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Basaloid follicular hamartoma.

Basaloid follicular hamartoma (BFH) is a rare, benign, superficial malformation of hair follicles that presents histologically as an epithelial proliferation of basaloid cells and clinically in various forms, with and without associated diseases.

This entity was first described in 1969 by Brown et al (1) as multiple papules in the nasolabial folds associated with myasthenia gravis and diffuse alopecia (Brown-Crounse syndrome). In 1985, the term basaloid follicular hamartoma was coined by Mehregan and Baker, (2) who reported a localized and solitary type of lesion without associated abnormalities. Recently, Morohashi et al (3) described BFH as an abortive growth of secondary hair germs with a limited differentiation toward the upper follicular portion.


Genetic studies have linked BFH to a mutation in the patched (PTCH) gene on chromosome band 9q23. The gene is part of the same pathway implicated in nevoid basal cell carcinoma syndrome (NBCCS) or Gorlin-Goltz syndrome, though its expression is less severe. (4,5) The PTCH gene encodes a receptor for the protein product of the sonic hedgehog gene (SHH), a member of the hedgehog family of genes that are involved in developmental patterning during embryonic development. The PTCH receptor forms a receptor complex with another transmembrane protein known as SMO (for "smoothened"). When SHH protein is absent, PTCH receptor inactivates SMO and keeps it from transducing a downstream signal. Binding of SHH protein to the PTCH receptor releases the suppression of SMO, causing the upregulation of hedgehog target genes through a signal cascade that involves transcription factors in the Gli family. (6,7) Unregulated signaling can lead to increased cell division resulting in abnormal growth and abnormal patterning. (8)

Mutations in this pathway have been implicated in numerous abnormalities including NBCCS, sporadic basal cell carcinomas, trichoblastomas, trichoepitheliomas (TEs), cylindromas, nevus sebaceous, and dentigous cysts. (7) Increased Gli-1 transcriptional activity, suggested as an underlying mechanism in BFH, is mitigated by treatment with retinoids, which decrease Gli-1 transcriptional activity. (7) Studies are needed to further delineate the current understanding of BFH development.


Basaloid follicular hamartoma has varying clinical presentations and associations and may be localized or generalized. Basaloid follicular hamartoma may present as individual or linearly arranged, small, skin-colored to brown papules or plaques, or as multiple lesions in a generalized distribution on the face, scalp, and occasionally, the trunk. Basaloid follicular hamartoma may be a familial, congenital, or acquired condition. It may occur alone or in association with other genodermatoses and diseases, including Bazex-Dupre-Christol syndrome (an X-linked dominant disease characterized by early onset of multiple basal cell carcinomas, congenital hypotrichosis, and follicular atrophoderma), and has been reported in association with myasthenia gravis, alopecia, systemic lupus erythematosus, and cystic fibrosis. (1,7,9,10,11)

The clinical differential diagnosis for BFH is dependent on the presentation. Individual papules may be misdiagnosed as basal cell carcinoma (BCC), intradermal melanocytic nevus, seborrheic keratosis, sebaceous hyperplasia, syringoma, angiofibroma, trichilemmoma, steatocystoma, TE, and hamartoma of sebaceous follicles. (4)

Plaques may present like the lesions of nevus sebaceous, lupus erythematosus, and sarcoidosis. Basaloid follicular hamartoma in a linear distribution may mimic linear epidermal nevus, lichen striatus, linear morphea, and basal cell nevus. (4)

Generalized BFH may represent generalized follicular hamartoma syndrome (Brown-Crounse syndrome), tuberous sclerosis, Cowden syndrome ("multiple hamartoma syndrome" involving organs from all 3 germinal layers), multiple trichoepitheliomas, NBCCS, Rombo syndrome (atrophoderma vermiculatum of the face, multiple milia, telangiectases, acral erythema, and a propensity to develop BCC), and multiple tumors of the follicular infundibulum. (4)


Because of the varied clinical presentations of BFH, histologic specimens may be received in multiple forms including punch biopsies, shaves, or frozen sections of skin, without definite identifying gross features to distinguish BFH from other common skin lesions.


Histologic examination narrows the differential diagnosis to lesions of epithelial basaloid proliferations and includes BFH, BCC, TE, and folliculocentric basaloid proliferation (FBP).

One of the most important considerations is whether the entity is benign or malignant. Finding follicular bulbs, papillary mesenchymal bodies, trichohyalin granules, hair shafts, shadow cells, and focal CD34 staining in adjacent tumor stromal cells all favor benign entities. (4)

Specifically, BFH consists of malformed and distorted hair follicles composed of cords and strands of basaloid cells. These cells are arranged in a radial and anastomosing fashion (Figure 1, A and B) and may arise from follicles and/or show an epidermal attachment. (12) The tumor cells are bland without nuclear pleomorphism, and mitotic activity is rare or absent. There is scant to no single cell necrosis. (4) While the presence of peripheral palisading has been reported, (1,13) this feature is typically lacking in the degree seen in BCC. (14,15) Stroma is scant or absent, and when present, consists of eosinophilic compact collagen with no fibrocytes. Clefts within the fibrous stroma have beenreported. (14,15) Minimal clefting between the tumor and stroma has been observed but is not a well-accepted feature of BFH. (12) Usually, mucinous ground substance, if present, is subtle. Whether follicular bulbs and papillae are seen is debatable. (14,16) Basaloid follicular hamartomas are seen only where normal follicles should be present. Therefore, they do not involve the interfollicular dermis nor do they involve the deeper reticular dermis. (16)

