Miliary Fibromas in Tuberous Sclerosis Complex

Abstract

Background:

Tuberous sclerosis complex (TSC) is a hamartoma syndrome characterized by multiple skin lesions, such as angiofibromas, shagreen patch, and miliary fibromas (MiF).

Objective:

To determine the clinical and histological features of MiF.

Methods:

A retrospective analysis was conducted on 133 adults with TSC. Photography was used to characterize the appearance and location of MiF. Histological features in 5 skin samples from 4 individuals were evaluated by a board-certified dermatopathologist.

Results:

MiF were observed in 19 of 133 (14%) individuals with TSC. MiF were 1 to 3 mm skin-colored, sessile papules scattered on the back and rarely buttocks or thighs. Most were scattered in a bilaterally symmetric distribution, but others were asymmetric or associated with a shagreen patch. Histological features of MiF included expansion of the papillary and periadnexal dermis with variable hamartomatous abnormalities involving adjacent epithelial components.

Conclusions:

MiF are distinct from other cutaneous lesions in TSC such as shagreen patches and angiofibromas. Recognition of this entity is important in defining the spectrum of TSC disease and reassuring individuals with TSC that these lesions are benign.

Introduction

Tuberous sclerosis complex (TSC) is an autosomal-dominant genodermatosis characterized by the development of multiple tumors in the brain, eyes, heart, kidneys, and skin. TSC is caused by a pathogenic variant in the tumor suppressor gene TSC1 or TSC2.¹ Dermatologic manifestations comprising part of the diagnostic criteria for TSC include pigmentary changes (hypomelanotic macules, confetti lesions) and skin hamartomas (angiofibromas, fibrous cephalic plaques, ungual fibromas, and shagreen patches).^2,3 Another skin lesion associated with TSC, called miliary fibromas (MiF) or miliary fibrous tubercles,⁴ comprise tiny skin-colored papules scattered on the trunk of individuals with TSC. They are “pinhead” sized, or roughly 2 mm in diameter, and described in the early literature as similar to “goose-flesh”.^4,5 MiF are sessile, distinguishing them from pedunculated skin tags (molluscum fibrosum pendulum), which may also be observed in individuals with TSC. MiF are not included in the diagnostic criteria for TSC and their potential significance for diagnosis and patient care has received little scrutiny. Thus, the goal of this study was to characterize clinical and pathological features of MiF that occur in individuals with TSC.

Materials and Methods

A retrospective analysis was performed on 133 adults who met the criteria for diagnosis of TSC according to the 2012 consensus guidelines.² All individuals provided written informed consent for studies at the National Institutes of Health in Bethesda, Maryland from 1998 to 2015, under protocols 00-H-0051 and 95-H-0186, which were approved by the National Heart, Lung, and Blood Institute Institutional Review Board. Individuals were evaluated for the presence or absence of MiF using dermatologic consult notes and accompanying clinical photographs. Samples of MiF were obtained from four individuals and sections stained with routine haematoxylin and eosin and elastic Verhoeff-Van Gieson stain. Photographs were used to classify lesions according to location and association with other TSC dermatologic manifestations. The association between genetic variants in TSC patients and the presence or absence of MiF was assessed using a chi-squared test.

Results

Demographics and Frequency

This study included 133 adults with TSC (128 women, 5 men). The cohort was enriched for those with lymphangioleiomyomatosis, a TSC-related lung disease that primarily affects adult women. Individuals ranged in age from 19 to 70 years (median age 38). 53 individuals had a known pathogenic or likely pathogenic variant in TSC2 and 6 individuals had a pathogenic variant in TSC1.

19 of the 133 individuals with TSC (14%) had MiF. MiF were asymptomatic and the age of onset was uncertain. Those with MiF were women aged 35 to 69 years (median age 46), 13 of whom had a known pathogenic or likely pathogenic variant in TSC2 and none with a known variant in TSC1. A TSC2 mutation was more common in patients with MiF than without MiF (p=0.013).

Clinical Appearance

MiF appeared as multiple superficial, sessile, skin-colored papules ranging in size from 1 to 3 mm. MiF were scattered with inconsistent spacing between mostly discrete lesions; some formed small clusters (Figures 1A, 2A). In four individuals, the number of papules in a given area was measured and an average of 12 papules per square centimeter was calculated.

Figure 1:

A) Miliary fibromas distributed across the back and buttocks of an adult woman with TSC. B) Shave biopsy from the clustered papules near the gluteal cleft. There are elongated, focally reticulated strands of squamous epithelium emanating from the base of epidermis (200x original magnification).

Figure 2:

A) Miliary fibromas on the back of an adult woman with TSC. B) Punch biopsy from the clustered papules left of midline. There is a thickened and sclerotic perifollicular fibrous sheath and an epithelial strand which emanates from the hair follicle into the surrounding fibrous root sheath (100x original magnification).

In the 19 adults with MiF, most or all lesions occurred on the back, most frequently the mid to lower back. In six individuals, the MiF predominated in a band overlying the spine and, in thirteen individuals, the lesions were anywhere across the back. Seventeen of 19 (89%) individuals had MiF on both sides of the back; in 11 individuals, MiF were fairly symmetric whereas in 6 individuals, the MiF predominated on a single side. In two individuals, the MiF were associated with a shagreen patch in the surrounding skin. One individual had MiF extending beyond the back to the buttocks and posterior thighs and one individual had MiF extending beyond the back to the shoulder blades and upper back.

