Case Report Received: April 28, 2014 Accepted after revision: September 3, 2014 Published online: January 24, 2015
Dermatology 2015;230:101–104 DOI: 10.1159/000368350
Fast-Growing Cutaneous Squamous Cell Carcinoma in a Patient Treated with Vismodegib Nicolas Poulalhon a Stéphane Dalle a, c Brigitte Balme b Luc Thomas a, c
Departments of a Dermatology and b Cutaneous Pathology, Centre Hospitalier Lyon Sud, Pierre Bénite, and c Lyon 1 Claude Bernard University, Villeurbanne, France
Abstract Background: Vismodegib therapy achieves a breakthrough in patients with locally advanced basal cell carcinoma (BCC). Yet, longterm safety of hedgehog pathway inhibitors remains to be established, while drug resistance is becoming a new challenging issue. Case Report: We report the case of a 90-yearold male initially referred for a locally advanced BCC of the nose. He had been previously treated by topical 5-fluorouracil for an adjacent microinvasive squamous cell carcinoma (SCC), with complete clinical response. Afterwards, vismodegib was initiated to treat his BCC. At week 16, both tumor and tumor ulceration obviously progressed. Palliative rhinectomy was performed. Histological examination found a deeply invasive SCC. Conclusion: Although our case must be interpreted with caution, a role of vismodegib as a promoter of cutaneous SCC should be considered, consistently with recently published evidence. Physicians should perform new biopsies whenever in doubt about new and/or progressive skin lesions in patients receiving hedgehog pathway inhibitors. © 2015 S. Karger AG, Basel
Introduction
Vismodegib is a first-in-class small molecule inhibitor of the hedgehog signaling pathway, currently approved by both the US Food and Drug Administration and the European Medicines Agency for the treatment of unresectable locally advanced or metastatic basal cell carcinoma (BCC). In a phase I clinical trial, response rates reached 49 and 30%, respectively, while median duration of response was limited to 7.6 months [1]. Therefore, understanding the mechanisms of primary and secondary
a
b
c
Fig. 1. Clinical pictures at baseline (a), 4 weeks after the end of the conservative treatment
of the microinvasive SCC of the right cheek (b), and after 16 weeks of oral treatment with vismodegib (c).
© 2015 S. Karger AG, Basel 1018–8665/15/2302–0101$39.50/0 E-Mail [email protected] www.karger.com/drm
resistance to vismodegib remains a crucial issue. Recently, Iarrobino et al. [2] reported a patient with metastatic BCC treated by the Smoothen (Smo) inhibitor vismodegib, who developed secondary tumoral relapse concomitant with the emergence of a squamous cell carcinoma (SCC) phenotype [3]. Herein, we present a challenging case of cutaneous SCC occurring under treatment with vismodegib and discuss further the putative role of Smo inhibitors in SCC carcinogenesis, in light of recent findings on Patched 1 (PTCH1) signaling pathways and recent clinical evidence.
Luc Thomas Department of Dermatology Centre Hospitalier Lyon Sud FR–69495 Pierre Bénite Cedex (France) E-Mail luc.thomas @ chu-lyon.fr
Downloaded by: UCSF Library & CKM 169.230.243.252 - 3/24/2015 4:37:53 PM
Key Words Basal cell carcinoma · Squamous cell carcinoma · Vismodegib
a
b
c
Case Report
A 90-year-old male patient, without prior medical history of cancer, was referred for two clinically distinct, contiguous face lesions (fig. 1a). The first one presented as an ulcerated pearly 45-mm tumor occupying almost all of the tip and the right ala of the nose and destroying partially the right nostril. The
102
second lesion consisted in an erythematosquamous, well-limited plaque 50 mm in its largest diameter, spanning from the medial part of the right cheek to the medial angle of the right eye, the right part of the dorsum, and the ipsilateral alar crease (with coalescence with the first lesion at this very point). Prior to any therapy, 4-mm punch biopsy specimens were obtained on the tip of
Dermatology 2015;230:101–104 DOI: 10.1159/000368350
the nose and close to the medial angle of the right eye, representative of lesions 1 and 2, respectively. Consistent with clinical findings, lesion 1 corresponded to an infiltrative BCC involving two thirds of the dermis, while lesion 2 was diagnosed histologically as a clear-cell SCC with an infiltrative component limited to the upper dermis (fig. 2a, b).
