Basaloid follicular hamartomas in pediatric Basal Cell Nevus Syndrome: A diagnostic challenge

Abstract Basal Cell Nevus Syndrome (BCNS) is an autosomal dominant inherited disease caused by PTCH1 (9q22.3‐q31) germline mutations. Skin manifestations are mainly characterized by hyperkeratosis of the palms and soles, palmoplantar pits and a strong predisposition to develop multiple basal cell carcinomas (BCCs). Recently, it has been hypothesized that basaloid follicular hamartomas (BFH) could be included in BCNS skin features. We present three pediatric cases of GS with BCCs and BFHs. Clinical, dermoscopic and immunohistochemical tools are reported.

Blood samples were drawn from patients after the provision of informed consent.

| Case 1
A 7-year-old girl, born to non-consanguineous parents, was referred to our department for the evaluation of numerous soft brownish papules on her face, trunk and back resembling skin tags. On clinical evaluation we also observed translucent pearly papules, mainly localized on the limbs, and on the dorsum of the feet and toes. Her parents reported that the lesions had appeared after birth. One of the skin tag-like lesions and one of the translucent papules were surgically removed, with a histological diagnosis of infundibulo-cystic BCC and BFH, respectively.
On careful examination, peculiar facial anomalies such as macrocephaly, broad nasal ridges, heavy and fused eyebrows, mild hypertelorism with down-slanting eyes and micrognathia were noted. Also, mandibular odontogenic keratocysts had been surgically removed at the age of 5 years. Genetic analysis of the PTCH1 gene showed c.878_904delTTA de novo mutation in a heterozygote state, confirming our suspicion of sporadic BCNS. Family history was negative for BCNS.

| Case 2
A 6-year-old Caucasian girl, born to non-consanguineous parents, was referred to our center with a suspicion of BCNS. She had undergone surgical removal of a medulloblastoma followed by chemotherapy and stem cell transplant at the age of one year and presented a history of BCNS on her father's side. On physical examination numerous erythematous skin tag-like lesions were observed on her neck and two were removed, with a histological diagnosis of infundibulocystic BCCs. Pearly translucent papules ranging from 1 to 2 mm in diameter on the trunk and the dorsum of foot and toes were also present. On anamnesis, the onset was at the age of six months, with a progressive growth in diameter over the years. Four of these lesions were removed, with a diagnosis of BFHs. Analysis of the PTCH1 gene confirmed the c.886delT mutation in a heterozygote state of PTCH1 gene, also present in her father.

| Clinical and dermoscopic results
In all the presented cases BCCs clinically appeared as brownish or erythematous papules resembling skin tags. BFHs showed pearly translucent skin-colored or hyperpigmented papules ranging from 1 to 3 mm in diameter (Figure 1a). These lesions were mainly localized on the acral areas, but also on the trunk and limbs. On dermoscopy, the BFHs presented blue-gray ovoid globules and nests similar to the features of BCC. However, the absence of vascular structures on the background suggested differential diagnosis (Figure 1b-c).

| Histological and immunohistochemical results
The histopathological examination of the eight surgically removed BFHs showed two-three layered epithelial cords adopting the so-   In our series, the early onset of several BFHs is reported in BCNS.
Clinically, small papules involved the dorsum, the lateral side of the hands and feet, the trunk, the face and the neck. A combination of clinical, dermatoscopic, histopathological and immunohistological data were analysed to perform the correct diagnosis.
Dermoscopy could improve the evaluation of differential diagnosis between BCC and BFH, especially in pediatric cases when BCNS is suspected. We evaluated the diagnostic criteria for BCC proposed by Menzies et al. 9 and found that achrocordon-like BCCs showed small blue-gray ovoid nests and fine vessels contouring the peduncle, in the absence of larger diameter vessels surmounting the lesions as described by Rodriguez et al. 5 In our experience, dermoscopy of the BFHs revealed only the presence blue-gray globules, in the absence of associated vascular structures pathognomonically described also in small diameter BCCs. 10 Regarding laboratory studies, recent immunohistochemical studies have suggested the use of single antibodies such as ki-67, Ber-EP4, CD34,CK 20, Bcl2 and AR to differentiate BCC from BFH.
Hence, the results are not standardized. [11][12][13][14][15][16] We believe that the use of an immunohistochemical panel including Ber-EP4, CD34 and Bcl2 and AR, could be useful in the differential diagnosis of adnexal neoplasms, BCC and mimickers, especially in small biopsies where the evaluation of all histological criteria could be limited. 17 In particular, our study proved that the two antibodies with notable differences between BFH and BCC were Bcl2 and CD34. Bcl2 was diffusely positive in all BCCs with no differences between the central and peripheral zone; while CD34 evaluated in the stromal component stained all the BFHs and was completely negative in the BCCs. In conclusion: (i) This study supports the potential link between BFH and BCNS; (ii) dermoscopic features could be useful in the differential diagnostic of BFH /BCC (iii) an immunohistochemical panel comprising CD34 and Bcl2 differentiated BFH from BCC.
In our experience, in line with the literature data, BFHs in BCNS may appear congenitally or early in life. Given their observation only in pediatric BCNS patients but not in adults, a possible involution over the years could be hypothesized and the need for aggressive treatment in pediatric patients is therefore questionable. A validation of these results on larger case series should be encouraged, as a wait-and-see approach might be suggested in these cases.