In contrast, BCC displays a variety of histologic patterns but is recognized as cords and islands of variably basophilic cells with hyperchromatic nuclei, embedded in a mucinous matrix, often surrounded by many fibroblasts and lymphocytes (Figure 1, A and C). Palisading of the cells at the periphery of the tumor islands is present. Clefts (separation artifact) are created as the stroma shrinks away from the epithelial tumor nests. Increased mitoses and single cell necrosis are also present. The neoplastic cells may involve and destroy preexisting hair follicles and interfollicular dermis and sometimes infiltrate deeper dermis, subcutaneous fat, and skeletal muscle. (8,16)

In 1987, Tozawa and Ackerman17 described a variant of basal cell carcinoma with follicular differentiation, named infundibulocystic basal cell carcinoma (ICBCC) (Figure 1, D). Since the histopathologic features of BFH are similar to those of ICBCC, some feel BFH and ICBCC represent a spectrum of the same entity. (18) The premalignant potential of BFH is currently undetermined, although BCC arising within BFH has been reported. (18) Requena et al (16) described histopathologic and clinical criteria distinguishing BFH from ICBCC that include more prevalent malignant features in ICBCC, such as necrotic neoplastic cells, mitotic figures, and local tissue destruction.

A benign lesion in the differential diagnosis of BFH is TE (Figure 1, E). This neoplasm is composed of epithelium that differentiates toward hair structures. Histologically, TE has distinct islands of basaloid cells in a lacelike or adenoid network and, occasionally, as solid aggregates. They exhibit a more nodular growth pattern than BFH. The tumor islands show peripheral palisading like BCC. However, the stroma lacks the retraction artifact seen in BCC. In TE, the fibrocytic stroma is more prominent than in BFH and it predominates over the epithelial portion. In TE, normal follicular bulbs and papillae are seen. (4,16,19) While both BFH and TE have keratin cysts consisting of a fully keratinized center surrounded by basophilic cells without high-grade atypia and mitoses, they are more prominent in TE.

Finally, FBP is a reactive lesion originating from mantle epithelium that occurs in clinically normal skin adjacent to a BCC (Figure 1, F). This is also known as "bulge" growth and may surround BCC for at least 3 mm. (19,20) The major histologic features of FBP include folliculocentric, vertically oriented neoplasm with prominent hyaline basement membrane at the periphery of most basaloid aggregates and an unaltered stroma. Follicular papillae are absent or underdeveloped, although the lesion originates from the follicular outer root sheath. Histologically, BFH and FBP can at times be indistinguishable. (20) The most notable difference between BFH and FBP is presence or absence of keratin cysts. No keratin cysts are reported in FBP, (20) whereas keratin cysts are seen in BFH, TE, and ICBCC. (19) No direct epidermal attachment is reported for FBP. Clear epidermal attachments are present in ICBCC and may be present in BFH. (12,19,20)


Most of the basaloid epithelial proliferations can be identified histologically. Of the above differential diagnosis, differentiating BFH from BCC can be the most problematic. In these cases, special stains may help to delineate the lesion.

Ki-67 (a proliferative marker associated with mitosis) and Bcl-2 staining are more prominent in BCC than BFH (Figure 2, A through D). Bcl-2 stains only the outermost basal cells in BFH. CD34 is positive in stromal cells next to tumor cells in BFH and is negative in BCC (Figure 2, E and F). CD10 stains the peritumoral stroma of BFH as well as matrical cells, while BCC of various subtypes have stromal and tumor cell positivity (9,21) (Figure 2, G and H). Other stains reported to be useful for differentiation include PCNA (a subunit DNA polymerase that shows the proliferative fraction of tumor cells), which shows more prominent staining in BCC than in BFH. Also, PTCH mRNA is diffusely overexpressed in BCC, but it is overexpressed in BFH, only in cells having direct contact with the dermis. Finally, monoclonal anti-desmoglein antibody shows decreased staining in BCC, as malignant cells lose desmosomes. (4,19)


Currently, there are no standard treatments for BFH. Correctly identifying BFH spares patients from unnecessary surgery, while allowing for periodic monitoring to detect malignant transformations or malignant growths within a BFH. Lesions with an increase in size or change of appearance should be biopsied. If associated with an autoimmune disease, treatment of the autoimmunity may cause regression of the associated cutaneous lesions.