MiF co-occurred with other characteristic TSC skin lesions, including angiofibromas in 18 individuals (95%), oral lesions (oral fibromas or dental pitting) in 16 (84%), hypopigmentation (hypopigmented macules or confetti lesions) in 16 (84%), ungual fibromas in 15 (79%), shagreen patches in 13 (68%), and fibrous cephalic plaques in 5 (26%).

Histopathologic appearance

In 5 biopsies of MiF in 4 individuals with TSC, we observed an expansion of the papillary and periadnexal dermis with variable involvement of the adnexa and overlying epithelium. In one individual, biopsy of clustered papules from near the upper gluteal fold revealed elongated, focally reticulated strands of squamous epithelium emanating from the base of the epidermis, thickening of papillary dermal collagen fibers (Figure 1B), and misshaped hair follicles. Biopsy from another individual revealed thin cords of epithelial cells emanating from the hair follicle into a thickened and sclerotic perifollicular fibrous sheath, resembling a fibrofolliculoma (Figure 2B). Additional epidermal and follicular abnormalities observed in biopsies included focal areas of epidermal hyperplasia and hyperkeratosis similar to epidermal nevus and telogen-like terminal hair follicles with an abnormally arranged follicular bulb and partially surrounded by myxoid stromal collagen, suggestive of a follicular hamartoma.

Discussion

MiF were identified in the skin overlying the thoracolumbar and sacral region of the back in 14% of adults with TSC in our cohort. MiF are not part of the clinical diagnostic criteria, but their presence supports a diagnosis of TSC. MiF are one member of a group of cutaneous findings that can be associated with TSC, including folliculocystic and collagen hamartomas,⁶ red comets on the nails,⁷ small collagenomas on the back,⁸ angiofibromas on the nipples⁹ or genitals,¹⁰ and molluscum fibrosum pendulum on the neck in children.¹¹ MiF are typically of little concern but those affected can be reassured that they are benign and part of the spectrum of skin findings observed in TSC.

MiF have been compared to shagreen patches based on their shared anatomic location. Nickel and Reed proposed that MiF were an abortive form of shagreen patches, as they could be observed at the periphery of shagreen patches on the back.⁵ Shagreen patches appear as oval skin-colored to pink plaques and may have smooth surfaces, dilated follicular openings (peau d’orange) or can be studded with small follicular papules.⁸ Histologically, shagreen patches show thickened, disorganized collagen bundles in the reticular dermis with decreased elastin fibers.⁸ Most show a zone of normal-appearing connective tissue below the epidermis, but some have involvement of the papillary dermis and can exhibit overlying epidermal changes similar to acanthosis nigricans.⁵ Most MiF in our cohort appeared as numerous discrete papules ranging in size from 1 to 3 mm. Histological changes involved the mesenchyme in proximity to the epidermis and hair follicles; broad bands of collagen were not observed in the reticular dermis. These observations prompt us to envision the distinction between MiF and shagreen patches on the back as analogous to the relationship between angiofibromas and fibrous cephalic plaques on the head. Like angiofibromas, MiF are smaller, more superficial and numerous in comparison to shagreen patches or fibrous cephalic plaques that are larger, deeper, and often solitary or few.

In histopathologic examination of MiF, we observed variable expansion of the papillary and periadnexal dermis accompanied by subtle epithelial changes. The expansion of the papillary and periadnexal dermis and abnormally shaped and immature hair follicles is similar to angiofibromas.¹² However, angiofibromas typically show dilated vessels and stellate fibroblasts and lack the finding of thin epithelial strands interconnecting rete ridges as observed in several MiF. In one biopsy specimen, thin cords of epithelial cells emanated from the hair follicle into a thickened and sclerotic perifollicular fibrous sheath, as observed in fibrofolliculomas. Multiple fibrofolliculomas are characteristic of Hornstein-Knickenberg syndrome (Birt-Hogg-Dubé syndrome), but TSC diagnosis was definite in this patient based on clinical features and genetic criteria (germline TSC2 variant). This is another example of the potential to observe fibrofolliculomatous changes infrequently in TSC, as previously documented in a facial papule¹³ and some fibrous cephalic plaques.¹⁴ Overall, these features suggest that mesenchymal-epithelial interactions are important in the formation of MiF, as has been shown for angiofibromas.^15,16

Limitations of our study include the composition of our cohort, which consisted mainly of adult women diagnosed with lymphangioleiomyomatosis. As such, our findings may be less generalizable to men or children with TSC. MiF were not observed in those with TSC1 variants, but only 6 individuals in this cohort had known variants in TSC1. These results are consistent with the dominance of TSC2 variants in those with lymphangioleiomyomatosis,¹⁷ and additional patients are required to establish any genotype-phenotype correlation for MiF. Finally, few tissue samples were available for histological analysis. Further clinical and histological analyses are warranted to more thoroughly investigate the pathogenesis of MiF observed in TSC.

MiF represent an additional manifestation of TSC with a distinct clinical phenotype. MiF occur in a similar anatomic location as shagreen patches but may be distinguished as numerous tiny papules that histologically show expansion of the papillary and periadnexal dermis and proliferation in the adjacent epithelium with thickening and epithelial strands. Individuals presenting with these lesions should be examined for other findings of TSC, or if known to have TSC they can be reassured that these lesions are benign.