Dermatology Online Journal
Familial basaloid follicular hamartoma: a report of one family
- Author(s): Patel, Anisha B
- Harting, Mandy S
- Smith-Zagone, Megan J
- Hsu, Sylvia
- et al.
Familial basaloid follicular hamartoma: a report of one familyDepartment of Dermatology, Baylor College of Medicine, Houston, TX. email@example.com
Anisha B Patel MD, Mandy S Harting MD, Megan J Smith-Zagone MD, Sylvia Hsu MD
Dermatology Online Journal 14 (4): 14
Basaloid follicular hamartoma is a rare but benign adnexal neoplasm that can simulate basal cell carcinoma. Both sporadic and familial variants have been described. We illustrate a family cluster of this unusual entity which presented as milia-like or hyperpigmented papules. Criteria for distinction between the hamartoma and carcinoma are delineated, although evolution of basaloid follicular hamartoma into basal cell carcinoma may also be a possibility.
Basaloid follicular hamartoma (BFH) is a rare benign adnexal tumor that has been described in multiple forms with varied associations [1-21]. It is a somewhat ambiguous diagnosis that has been repeatedly debated, defined, and re-defined in the literature for the past 30 years . Because of its clinical and histological similarities to basal cell carcinoma (BCC), its diagnosis is particularly important as it can avoid unnecessary surgical procedures.
There is evidence that familial BFH may be related to or have the potential to evolve into BCCs [23-24]. BFH has been linked to a mutation in the PTCH (patched) gene on chromosome 9q23; however, this mutation is thought to be less severe than the PTCH gene mutation demonstrated in nevoid basal cell carcinoma syndrome (NBCS) [23, 24, 25]. The potential relationship between the two diagnoses makes BFH, especially its hereditary form, a more significant diagnosis. This loss of function mutation causes premature degradation of the patched protein, a tumor suppressor protein. It works in the Sonic hedgehog (SHH) pathway, which controls tissue patterning by acting as a suppressor of the smoothened (SMO) protein. SMO is a receptor for the hedgehog (HH) protein, causing its activation. Thus, if PTCH levels are decreased, SMO levels are increased, and more HH is activated. Basaloid follicular hamartoma can present in both the sporadic form, with two mutated genes, or in the familial form, with only one mutated gene and one ineffective gene . Rarely, there have been isolated reports of BCCs occurring in association with and possibly evolving from BFH plaques . Although no causative links have been found, the potential evolution of BFH into BCC must be entertained.
As more cases are discovered, the clinical and histological characteristics of BFH that are associated with systemic diseases, malignant lesions, and hereditary patterns can be better defined. In addition to presenting a family with hereditary BFH without associations, this report reviews the literature and the varying definitions and differentials based on the clinical presentation of BFH, helping to better clarify which BFH presentations are at greater risk for misdiagnosis or malignant involvement.
|Figure 1. Hyperpigmented papules on antecubital fossa of Patient 1|
The patient is a 15-year-old young man presented with hyperpigmented papules on his neck, as well as bilateral antecubital and popliteal fossae (Fig. 1). He has had these lesions since birth, and reports sensitivity to both ultraviolet light and water. The patient has no known medical illnesses and denies hypotrichosis and hypohidrosis. There is no evidence of palmar or plantar pitting. He has had no previous treatments. Two biopsies were taken from the antecubital fossae, both showing basaloid proliferation consistent with basaloid follicular hamartoma (Figs. 2 and 3).
The patient is a 16-year-old woman who is the brother of patient 1. She presents with milia-like papules on her face and hyperpigmented papules in the same distribution as her brother, with the addition of papules on her dorsal feet (Fig. 4). She has had these lesions since birth. The patient has no known medical illnesses and denies hypotrichosis and hypohidrosis. There is no evidence of palmar or plantar pitting. She has had no previous treatments. One biopsy was taken from the right dorsal foot, which showed a basaloid proliferation consistent with basaloid follicular hamartoma. Another biopsy taken from the right cheek was consistent with a milium.
|Figure 4||Figure 5|
|Figure 4. Milia-like papules on cheeks of Patient 2|
Figure 5. Hyperpigmented papules on antecubital fossa of Patient 3
The patient is a 42-year-old woman who is the mother of patients 1 and 2. She presents with similarly distributed hyperpigmented papules (Fig. 5). There is no evidence of palmar or plantar pitting. Because of the diagnoses in her children, biopsies were not taken for this patient.
