be an abnormal formation of vellus hair follicles and is limited to locations with preexisting follicles. Histopathological examination of BFH reveals a discrete epithelial proliferation of anastomosing cords and strands of basaloid cells with scant or absent stroma. Clefting between the tumor and stroma is minimal. Horn cysts and pigmentation are often present.13 Infundibulocystic BCC also appears as basaloid cords and strands that destroy hair follicles, but are distinguished from BFH by their destruction in the interfollicular dermis, as well.8 BCC also tends to have more mitotic figures and necrosis than BFH.1 Immunohistochemistry can also be a useful tool in distinguishing BFH from BCC.14 The stroma of all BCCs, including fibroepithelioma of Pinkus, is CD342, whereas BFH
Generalized Basaloid Follicular Hamartoma Syndrome
and other benign follicular tumors are CD34+. BCC is diffusely BER-EP4+, whereas BFH is BER-EP42.15 Although BCC expresses androgen receptors, BFH does not.16 Ki-67-positive staining nuclei are numerous in BCC but low in BFH.17 BCL-2 positive cells are scattered throughout the lobules and cords of BCC but are restricted to the periphery of the trabeculae in BFH.15 CK20+ Merkel cells are more common in BFH, but can rarely occur in BCC.16 The pathogenesis of BFH is linked to a mutation in the patched (PTCH) gene on chromosome 9q23, which is the same gene implicated in nevoid basal cell carcinoma syndrome (Gorlin–Goltz syndrome). However, the expression of the mutation in BFH is not as severe.18 The PTCH gene encodes the receptor for sonic hedgehog (SHH), a signaling protein involved in developmental patterning. The PTCH receptor normally complexes with smoothened (SMO), a transmembrane G-protein receptor. In the absence of SHH, PTCH receptor inactivates SMO and prevents transduction of a downstream signal. Binding of SHH to the PTCH receptor releases inhibition of SMO, upregulating SHH genes involving Gli transcription factors.19 Constitutive signaling leads to increased cell division and abnormal growth. Although this pathway may contribute to BFH formation, further studies are needed to explore the pathogenesis of BFH development. In summary, BFH is a rare, generally benign follicular hamartoma that is diagnosed histopathologically because of its variable clinical presentation. Patients with BFH have a good prognosis. Observation without treatment of BFH is not unreasonable given its stable nature; however, patients often opt for treatment for cosmetic reasons.4,7 Although there are no standardized treatments for BFH, current management includes surgical excision, cryosurgery, laser surgery, and photodynamic therapy for diffuse or extensive lesions.20,21 Surgical excision is preferred for localized lesions because of the small risk of malignant progression of BFH.21 New options for treatment of BFH are emerging. Experimental treatment with 5-aminolevulinic acid–mediated photodynamic therapy has been shown to be safe and effective.20 Oral and topical retinoids have also been successful in cases with increased Gli-1 transcription, seen in BFH associated with autoimmune disease because retinoids decrease Gli-1 transcriptional activity.19 Vismodegib, a new inhibitor of the hedgehog signaling pathway that binds the SMO receptor leading to decreased tumor cell proliferation, may have some role in patients with BFHS. Further studies are needed, however, to evaluate the effectiveness of vismodegib in treating BFHS. Our case highlights the importance of monitoring BFH lesions for malignant transformation to BCC if they are not removed. Rapid changes in size or appearance of these lesions should prompt immediate biopsy. In the absence of concerning features, aggressive treatments such as Mohs micrographic surgery are not indicated.8 REFERENCES
FIGURE 3. Histopathology of biopsied lesion (·20 magnification, hematoxylin–eosin stain). Higher power of a classic basaloid proliferation seen in BCC with peripheral palisading and clefting. Copyright 2014 Wolters Kluwer Health, Inc. All rights reserved.
1. Wheeler CE Jr, Carroll MA, Groben PA, et al. Autosomal dominantly inherited generalized basaloid follicular hamartoma syndrome: report of a new disease in a North Carolina family. J Am Acad Dermatol. 2000;43: 189–206. 2. Metry D, Guill C. Generalized basaloid follicular hamartoma syndrome. J Am Acad Dermatol. 2001;45:644–646.
www.amjdermatopathology.com |
e39
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Gumaste et al
Am J Dermatopathol Volume 37, Number 3, March 2015
3. Jih DM, Shapiro M, James WD, et al. Familial basaloid follicular hamartoma: lesional characterization and review of the literature. Am J Dermatopathol. 2003;25:130–137. 4. Lee PL, Lourduraj LT, Palko MJ III, et al. Hereditary basaloid follicular hamartoma syndrome. Cutis. 2006;78:42–46. 5. Brown AC, Crounse RG, Winkelmann RK. Generalized hair-follicle hamartoma, associated with alopecia, aminoacidura, and myasthenia gravis. Arch Dermatol. 1969;99:478–493. 6. Mehregan AH, Baker S. Basaloid follicular hamartoma: three cases with localized and systematized unilateral lesions. J Cutan Pathol. 1985;12:55–65. 7. Brownstein MH. Basaloid follicular hamartoma: solitary and multiple types. J Am Acad Dermatol. 1992;27:237–240. 8. Saxena A, Shapiro M, Kasper DA, et al. Basaloid follicular hamartoma: a cautionary tale and review of the literature. Dermatol Surg. 2007;33:1130–1135. 9. Eng C. Will the real Cowden syndrome please stand up: revised diagnostic criteria. J Med Genet. 2000;37:828–830. 10. Weltfriend S, David M, Ginzburg A, et al. Generalized hair follicle hamartoma: the third case report in association with myasthenia gravis. Am J Dermatopathol. 1987;9:428–432. 11. Mascaro JM Jr, Ferrando J, Bombi JA, et al. Congenital generalized follicular hamartoma associated with alopecia and cystic fibrosis in three siblings. Arch Dermatol. 1995;131:454–458. 12. Morton S, Stevens A, Powell RJ. Basaloid follicular hamartoma, total body hair loss and SLE. Lupus. 1998;7:207–209. 13. Mills O, Thomas LB. Basaloid follicular hamartoma. Arch Pathol Lab Med. 2010;134:1215–1219.
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