Poulalhon /Dalle /Balme /Thomas
Downloaded by: UCSF Library & CKM 169.230.243.252 - 3/24/2015 4:37:53 PM
Fig. 2. Comparative histological and immunostaining patterns. a Pictures related to the pretherapy biopsy specimen obtained on the tip of the nose (lesion 1). b Pictures related to the pretherapy biopsy specimen taken close to the medial angle of the right eye (lesion 2). c Pictures of one representative area of the rhinectomy specimen. For readability purposes, pictures of three other areas of the latter are not represented here (see Results in the text). Pictures on the first line are hematoxylin and eosin stains. Next lines show p63, CK5/6, CK7, EMA, and BerEP4/HEA immunostaining, successively. Original magnification ×10 (all slides).
Fast-Growing SCC in a Patient Treated with Vismodegib
thelial membrane antigen (EMA) antibodies were performed in the same run on the rhinectomy specimen (4 samples from distinct tumoral areas) as well as both pretherapy biopsy specimens (fig. 2). As expected, all 3 tumor samples were positive for CK5/6 and p63. CK7 was negative in all specimens. EMA was negative in lesion 1, focally positive in lesion 2, whereas it was either positive (2 areas) or focally positive (2 areas) in the rhinectomy specimen. Finally, HEA/BerEP4 was positive in lesion 1 and negative in lesion 2. In the rhinectomy specimen, HEA/BerEP4 was expressed focally at the periphery of some tumoral aggregates observed in 1 of 4 samples, and strictly negative in 3 other samples. Taken together, these results were consistent with histopathological diagnoses of BCC in lesion 1 and SCC in lesion 2, while they were much more suggestive of SCC (with minor trichoblastic component) than of BCC in the posttherapy rhinectomy specimen. Discussion
Such dramatic and unexpected clinical and histological alterations occurring within the first 4 months of vismodegib treatment led us to address the potential role of this drug, as did Iarrobino et al. [2] in their case. In our patient, however, proper interpretation of secondary evolution into invasive SCC may be hampered by the initial presence on the right cheek (immediately adjacent to nasal BCC) of a microinvasive SCC. Moreover, the treatment applied to the latter (topical 5-FU) was not standard of care, and clinical response was not ascertained by histology: as a result, the risk of SCC local recurrence was not negligible. Therefore, it cannot be ruled out that the patient’s clinical nasal progression may be explained by clinical and histological relapse of the pretreated right-cheek SCC, with subsequent contiguous extent to reach and engulf the nasal pyramid. However, based on comparative clinical photographs, alterations observed at week 16 did not seem to spread from the right-cheek cicatricial area towards the nose, but rather to involve the nasal pyramid as a whole. The alternative hypothesis would be the histological transition from BCC to SCC features, independent of the right-cheek tumor treated beforehand. Whatever may be the initial location of this SCC tumor, the potential role of vismodegib deserves to be addressed in our
patient, based on chronological considerations. Indeed, the striking growth of the nasal lesion occurred solely after this therapy was started. On the contrary, neither clinically measurable alteration of nasal BCC, nor evidence of local recurrence of the right-cheek SCC had been noted during the 10-week time interval between the last application of 5-FU and the onset of vismodegib. Nonetheless, in the event of SCC spreading from the 5-FU-pretreated area, such a delayed clinical flare-up could alternatively be regarded as an aggressive relapsing SCC, without vismodegib being necessarily a triggering factor. Moreover, there is some recent evidence supporting an extrinsic causality of vismodegib. First, several cases of cutaneous SCC have been reported in BCC patients treated with vismodegib, as mentioned in the European Medicines Agency’s product information. However, until recently, it had not been determined whether these adverse events were related to vismodegib, all the more so as patients with BCC have an increased risk of developing cutaneous SCC [3]. Nevertheless, Orouji et al. [4] recently described the rapid occurrence of several moderately to highly differentiated SCCs in a patient treated with vismodegib. Secondly, the emergence of an SCC component from the BCC tumor bed during vismodegib treatment has already been reported in several vismodegib-treated patients. Iarrobino et al. [2] reported the delayed emergence of SCC phenotype in a BCC metastatic lymph node in a patient treated by vismodegib. Based on this case, they hypothesized that secondary regrowth of BCC under vismodegib could be explained by transdifferentiation from BCC to SCC. According to these authors, putative underlying mechanisms included the recruitment of preexisting SCC cells, and/or alterations of BCC signaling, and/or the progression of the original population to a more poorly differentiated phenotype [2]. Consistent with the latter observation, Zhu et al. [5] recently presented 2 new cases of clinically significant SCC arising within the tumor bed of a locally advanced BCC during vismodegib treatment. Both patients, as well as the patient previously described by Iarrobino et al. [2], were initially responsive to vismodegib and biopsy was guided by secondary relapse, contrary to our case. At the molecular level, several research works may provide a rationale for the occurrence of SCC in the setting of alterations
