Results showed that the median age at the time of surgical excision was different among tumors deriving from different sites (P < 1 × 10–3). In particular, the age at the time of surgical excision of BCCs localized within the Tessier cleft number 3 was the lowest, and it was significantly lower than that characterizing other cleft regions (n = 144, 26%, median age = 68.5 years, IQR = 55–77 vs n = 412, 74%, median age = 74.5 years, IQR = 67–80, P < 1 × 10–5) or the remaining sample (n = 144, 23%, median age = 68.5, IQR = 55–77, vs n = 483, 77%, median age = 74 years, IQR = 67–80, P < 1 × 10–5) (Table 2). No statistically significant difference in terms of sex distribution was observed among different sites (P = 0.53), suggesting that the proportion of cleft sites harboring BCCs was equally distributed between males and females.
Our study demonstrated a statistically significant correspondence between the sites of onset of BCCs of the head and neck and the sites of craniofacial clefts and congenital fistulas and cysts of the neck. In detail, a greater number of tumor records were also demonstrated in the sites of most frequent craniofacial clefts and neck clefts, cysts, and fistulas.
The Tessier classification of craniofacial clefts,5,7,8 subsequently completed by Moore et al6 and David et al,9 ordered the paths of various congenital clefts of the face with progressive numbers from 0 to 14 plus number 30 (Figs. 1, 2). The congenital cleft malformations of the neck are known to sit on well-established sites along the anterior border of each sternocleidomastoid muscle and along one line running from the chin to the clavicular notch in the anterior midline,10–13 the latter corresponding to the Tessier cleft number 30 (Fig. 3). All these clefts may display a variable degree of clinical expression ranging from a proper cleft, to a fistula, a cyst, and/or a fibrotic band.
In postnatal life, the sites of congenital head and neck cleft malformations are likely to match the sites of fusion and/or merging of embryonic processes.
It has long been held that embryologic fusion planes might be related with the sites of onset and spread paths of BCCs thus suggesting an embryologic role for the pathogenesis of such a peculiar malignancy.1–4
It is common knowledge in clinical dermatology that several skin proliferative diseases have a predilection for the pathways of epidermal cell migration and proliferation during the fetal development. These pathways, the so-called Blaschko lines, are believed to trace the migration of embryonic cells.14,15
As well dissertated by Pinkus16 since 1966, BCC might be supposed at the “red hot” end of a spectrum featuring a sort of progressive regression of skin organoid structure with constant combined involvement of epithelium and stroma. Such a close interaction between epithelium and stroma differentiates BCCs from other pure epithelial malignancies where there is transformation of individual epithelial cells into strains of cancer cells featuring a typical stroma-dissociated invasiveness. Even in their most primordial form, BCCs preserve the basic feature of adnexal primordial in the skin like some sort of fibroepithelial products of organized interdependent growth. Such evidence has directed the question for pathogenesis to embryogenesis. It seemed therefore not unreasonable to conceive of such an organoid skin tumor as a monstrous attempt at adnexogenesis in postnatal life through interaction of pathological ectodermal and mesodermal components which form fibroepithelial growths of varying degrees of maturity.
The Hedgehog signaling pathway plays a relevant role in embryogenesis across multiple species including mammals and humans.17–21 Its activity seems to be reduced or absent in adult individuals. Recent clinical translational investigations demonstrated that aberrant reactivation of the pathway is involved in the development of a number of human malignancies including both inherited and sporadic BCCs.19 Such an evidence has been further confirmed by a number of experimental animal studies.20 All these reports would strongly support the time honored hypothesis of an embryologic role for the pathogenesis of BCC. Actually ongoing clinical studies are evaluating the response to Hedgehog pathway inhibitors for inoperable and locally advanced BCCs.19,22 Perturbed Hedgehog signaling is also demonstrated to play a major role in craniofacial development, and mutations in a number of pathway constituents underlie craniofacial disease.23
According to our data, the greatest number of tumor records was observed along the Tessier cleft number 3. The latter is both the most common of the Tessier craniofacial clefts24 and the most intricate and destructive one.5 Such a correspondence would support our hypothesis that a greater link might exist between both disembryogenic and carcinogenic potential in the same anatomical site.
Interestingly, our data also demonstrated a statistically significant correlation between the site accounting for the greatest number of tumor records, the Tessier cleft number 3, and an earlier age of onset. Such a finding might suggest a reduced resistance to carcinogenic effects of the well-known external environmental causes in the sites of fusion and/or merging of embryonic processes.
Further studies should be focused in identifying the presence of dormant embryonic stem cells along these fusion lines using embryonic or stem cell and/or Hedgehog pathway proteins markers.
Undoubtedly, the results of these forthcoming studies might significantly contribute to a thorough understanding of both the pathogenesis and the clinical behavior of such a unique skin tumor.
