Limits...
Cutaneous epithelial tumors induced by vemurafenib involve the MAPK and Pi3KCA pathways but not HPV nor HPyV viral infection.

Frouin E, Guillot B, Larrieux M, Tempier A, Boulle N, Foulongne V, Girard C, Costes V, Solassol J - PLoS ONE (2014)

Bottom Line: No mutations were found within BRAF and NRAS.Finally, no correlation was found between the mutated gene or type of mutation and the type of cutaneous tumor or clinical response to vemurafenib.In conclusion, neither HPV nor HPyV seem to be involved in the development of squamoproliferative lesions induced by verumafenib.

View Article: PubMed Central - PubMed

Affiliation: Department of Biopathology, CHU Montpellier, Montpellier, France; University of Montpellier I, Montpellier, France.

ABSTRACT
The inhibitors of mutant BRAF that are used to treat metastatic melanoma induce squamoproliferative lesions. We conducted a prospective histopathological and molecular study on 27 skin lesions from 12 patients treated with vemurafenib. Mutation hot spots in HRAS, NRAS, KRAS, BRAF, and Pi3KCA were screened. HPV and HPyV infection status were also determined. The lesions consisted of 19 verrucal papillomas, 1 keratoacanthoma and 7 squamous cell carcinomas. No mutations were found within BRAF and NRAS. KRAS, HRAS, and Pi3KCA oncogenic mutations were found in 10 (83.3%), 7 (58.3%), and 4 (33.3%) patients respectively; however, these mutations were not consistent within all tumors of a given patient. Pi3KCA mutation was always associated with a mutation in HRAS. Finally, no correlation was found between the mutated gene or type of mutation and the type of cutaneous tumor or clinical response to vemurafenib. P16 protein level was not indicative of HPV infection. HPV was detected in only two lesions. Two cases had MCPyV, and one had HPyV7. In conclusion, neither HPV nor HPyV seem to be involved in the development of squamoproliferative lesions induced by verumafenib. By contrast, HRAS and KRAS play a predominant role in the physiopathology of these tumors.

Show MeSH

Related in: MedlinePlus

Histopathology and immunohistochemical findings of VP and SCC induced by vemurafenib.(A) Typical VP with verrucous and papillomatous architecture covered by hyperkertosis (HE, x20). (B) Note the preeminent granulomatous layer with clear keratinocytes suggestive of an HPV infection (HE, x200). (C) VP with acantholysis (HE, x100). (D) VP with invasion of the superficial dermis (HE, x20). (E) Strong P16 positivity in a SCC. This tumor did not have any HPV (x100). (F) Heterogenous P16 expression in a VP (x100).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4215900&req=5

pone-0110478-g001: Histopathology and immunohistochemical findings of VP and SCC induced by vemurafenib.(A) Typical VP with verrucous and papillomatous architecture covered by hyperkertosis (HE, x20). (B) Note the preeminent granulomatous layer with clear keratinocytes suggestive of an HPV infection (HE, x200). (C) VP with acantholysis (HE, x100). (D) VP with invasion of the superficial dermis (HE, x20). (E) Strong P16 positivity in a SCC. This tumor did not have any HPV (x100). (F) Heterogenous P16 expression in a VP (x100).

Mentions: Twenty-seven lesions were analyzed. VPs were verrucous (18 lesions) and papillomatous (16 lesions) (fig. 1.A). Hypergranulosis and clear keratinocytes within superficial portions were observed, respectively, in 19 and 5 VPs and were suggestive of a possible viral origin (fig. 1B). Two VPs displayed acantholysis (fig. 1C). Two VP were slightly invasive (fig.1D). KA was typical. SCCs were always well differentiated. Hypergranulosis and clear keratinocytes were observed in 4 and 3 lesions, respectively. No vascular or neural invasion was observed. None of the lesions recurred and none of the patients developed metastasis.


Cutaneous epithelial tumors induced by vemurafenib involve the MAPK and Pi3KCA pathways but not HPV nor HPyV viral infection.

Frouin E, Guillot B, Larrieux M, Tempier A, Boulle N, Foulongne V, Girard C, Costes V, Solassol J - PLoS ONE (2014)

Histopathology and immunohistochemical findings of VP and SCC induced by vemurafenib.(A) Typical VP with verrucous and papillomatous architecture covered by hyperkertosis (HE, x20). (B) Note the preeminent granulomatous layer with clear keratinocytes suggestive of an HPV infection (HE, x200). (C) VP with acantholysis (HE, x100). (D) VP with invasion of the superficial dermis (HE, x20). (E) Strong P16 positivity in a SCC. This tumor did not have any HPV (x100). (F) Heterogenous P16 expression in a VP (x100).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4215900&req=5

pone-0110478-g001: Histopathology and immunohistochemical findings of VP and SCC induced by vemurafenib.(A) Typical VP with verrucous and papillomatous architecture covered by hyperkertosis (HE, x20). (B) Note the preeminent granulomatous layer with clear keratinocytes suggestive of an HPV infection (HE, x200). (C) VP with acantholysis (HE, x100). (D) VP with invasion of the superficial dermis (HE, x20). (E) Strong P16 positivity in a SCC. This tumor did not have any HPV (x100). (F) Heterogenous P16 expression in a VP (x100).
Mentions: Twenty-seven lesions were analyzed. VPs were verrucous (18 lesions) and papillomatous (16 lesions) (fig. 1.A). Hypergranulosis and clear keratinocytes within superficial portions were observed, respectively, in 19 and 5 VPs and were suggestive of a possible viral origin (fig. 1B). Two VPs displayed acantholysis (fig. 1C). Two VP were slightly invasive (fig.1D). KA was typical. SCCs were always well differentiated. Hypergranulosis and clear keratinocytes were observed in 4 and 3 lesions, respectively. No vascular or neural invasion was observed. None of the lesions recurred and none of the patients developed metastasis.

Bottom Line: No mutations were found within BRAF and NRAS.Finally, no correlation was found between the mutated gene or type of mutation and the type of cutaneous tumor or clinical response to vemurafenib.In conclusion, neither HPV nor HPyV seem to be involved in the development of squamoproliferative lesions induced by verumafenib.

View Article: PubMed Central - PubMed

Affiliation: Department of Biopathology, CHU Montpellier, Montpellier, France; University of Montpellier I, Montpellier, France.

ABSTRACT
The inhibitors of mutant BRAF that are used to treat metastatic melanoma induce squamoproliferative lesions. We conducted a prospective histopathological and molecular study on 27 skin lesions from 12 patients treated with vemurafenib. Mutation hot spots in HRAS, NRAS, KRAS, BRAF, and Pi3KCA were screened. HPV and HPyV infection status were also determined. The lesions consisted of 19 verrucal papillomas, 1 keratoacanthoma and 7 squamous cell carcinomas. No mutations were found within BRAF and NRAS. KRAS, HRAS, and Pi3KCA oncogenic mutations were found in 10 (83.3%), 7 (58.3%), and 4 (33.3%) patients respectively; however, these mutations were not consistent within all tumors of a given patient. Pi3KCA mutation was always associated with a mutation in HRAS. Finally, no correlation was found between the mutated gene or type of mutation and the type of cutaneous tumor or clinical response to vemurafenib. P16 protein level was not indicative of HPV infection. HPV was detected in only two lesions. Two cases had MCPyV, and one had HPyV7. In conclusion, neither HPV nor HPyV seem to be involved in the development of squamoproliferative lesions induced by verumafenib. By contrast, HRAS and KRAS play a predominant role in the physiopathology of these tumors.

Show MeSH
Related in: MedlinePlus