Dermatology Online Journal

Familial basaloid follicular hamartoma: a report of one family
Anisha B Patel MD, Mandy S Harting MD, Megan J Smith-Zagone MD, Sylvia Hsu MD
Dermatology Online Journal 14 (4): 14

Department of Dermatology, Baylor College of Medicine, Houston, TX. shsu@bcm.edu

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Abstract

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.

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Introduction

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 [22]. 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 [25]. Rarely, there have been isolated reports of BCCs occurring in association with and possibly evolving from BFH plaques [26]. 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.

Case report

Patient 1

Figure 1
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).

Figure 2	Figure 3
Figure 2. Small nests of basaloid cells within the superficial dermis multiple horn cysts, scant stroma, and clefting between some tumor cells and stroma consistent with BFH. Figure 3. The nests show some peripheral palisading nuclei and associated scant fibrous to mucinous stroma. Some nests show association with follicles and connection to the epidermis. Rare mitoses are present. Melanin pigment is present in some basaloid cells.

Patient 2

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

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.

Comments

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 [4]. 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 [4]. 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 [33]. Finally, when presenting in a linear distribution, the differential diagnosis includes linear epidermal nevus, lichen striatus, linear morphea, and basal cell nevus [33].

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 [3]. 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 [37].

Conclusion

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].

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