The results of our study support the hypothesis of an embryologic role for the pathogenesis of BCC, with elective reactivation of the Hedgehog pathway in specific anatomical sites characterized by a high disembryogenic potential.
We thank Alan Serge McGhee, MSc, Glasgow City Council Education Department, for his contribution to the submission of this dissertation. We also thank Floriana Cazzola and Gian Mario Pelizzoli for their much appreciated technical support.
1. Wentzell JM, Robinson JK. Embryologic fusion planes and the spread of cutaneous carcinoma: a review and reassessment. J Dermatol Surg Oncol. 1990;16:1000–1006
2. Granström G, Aldenborg F, Jeppsson PH. Influence of embryonal fusion lines for recurrence of basal cell carcinomas in the head and neck. Otolaryngol Head Neck Surg. 1986;95:76–82
3. Panje WR, Ceilley RI. The influence of embryology of the mid-face on the spread of epithelial malignancies. Laryngoscope. 1979;89:1914–1920
4. Newman JC, Leffell DJ. Correlation of embryonic fusion planes with the anatomical distribution of basal cell carcinoma. Dermatol Surg. 2007;33:957–964; discussion 965
5. Tessier P. Anatomical classification facial, cranio-facial and latero-facial clefts. J Maxillofac Surg. 1976;4:69–92
6. Moore MH, David DJ, Cooter RD. Hairline indicators of craniofacial clefts. Plast Reconstr Surg. 1988;82:589–593
7. Tessier P. Colobomas: vertical and oblique complete facial clefts. Simultaneous operation of the eyelid, inner canthus, cheek nose and lip Orbitomaxillary bone graft. Panminerva Med. 1969;11:95–101
8. Tessier P. Fente orbito-faciales verticales et obliques (colobomas) completes et frustes. Ann Chir Plast. 1969;14:301–311
9. David DJ, Moore MH, Cooter RD. Tessier clefts revisited with a third dimension. Cleft Palate J. 1989;26:163–184
10. Jellouli Elloumi A, Souissi R, Trabelsi A, et al. [Congenital cysts and fistulas of the face and neck: often unrecognized dysembryoplasias]. Tunis Med. 1999;77:117–126
11. Stricker M, Flot F, Malka G, et al. [Cysts and fistulas of embryonal origin of the face]. Rev Stomatol Chir Maxillofac. 1976;77:109–112
12. Beauvillain de Montreuil C, Hamon S, Litoux P. Congenital cysts and fistulae of the face and the neck. Ann Dermatol Venereol. 1988;115:855–858
13. Lachard J, Gola R. Congenital cysts and fistulas of the neck. Rev Prat. 1983;33:1557–1563
14. Blaschko A Die Nervenverteilung in der Haut in ihrer Beziehung zu den Erkrankungen der Haut. Beilage zu den Verhandlungen der Deutschen Dermatologischen Gesellschaft. VII Congress zu Breslau. 1901 Mai. Wien Leipzig Braumüller
15. Jackson R. The lines of Blaschko: a review and reconsideration: observations of the cause of certain unusual linear conditions of the skin. Br J Dermatol. 1976;95:349–360
16. Pinkus H. Adnexal tumors, benign, not-so-benign and malignant. Adv Biol Skin. 1966;7:255–276
17. Callahan CA, Oro AE. Monstrous attempts at adnexogenesis: regulating hair follicle progenitors through Sonic hedgehog signaling. Curr Opin Genet Dev. 2001;11:541–546
18. Hutchin ME, Kariapper MS, Grachtchouk M, et al. Sustained Hedgehog signaling is required for basal cell carcinoma proliferation and survival: conditional skin tumorigenesis recapitulates the hair growth cycle. Genes Dev. 2005;19:214–223
19. Caro I, Low JA. The role of the hedgehog signaling pathway in the development of basal cell carcinoma and opportunities for treatment. Clin Cancer Res. 2010;16:3335–3339
20. Epstein EH. Basal cell carcinomas: attack of the hedgehog. Nat Rev Cancer. 2008;8:743–754
21. Grachtchouk M, Pero J, Yang SH, et al. Basal cell carcinomas in mice arise from hair follicle stem cells and multiple epithelial progenitor populations. J Clin Invest. 2011;121:1768–1781
22. Sandhiya S, Melvin G, Kumar SS, et al. The dawn of hedgehog inhibitors: Vismodegib. J Pharmacol Pharmacother. 2013;4:4–7
23. Metzis V, Courtney AD, Kerr MC, et al. Patched1 is required in neural crest cells for the prevention of orofacial clefts. Hum Mol Genet. 2013;22:5026–5035
© 2014 American Society of Plastic Surgeons
24. Bradley JP, Hurwitz DJ, Carstens MHMathes SJ, Hentz VR. Embriology, classifications, and descriptions of craniofacial clefts. In: Plastic Surgery. 2006Vol. 4, 2nd ed Philadelphia, PA Saunders Elsevier:25