Dermatology 2015;230:101–104 DOI: 10.1159/000368350
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In this setting, mutilating surgery was considered unreasonable. Therefore, after multidisciplinary consultation, a two-step medical strategy was preferred. First, a conservative topical treatment with 5-fluorouracil (5-FU) was applied to the erythematosquamous plaque with a 5-mm lateral margin, once daily for 1 month, then 3 times a week for 1 month. Complete clinical response was noted at 4 weeks after the end of therapy (fig. 1b). Afterwards, vismodegib 150 mg/day was started under the supervision of a nurse to treat the locally advanced BCC of the nose. Main adverse events related to vismodegib were grade 2 asthenia and myalgia. Photographs were taken every 8 weeks and tumoral evolution was assessed using RECIST v1.1 clinical criteria. At week 8, the disease was considered stable. However, at week 16, the target lesion undoubtedly progressed since its largest diameter increased to 60 mm (+33% from baseline); therefore vismodegib was discontinued. Concomitantly, the global clinical appearance of the lesion strikingly evolved into an exophytic, granulating and ulcerative tumor with raised margin advancing toward the right cheek and the nasal bridge (fig. 1c). Therefore, a 4-mm punch biopsy specimen was taken from lesional skin of the nasal bridge. Histological analysis showed infiltration of (at least) the entire thickness of the dermis by a carcinoma exhibiting different features from those observed on the pretherapy lesion 1 biopsy specimen, although no accurate diagnosis could be made yet on the basis of the examination of a too small specimen. Given disfiguring evolution, as well as functional impairment, the patient was proposed palliative rhinectomy in order to accommodate an epithesis. Histologically, the tumor originated from the epidermis and infiltrated underlying tissues including the cartilage, with positive deep resection margin (fig. 2c). It was organized into eosinophilic spans and masses containing multiple images of keratinization. Neither neuro- nor angiotropism was detected. Frequent mitoses were noted (9 per field at magnification ×40, some of which being atypical) as well as multiple cell atypia. Although features of trichoblastic or intermediate carcinoma were visible in a few areas, final histopathological diagnosis was SCC combining keratinizing, moderately differentiated with poorly differentiated components. Immunohistochemistry with antip63, cytokeratin (CK) 5/6, CK7, human epithelial antigen (HEA)/BerEP4, and epi-
of BCC signaling [6–8]. The carcinogenesis of familial as well as most sporadic BCCs is known to result from Sonic Hedgehog (SHH) pathway constitutive hyperactivation, most often by inactivating Patched 1 (PTCH1) mutations, with subsequent Smo release, then Gli-dependent up-regulation of SHH target genes. Aside from its classic BCC tumor suppressor activity, several authors have pointed out that PTCH1 may have other functions, independently of the SHH pathway, such as the regulation of apoptosis [6]. In 2007, Wakabayashi et al. [7] showed that a polymorphic variant of the Patched gene found in FVB mice, a strand with an SCC-prone genetic background, was sufficient to promote Hrasinduced SCC. In the same way, Kang et al. [8] recently demonstrated that overexpression of the Ptch1FVB allele driven by the ker-
atin 14 promoter synergizes with chemically induced Hras mutations to promote SCC development in adult mice, while they exhibited developmental signs consistent with inhibition of the SHH signaling pathway. Therefore, it was proposed that Ptch1 plays a critical role in both BCC and SCC development, inhibiting BCCs and promoting SCCs [6, 7]. We assume that clinical data are not unequivocal in our patient, and scientific results on animal models must be taken with caution. However, in our view, the clinical experience of our patient, together with recently published cases, raises the issue of a potential deleterious effect of SHH pathway inhibitors. Therefore, carcinogenicity studies with vismodegib are needed. As has been postulated by Wakabayashi et al. [7] at an early stage of the development of SHH
inhibitors, physicians should be warned against their potential unexpected effects in promoting cell fate decisions leading to tumor cell types distinct from BCCs, including SCCs.