Basaloid follicular hamartoma presents in multiple forms with varying clinical and histological presentations. This paper seeks to delineate these presentations as best possible and correlate clinical presentation with associations and potential risk for malignancy.
Our patients present with familial BFH without associations, most commonly seen as 1-2 mm diameter skin-colored or hyperpigmented papules on the face, scalp, and trunk. Often, small milia-like and comedone-like papules are present as well [2, 3, 7, 18]. Histologically, BFH has been defined as well-demarcated epithelial proliferations in the upper portion of the dermis with overlying normal epidermis. The dermis has thin anastamosing strands and thicker cords of well-differentiated squamoid and basaloid cells. Small horn cysts and melanin are common. The tumor is surrounded by scant, loose, fibrocytic connective tissue stroma. There is scant to no inflammatory infiltrate, necrosis, atypia, or mitosis. Different descriptions of BFH vary in their definitions regarding whether or not the tumor has epidermal connections, clefts between tumor and stroma, mucin near the epithelium, and follicular bulbs or papillae [2, 3, 4, 7, 18, 21, 27].
Basaloid follicular hamartoma has been reported as localized and generalized forms . The localized form can manifest as linear and unilateral lesions, as small papules, or as plaques with alopecia. The generalized form may present as familial, congenital, or acquired. The familial form is autosomal dominantly inherited and can be found in association with hypotrichosis, hypohidrosis, and palmoplantar pitting [15, 18]. The generalized congenital BFH has been associated with alopecia and cystic fibrosis . Furthermore, the generalized acquired form has been reported in association with myasthenia gravis and alopecia [5, 28].
Although diagnosis can be better confirmed with different staining techniques, these procedures were not undertaken with the presented patients because of their classic findings. Further confirmatory evidence can be obtained by using stains for Ki-67, proliferating cell nuclear antigen (PCNA), Bcl-2, PTCH mRNA, and CD34. These techniques might be particularly useful if malignancy is in question. Ki-67 is a proliferative marker associated with mitosis that, when stained for in BFH versus BCC, is less prominent in BFH. PCNA is a subunit of DNA polymerase that indicates the proliferative fraction of a population of cells, and when stained for in BFH versus BCC, is less prominent in BFH. Similarly, Bcl-2 staining is less prominent in BFH versus BCC. PTCH mRNA is overexpressed in BCC diffusely, but is overexpressed in BFH only in cells having direct contact with the dermis. However, CD34 is positive only in stromal cells next to the tumor cells in BFH, and it is not detectable in BCC. Finally, monoclonal antidesmoglein antibody (33-3D) can be used to distinguish between BFH and BCC, as malignant cells should lose desmosomes and have decreased staining [24, 27, 29, 30, 31].
The differential diagnosis for BFH depends on its presentation. Differential diagnosis could include generalized follicular hamartoma syndrome, tuberous sclerosis, Cowden disease, multiple trichoepitheliomas, nevoid basal cell nevus syndrome, Rombo syndrome, and multiple tumors of the follicular infundibulum [3, 7, 18, 20, 28, 37].
The most common misdiagnoses for individual lesions include BCC, intradermal melanocytic nevus, seborrheic keratosis, and sebaceous hyperplasia. Other neoplasms with a similar clinical presentation include syringoma, angiofibroma, trichilemmoma, steatocystoma, trichoepithelioma, basal cell hamartoma with follicular differentiation, and hamartoma of sebaceous follicles [3, 5, 18, 32, 33]. When presenting as a plaque, nevus sebaceus, lupus erythematosus, and sarcoidosis should be considered . Finally, when presenting in a linear distribution, the differential diagnosis includes linear epidermal nevus, lichen striatus, linear morphea, and basal cell nevus .
When considering histological characteristics, BFH has a narrow set of differential diagnoses. There has been debate in the literature about the differences among these diagnoses, but it appears that the most important classification is whether or not the lesion is benign or malignant. The presence of follicular bulbs, papillary mesenchymal bodies, trichohyalin granules, hair shafts, shadow cells, and focal CD34 stain in adjacent tumor mesenchyme are benign characteristics.
The histologic diagnoses of BFH and trichoepithelioma may overlap. The two are similar in that they may have abortive hair follicle-like structures and keratin cysts. Trichoepithelioma, however, will characteristically have more keratin cysts, a more prominent cellular stroma, more cribriform and nodular growth pattern, and follicular differentiation with papillar mesenchymal bodies [3, 29, 34].