Some experimental therapies have been reported. In a report of cases, (22) 5-aminolevulinic acid photodynamic therapy was found to be a safe, well-tolerated, and effective treatment for extensive areas of diffuse BCC and BFH, and it appeared to be the treatment of choice in children. Oral and topical retinoids caused regression of cutaneous BFH in another report. (7) This therapy was effective because retinoids decrease Gli-1 transcriptional activity. A recent study (23) found a hitherto unknown requirement for ligand-driven, canonical Wnt/[beta]-catenin signaling for hedgehog pathway-driven tumorigenesis and has thus identified a new possible pharmacologic target for BFH. With additional studies, as a better understanding of BFH is obtained, pharmacologic agents are promising future treatment possibilities.


We would like to thank Michael Morgan, MD, for providing his dermatopathologic expertise and for contributing to the case material.


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(2.) Mehregan AH, Baker S. Basaloid follicular hamartoma: three cases with localized and systematized unilateral lesions. J Cutan Pathol. 1985;12(1):55-65.

(3.) Morohashi M, Sakamoto F, Takenouchi T, Hashimoto T, Tago O, Ito M. A case of localized follicular hamartoma: an ultrastructural and immunohistochemical study. J Cutan Pathol. 2000;27(4):191-198.

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(7.) Smith KJ, Skelton H. Basaloid follicular hamatomas associated with autoimmune disease: a possible role for retinoids in therapy. J Am Acad Dermatol. 2003;49(6):1067-1070.

(8.) Kumar V, Abbas A, Fausto N. The skin. In: Robbins and Cotran Pathologic Basis of Disease. 7th ed. Philadelphia, PA: Elsevier Saunders; 2005:1244-1246.

(9.) Ramos-Ceballos F, Pahaei S, Kincannon J, Morgan M, Smoller B. 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(5):477-483.

(10.) Mascaro JM Jr, Ferrando J, Bombi JA, Lambruschini N, Mascaro JM. Congenital generalized follicular hamartoma associated with alopecia and cystic fibrosis of three siblings. Arch Dermatol. 1995;131(4):454-458.

(11.) Starink TM, Lane EB, Meijer CJ. Generalized trichoepitheliomas with alopecia and myasthenia gravis: clinicopathologic and immunohistochemical study and comparison with classic and desmoplastic trichoepithelioma. J Am Acad Dermatol. 1986;15(5, pt 2):1104-1112.

(12.) Wheeler CE Jr, Carroll MA, Groben PA, Briggaman RA, Prose NS, Davis DA. Autosomal dominantly inherited generalized basaloid follicular hamartoma syndrome: report of a new disease in a North Carolina family. J Am Acad Dermatol. 2000;43(2, pt1):189-206.

(13.) Ridley CM, Smith N. Generalized hair follicle hamartoma associated with alopecia and myasthenia gravis: report of a second case. Clin Exp Dermatol. 1981;6(3):283-289.

(14.) Jih D, Shapiro M, James W, et al. Familial basaloid follicular hamartoma: lesional characterization and review of the literature. Am J Dermatopathol. 2003;


(15.) Brownstein MH. Basaloid follicular hamartoma: solitary and multiple

types. J Am Acad Dermatol. 1992;27(2, pt 1):237-240.

(16.) Requena L, del Carmen Farina M, Robledo M, et al. Multiple hereditary infundibulocystic basal cell carcinomas. Arch Dermatol. 1999;135(10):1227 1235.

(17.) Tozawa T, Ackerman AB. Basal cell carcinoma with follicular differentiation. Am J Dermatopathol. 1987;9(6):474-482.

(18.) Yoshida Y, Urabe K, Mashino T, et al. Basal cell carcinomas in association with basaloid follicular hamartoma. Dermatology. 2003;207:57-60.

(19.) Saxena A, Shapiro M, Kasper D, Fitzpatrick J, Mellette J Jr. Basaloid follicular hamartoma: a cautionary tale and review of the literature. Dermatol Surg. 2007; 33(9):1130-1135.

(20.) Leshin B, White WL. Folliculocentric basaloid proliferation: the bulge (der Wulst) revisited. Arch Dermatol. 1990;126(7):900-906.

(21.) Yada K, Kashima K, Daa T, Kitano S, Fujiwara S, Yokoyama S. Expression of CD10 in basal cell carcinoma. Am J Dermatopathol. 2004;26(6):463-471.

(22.) Oseroff A, Shieh S, Frawley N, 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(1):60-67.

(23.) Yang SH, Andl T, Grachtchouk V, et al. Pathological responses to oncogenic Hedgehog signaling in skin are dependent on canonical Wnt/beta catenin signaling. Nat Genet. 2008;40(9):1130-1135. Omie Mills, MD; L. Brannon Thomas, MD

Accepted for publication June 11, 2009.

From the Department of Pathology and Cell Biology, University of South Florida, Palmetto (Drs Mills and Thomas) and James A. Haley Veterans Hospital, Tampa, Florida (Dr Thomas).

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Omie Mills, MD, Department of Pathology and Cell Biology, University of South Florida, 1615 52nd Dr W, Palmetto, FL 34221 (e-mail: omills@
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Author:Mills, Omie; Thomas, L. Brannon
Publication:Archives of Pathology & Laboratory Medicine
Date:Aug 1, 2010
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