4 Orouji A, Goerdt S, Utikal J, Leverkus M: Multiple highly and moderately differentiated squamous cell carcinomas of the skin during vismodegib treatment of inoperable basal cell carcinoma. Br J Dermatol 2014;171:431– 433. 5 Zhou GA, Sundram U, Chang AS: Two different scenarios of squamous cell carcinoma within advanced basal cell carcinomas: cases illustrating the importance of serial biopsy during vismodegib usage. JAMA Dermatol 2014;150:970–973.
6 Atwood SX, Whitson RJ, Oro AE: ‘Patch’ing up our tumor signaling knowledge. J Invest Dermatol 2013;133:1131–1133. 7 Wakabayashi Y, Mao JH, Brown K, et al: Promotion of Hras-induced squamous carcinomas by a polymorphic variant of the Patched gene in FVB mice. Nature 2007; 445: 761– 765. 8 Kang HC, Wakabayashi Y, Jen KY, et al: Ptch1 overexpression drives skin carcinogenesis and developmental defects in K14Ptch(FVB) mice. J Invest Dermatol 2013;133:1311–1320.
Acknowledgment
This work was supported in part by grants to L. Thomas from Lyon 1 University, the Hospices Civils de Lyon and the Ligue Contre le Cancer du Rhône. Disclosure Statement
The authors have no financial disclosures to make.
1 Sekulic A, Migden MR, Oro AE, et al: Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med 2012;366:2171–2179. 2 Iarrobino A, Messina JL, Kudchadkar R, Sondak VK: Emergence of a squamous cell carcinoma phenotype following treatment of metastatic basal cell carcinoma with vismodegib. J Am Acad Dermatol 2013;69:e33–e34. 3 European Medicines Agency: Erivedge (vismodegib). Product information. http:// www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002602/WC500146817.pdf (accessed October 24, 2013).
104
Dermatology 2015;230:101–104 DOI: 10.1159/000368350
Poulalhon /Dalle /Balme /Thomas
Downloaded by: UCSF Library & CKM 169.230.243.252 - 3/24/2015 4:37:53 PM
References
Dermatology 2015;230:101–104 DOI: 10.1159/000368350
Fast-Growing Cutaneous Squamous Cell Carcinoma in a Patient Treated with Vismodegib Nicolas Poulalhon a Stéphane Dalle a, c Brigitte Balme b Luc Thomas a, c
Departments of a Dermatology and b Cutaneous Pathology, Centre Hospitalier Lyon Sud, Pierre Bénite, and c Lyon 1 Claude Bernard University, Villeurbanne, France
Abstract Background: Vismodegib therapy achieves a breakthrough in patients with locally advanced basal cell carcinoma (BCC). Yet, longterm safety of hedgehog pathway inhibitors remains to be established, while drug resistance is becoming a new challenging issue. Case Report: We report the case of a 90-yearold male initially referred for a locally advanced BCC of the nose. He had been previously treated by topical 5-fluorouracil for an adjacent microinvasive squamous cell carcinoma (SCC), with complete clinical response. Afterwards, vismodegib was initiated to treat his BCC. At week 16, both tumor and tumor ulceration obviously progressed. Palliative rhinectomy was performed. Histological examination found a deeply invasive SCC. Conclusion: Although our case must be interpreted with caution, a role of vismodegib as a promoter of cutaneous SCC should be considered, consistently with recently published evidence. Physicians should perform new biopsies whenever in doubt about new and/or progressive skin lesions in patients receiving hedgehog pathway inhibitors. © 2015 S. Karger AG, Basel
Introduction
Vismodegib is a first-in-class small molecule inhibitor of the hedgehog signaling pathway, currently approved by both the US Food and Drug Administration and the European Medicines Agency for the treatment of unresectable locally advanced or metastatic basal cell carcinoma (BCC). In a phase I clinical trial, response rates reached 49 and 30%, respectively, while median duration of response was limited to 7.6 months [1]. Therefore, understanding the mechanisms of primary and secondary
a
b
c
Fig. 1. Clinical pictures at baseline (a), 4 weeks after the end of the conservative treatment
of the microinvasive SCC of the right cheek (b), and after 16 weeks of oral treatment with vismodegib (c).