Basaloid follicular hamartoma and infundibulocystic BCCs appear similar in that they are both small, well-circumscribed, and lack ulcerations. They have the following histologic characteristics in common: scant stroma (although BCC has less stroma), anastamosing cords of epithelial cells, follicular germs and papillae, hair follicle association, clefts within stroma, and no epidermal changes. Both lesions may have melanin, amyloid deposits, mild lymphocytic infiltrate, and keratin cysts. They are distinguished in that infundibulocystic BCCs often have larger lesions with increased destruction of normal architecture. Like other BCCs, they have peripheral pallisading nuclei, clefts between tumor masses and stroma, atypia, mitotic figures, and necrosis. There is decreased anastamosis of tumor islands, possible continuity with nodular BCC, and extension into the reticular dermis or deeper. Infundibulocystic BCCs also affect the interfollicular dermis, whereas BFH is folliculocentric [3, 21, 34, 35, 36].
Multiple methods of treatment have been attempted in the literature without success. The tumors have a high rate of recurrence; although, except in a few isolated incidents, are not related to malignant change . In general, these lesions are not treated, but are monitored by physicians, particularly in children in which BFH and BCC may be hard to distinguish .
Basaloid follicular hamartoma is a rare benign adnexal tumor that can present in many different clinical forms. Because of its clinical and histological similarities to basal cell carcinoma (BCC), molecular relationship with nevoid basal cell nevus syndrome, and questionable evolution into BCC, its diagnosis is of particular interest. There are a wide variety of isolated and generalized lesions that present similarly to BFH, some of which are associated with BCC, and it is important to distinguish among these as well. Familial cases of BFH appear to have the highest risk for malignant transformation because of the genetic similarities to NBCS. Although there are no current recommended treatments, these lesions should be monitored and carefully diagnosed to avoid unnecessary treatment [3, 37].
References1. Jih DM, Shapiro M, James WD, Levin M, Gelfand J, Williams PT, Oakey RJ, Fakharzadeh S, Seykora JT. Familial basaloid follicular hamartoma: lesional characterization and review of the literature. Am J Dermatopathol 2003 Apr; 25(2):130-7. PubMed
2. Brownstein MH. Basaloid follicular hamartoma: solitary and multiple types [see comments]. J Am Acad Dermatol 1992; 27(Part 1):237-40. PubMed
3. Girardi M, Federman GL, McNiff JM. Familial multiple basaloid follicular hamartomas: a report of two affected sisters. Pediatr Dermatol 1999; 16:281-4. PubMed
4. Mehregan AH, Baker S. Basaloid follicular hamartoma: three cases with localized and systematized unilateral lesions. J Cutan Pathol 1985; 12:55-65. PubMed
5. Nelson BR, Johnson TM, Waldinger T, et al. Basaloid follicular hamartoma: a histologic diagnosis with diverse clinical presentations [letter; see comments]. Arch Dermatol 1993; 129:915-7. PubMed
6. Toyoda M, Kagoura M, Morohashi M. Solitary basaloid follicular hamartoma. J Dermatol 1998; 25:434-7. PubMed
7. 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(Part 1):189-206. PubMed
8. Ridley CM, Smith N. Generalized hair follicle hamartoma associated with alopecia and myasthenia gravis: report of a second case. Clin Exp Dermatol 1981; 6:283-9. PubMed
9. 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; 9:428-32. PubMed
10. Akasaka T, Kon S, Mihm MC Jr. Multiple basaloid cell hamartoma with alopecia and autoimmune disease (systemic lupus erythematosus). J Dermatol 1996; 23:821-4. PubMed
11. Morton S, Stevens A, Powell RJ. Basaloid follicular hamartoma, total body hair loss and SLE. Lupus 1998; 7:207-9. PubMed
12. Jimenez-Acosta FJ, Redondo E, Baez O, et al. Linear unilateral basaloid follicular hamartoma. J Am Acad Dermatol 1992; 27(Part 2):316-9. PubMed