© 2015 S. Karger AG, Basel 1018–8665/15/2302–0101$39.50/0 E-Mail [email protected] www.karger.com/drm
resistance to vismodegib remains a crucial issue. Recently, Iarrobino et al. [2] reported a patient with metastatic BCC treated by the Smoothen (Smo) inhibitor vismodegib, who developed secondary tumoral relapse concomitant with the emergence of a squamous cell carcinoma (SCC) phenotype [3]. Herein, we present a challenging case of cutaneous SCC occurring under treatment with vismodegib and discuss further the putative role of Smo inhibitors in SCC carcinogenesis, in light of recent findings on Patched 1 (PTCH1) signaling pathways and recent clinical evidence.
Luc Thomas Department of Dermatology Centre Hospitalier Lyon Sud FR–69495 Pierre Bénite Cedex (France) E-Mail luc.thomas @ chu-lyon.fr
Downloaded by: UCSF Library & CKM 169.230.243.252 - 3/24/2015 4:37:53 PM
Key Words Basal cell carcinoma · Squamous cell carcinoma · Vismodegib
a
b
c
Case Report
A 90-year-old male patient, without prior medical history of cancer, was referred for two clinically distinct, contiguous face lesions (fig. 1a). The first one presented as an ulcerated pearly 45-mm tumor occupying almost all of the tip and the right ala of the nose and destroying partially the right nostril. The
102
second lesion consisted in an erythematosquamous, well-limited plaque 50 mm in its largest diameter, spanning from the medial part of the right cheek to the medial angle of the right eye, the right part of the dorsum, and the ipsilateral alar crease (with coalescence with the first lesion at this very point). Prior to any therapy, 4-mm punch biopsy specimens were obtained on the tip of
Dermatology 2015;230:101–104 DOI: 10.1159/000368350
the nose and close to the medial angle of the right eye, representative of lesions 1 and 2, respectively. Consistent with clinical findings, lesion 1 corresponded to an infiltrative BCC involving two thirds of the dermis, while lesion 2 was diagnosed histologically as a clear-cell SCC with an infiltrative component limited to the upper dermis (fig. 2a, b).
Poulalhon /Dalle /Balme /Thomas
Downloaded by: UCSF Library & CKM 169.230.243.252 - 3/24/2015 4:37:53 PM
Fig. 2. Comparative histological and immunostaining patterns. a Pictures related to the pretherapy biopsy specimen obtained on the tip of the nose (lesion 1). b Pictures related to the pretherapy biopsy specimen taken close to the medial angle of the right eye (lesion 2). c Pictures of one representative area of the rhinectomy specimen. For readability purposes, pictures of three other areas of the latter are not represented here (see Results in the text). Pictures on the first line are hematoxylin and eosin stains. Next lines show p63, CK5/6, CK7, EMA, and BerEP4/HEA immunostaining, successively. Original magnification ×10 (all slides).
Fast-Growing SCC in a Patient Treated with Vismodegib
thelial membrane antigen (EMA) antibodies were performed in the same run on the rhinectomy specimen (4 samples from distinct tumoral areas) as well as both pretherapy biopsy specimens (fig. 2). As expected, all 3 tumor samples were positive for CK5/6 and p63. CK7 was negative in all specimens. EMA was negative in lesion 1, focally positive in lesion 2, whereas it was either positive (2 areas) or focally positive (2 areas) in the rhinectomy specimen. Finally, HEA/BerEP4 was positive in lesion 1 and negative in lesion 2. In the rhinectomy specimen, HEA/BerEP4 was expressed focally at the periphery of some tumoral aggregates observed in 1 of 4 samples, and strictly negative in 3 other samples. Taken together, these results were consistent with histopathological diagnoses of BCC in lesion 1 and SCC in lesion 2, while they were much more suggestive of SCC (with minor trichoblastic component) than of BCC in the posttherapy rhinectomy specimen. Discussion
Such dramatic and unexpected clinical and histological alterations occurring within the first 4 months of vismodegib treatment led us to address the potential role of this drug, as did Iarrobino et al. [2] in their case. In our patient, however, proper interpretation of secondary evolution into invasive SCC may be hampered by the initial presence on the right cheek (immediately adjacent to nasal BCC) of a microinvasive SCC. Moreover, the treatment applied to the latter (topical 5-FU) was not standard of care, and clinical response was not ascertained by histology: as a result, the risk of SCC local recurrence was not negligible. Therefore, it cannot be ruled out that the patient’s clinical nasal progression may be explained by clinical and histological relapse of the pretreated right-cheek SCC, with subsequent contiguous extent to reach and engulf the nasal pyramid. However, based on comparative clinical photographs, alterations observed at week 16 did not seem to spread from the right-cheek cicatricial area towards the nose, but rather to involve the nasal pyramid as a whole. The alternative hypothesis would be the histological transition from BCC to SCC features, independent of the right-cheek tumor treated beforehand. Whatever may be the initial location of this SCC tumor, the potential role of vismodegib deserves to be addressed in our
patient, based on chronological considerations. Indeed, the striking growth of the nasal lesion occurred solely after this therapy was started. On the contrary, neither clinically measurable alteration of nasal BCC, nor evidence of local recurrence of the right-cheek SCC had been noted during the 10-week time interval between the last application of 5-FU and the onset of vismodegib. Nonetheless, in the event of SCC spreading from the 5-FU-pretreated area, such a delayed clinical flare-up could alternatively be regarded as an aggressive relapsing SCC, without vismodegib being necessarily a triggering factor. Moreover, there is some recent evidence supporting an extrinsic causality of vismodegib. First, several cases of cutaneous SCC have been reported in BCC patients treated with vismodegib, as mentioned in the European Medicines Agency’s product information. However, until recently, it had not been determined whether these adverse events were related to vismodegib, all the more so as patients with BCC have an increased risk of developing cutaneous SCC [3]. Nevertheless, Orouji et al. [4] recently described the rapid occurrence of several moderately to highly differentiated SCCs in a patient treated with vismodegib. Secondly, the emergence of an SCC component from the BCC tumor bed during vismodegib treatment has already been reported in several vismodegib-treated patients. Iarrobino et al. [2] reported the delayed emergence of SCC phenotype in a BCC metastatic lymph node in a patient treated by vismodegib. Based on this case, they hypothesized that secondary regrowth of BCC under vismodegib could be explained by transdifferentiation from BCC to SCC. According to these authors, putative underlying mechanisms included the recruitment of preexisting SCC cells, and/or alterations of BCC signaling, and/or the progression of the original population to a more poorly differentiated phenotype [2]. Consistent with the latter observation, Zhu et al. [5] recently presented 2 new cases of clinically significant SCC arising within the tumor bed of a locally advanced BCC during vismodegib treatment. Both patients, as well as the patient previously described by Iarrobino et al. [2], were initially responsive to vismodegib and biopsy was guided by secondary relapse, contrary to our case. At the molecular level, several research works may provide a rationale for the occurrence of SCC in the setting of alterations
Dermatology 2015;230:101–104 DOI: 10.1159/000368350
103
Downloaded by: UCSF Library & CKM 169.230.243.252 - 3/24/2015 4:37:53 PM
In this setting, mutilating surgery was considered unreasonable. Therefore, after multidisciplinary consultation, a two-step medical strategy was preferred. First, a conservative topical treatment with 5-fluorouracil (5-FU) was applied to the erythematosquamous plaque with a 5-mm lateral margin, once daily for 1 month, then 3 times a week for 1 month. Complete clinical response was noted at 4 weeks after the end of therapy (fig. 1b). Afterwards, vismodegib 150 mg/day was started under the supervision of a nurse to treat the locally advanced BCC of the nose. Main adverse events related to vismodegib were grade 2 asthenia and myalgia. Photographs were taken every 8 weeks and tumoral evolution was assessed using RECIST v1.1 clinical criteria. At week 8, the disease was considered stable. However, at week 16, the target lesion undoubtedly progressed since its largest diameter increased to 60 mm (+33% from baseline); therefore vismodegib was discontinued. Concomitantly, the global clinical appearance of the lesion strikingly evolved into an exophytic, granulating and ulcerative tumor with raised margin advancing toward the right cheek and the nasal bridge (fig. 1c). Therefore, a 4-mm punch biopsy specimen was taken from lesional skin of the nasal bridge. Histological analysis showed infiltration of (at least) the entire thickness of the dermis by a carcinoma exhibiting different features from those observed on the pretherapy lesion 1 biopsy specimen, although no accurate diagnosis could be