13. Harman M, Inaloz HS, Akdeniz S, et al. Congenital non-familial unilateral basaloid follicular hamartoma. J Eur Acad Dermatol Venereol 1999; 13:210-3. PubMed
14. Kato N, Ueno H, Nakamura J. Localized basaloid follicular hamartoma. J Dermatol 1992; 19:614-7. PubMed
15. Delacretaz J, Balsiger F. Hamartome folliculaire multiple familial. Dermatologica 1979; 159:316-24. PubMed
16. 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; 131:454-8. PubMed
17. Ricks M, Elston DM, Sartori CR. Multiple basaloid follicular hamartomas associated with acrochordons, seborrhoeic keratoses and chondrosarcoma. Br J Dermatol 2002; 146:1068-70. PubMed
18. Lee PL, Lourduraj LT, Palko MJ 3rd, Jukic DM, English JC 3rd. Hereditary basaloid follicular hamartoma syndrome. Cutis 2006 Jul; 78(1): 42-6. PubMed
19. Johnson WC, Hookerman BJ. Basal cell hamartoma with follicular differentiation. Arch Dermatol 1972 Jan; 105(1): 105-6. PubMed
20. Pujol RM, Nadal C, Matias-Guiu X, Peyrí J, Ferrándiz C, Palou J, de Moragas JM. Multiple follicular hamartomas with sweat gland and sebaceous differentiation, vermiculate atrophoderma, milia, hypotrichosis, and late development of multiple basal cell carcinomas. J Am Acad Dermatol 1998 Nov; 39(5 Pt 2): 853-7. PubMed
21. Walsh N, Ackerman AB. Basaloid follicular hamartoma: solitary and multiple types. J Am Acad Dermatol 1993 Jul; 29(1): 125-9. PubMed
22. Goldhahn RT Jr. Basaloid follicular hamartoma. J Am Acad Dermatol 1994 Jul; 31(1): 131-2. PubMed
23. Gailani MR, Bale AE. Acquired and inherited basal cell carcinomas and the patched gene. Adv Dermatol 1999; 14:261-83. PubMed
24. Unden AB, Zaphiropoulos PG, Bruce K, Toftgard R, Stahle-Backdahl M. Human patched (PTCH) mRNA is overexpressed consistently in tumor cells of both familial and sporadic basal cell carcinoma. Cancer Res. 1997 Jun 15;57(12):2336-40. PubMed
25. Hahn H, Wicking C, Zaphiropoulous PG, et al. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 1996; 85:841-51. PubMed
26. Yoshida Y, Urabe K, Mashino T, Duan H, Kiryu H, Masuda T, Koga T, Furue M. Basal cell carcinomas in association with basaloid follicular hamartoma. Dermatology 2003; 207:57-60. PubMed
27. 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; 28:538-41. PubMed
28. Miyakawa S, Araki Y, Sugawara M. Generalized trichoepitheliomas with alopecia and myasthenia gravis. J Am Acad Dermatol 1988; 19(Part 1):361-2. PubMed
29. Saxena A, Shaprio M, Kasper DA, Fitzpatrick JE, Mellette JR Jr. Basaloid follicular hamartoma: A cautionary tale and review of the literature. Dermatol Surg 2007; OnlineEarly Articles.
30. Stashower ME, Smith K, Corbett D, Skelton HG. Basaloid/follicular hyperplasia overlying connective tissue /mesenchymal hamartomas simulating basal cell carcinomas. J Am Acad Dermatol 2001; 45: 886-91. PubMed
31. Abdelsayed RA, Guijarro-Rojas M, Ibrahim NA, et al. Immunohistochemical evaluation of basal cell carcinoma and trichoepithelioma using Bcl-2, Ki-67, PCNA and P53. J Cutan Pathol 2000; 27:169-75. PubMed
32. 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: 191-8. PubMed
33. El-Darouti MA, Marzouk SA, Abdel-Halim MR, Zidan AZ, Fawzy MM. Basaloid follicular hamartoma. Int J Dermatol 2005 May; 44(5): 361-5. PubMed
34. Requena L, Farina MC, Robledo M, Sangueza OP, Sanchez E, Villanueva A, Marquina A, Tamarit R. Multiple hereditary infundibulocystic basal cell carcinomas: a genodermatosis different from nevoid basal cell carcinoma syndrome. Arch Dermatol 1999 Oct; 135(10): 1227-35. PubMed
35. Tozawa T, Ackerman AB. Basal cell carcinoma with follicular differentiation. Am J Dermatopathol 1987; 9:474-82. PubMed
36. Walsh N, Ackerman AB. Infundibulocystic basal cell carcinoma: a newly described variant. Mod Pathol 1990; 3:599-608. PubMed
37. Metry D, Guill C. Generalized basaloid follicular hamartoma syndrome. J Am Acad Dermatol 2001; 45(4): 644-6. PubMed
© 2008 Dermatology Online Journal