made yet on the basis of the examination of a too small specimen. Given disfiguring evolution, as well as functional impairment, the patient was proposed palliative rhinectomy in order to accommodate an epithesis. Histologically, the tumor originated from the epidermis and infiltrated underlying tissues including the cartilage, with positive deep resection margin (fig. 2c). It was organized into eosinophilic spans and masses containing multiple images of keratinization. Neither neuro- nor angiotropism was detected. Frequent mitoses were noted (9 per field at magnification ×40, some of which being atypical) as well as multiple cell atypia. Although features of trichoblastic or intermediate carcinoma were visible in a few areas, final histopathological diagnosis was SCC combining keratinizing, moderately differentiated with poorly differentiated components. Immunohistochemistry with antip63, cytokeratin (CK) 5/6, CK7, human epithelial antigen (HEA)/BerEP4, and epi-
of BCC signaling [6–8]. The carcinogenesis of familial as well as most sporadic BCCs is known to result from Sonic Hedgehog (SHH) pathway constitutive hyperactivation, most often by inactivating Patched 1 (PTCH1) mutations, with subsequent Smo release, then Gli-dependent up-regulation of SHH target genes. Aside from its classic BCC tumor suppressor activity, several authors have pointed out that PTCH1 may have other functions, independently of the SHH pathway, such as the regulation of apoptosis [6]. In 2007, Wakabayashi et al. [7] showed that a polymorphic variant of the Patched gene found in FVB mice, a strand with an SCC-prone genetic background, was sufficient to promote Hrasinduced SCC. In the same way, Kang et al. [8] recently demonstrated that overexpression of the Ptch1FVB allele driven by the ker-
atin 14 promoter synergizes with chemically induced Hras mutations to promote SCC development in adult mice, while they exhibited developmental signs consistent with inhibition of the SHH signaling pathway. Therefore, it was proposed that Ptch1 plays a critical role in both BCC and SCC development, inhibiting BCCs and promoting SCCs [6, 7]. We assume that clinical data are not unequivocal in our patient, and scientific results on animal models must be taken with caution. However, in our view, the clinical experience of our patient, together with recently published cases, raises the issue of a potential deleterious effect of SHH pathway inhibitors. Therefore, carcinogenicity studies with vismodegib are needed. As has been postulated by Wakabayashi et al. [7] at an early stage of the development of SHH
inhibitors, physicians should be warned against their potential unexpected effects in promoting cell fate decisions leading to tumor cell types distinct from BCCs, including SCCs.
4 Orouji A, Goerdt S, Utikal J, Leverkus M: Multiple highly and moderately differentiated squamous cell carcinomas of the skin during vismodegib treatment of inoperable basal cell carcinoma. Br J Dermatol 2014;171:431– 433. 5 Zhou GA, Sundram U, Chang AS: Two different scenarios of squamous cell carcinoma within advanced basal cell carcinomas: cases illustrating the importance of serial biopsy during vismodegib usage. JAMA Dermatol 2014;150:970–973.
6 Atwood SX, Whitson RJ, Oro AE: ‘Patch’ing up our tumor signaling knowledge. J Invest Dermatol 2013;133:1131–1133. 7 Wakabayashi Y, Mao JH, Brown K, et al: Promotion of Hras-induced squamous carcinomas by a polymorphic variant of the Patched gene in FVB mice. Nature 2007; 445: 761– 765. 8 Kang HC, Wakabayashi Y, Jen KY, et al: Ptch1 overexpression drives skin carcinogenesis and developmental defects in K14Ptch(FVB) mice. J Invest Dermatol 2013;133:1311–1320.
Acknowledgment
This work was supported in part by grants to L. Thomas from Lyon 1 University, the Hospices Civils de Lyon and the Ligue Contre le Cancer du Rhône. Disclosure Statement
The authors have no financial disclosures to make.
1 Sekulic A, Migden MR, Oro AE, et al: Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med 2012;366:2171–2179. 2 Iarrobino A, Messina JL, Kudchadkar R, Sondak VK: Emergence of a squamous cell carcinoma phenotype following treatment of metastatic basal cell carcinoma with vismodegib. J Am Acad Dermatol 2013;69:e33–e34. 3 European Medicines Agency: Erivedge (vismodegib). Product information. http:// www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002602/WC500146817.pdf (accessed October 24, 2013).
104
Dermatology 2015;230:101–104 DOI: 10.1159/000368350
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Downloaded by: UCSF Library & CKM 169.230.243.252 - 3/24/2015 4:37:53 PM
References
