0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Research Letter |

Vismodegib as Eye-Sparing Adjuvant Treatment for Orbital Basal Cell Carcinoma FREE

Alon Kahana, MD, PhD1; Francis P. Worden, MD2; Victor M. Elner, MD, PhD1
[+] Author Affiliations
1Eye Plastic and Orbital Surgery Service, Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor
2Hematology and Oncology Section, Department of Internal Medicine, University of Michigan, Ann Arbor
JAMA Ophthalmol. 2013;131(10):1364-1366. doi:10.1001/jamaophthalmol.2013.4430.
Text Size: A A A
Published online

Orbital invasion of basal cell carcinoma (BCC) may lead to disfigurement, blindness, or even death.1 Orbital exenteration, although disfiguring and blinding, is often the only option for cure when incompletely excised medial canthal tumors extend into the orbit.2 The US Food and Drug Administration has recently approved a hedgehog pathway inhibitor3 with an adequate safety profile,4 vismodegib (Erivedge), for oral treatment of basal cell nevus syndrome5 and locally advanced or metastatic BCC.6 We describe a patient with BCC invading the medial orbit who was treated with oral vismodegib, resulting in near-total tumor shrinkage that permitted complete excision with clear surgical margins. Histopathologically, the excised tissue contained scattered residual tumor cells exhibiting squamous differentiation and low proliferative capacity.

A 79-year-old man developed left lower eyelid retraction 10 years after BCC excision. Examination demonstrated normal vision, limited left ductions, increased left tear lake, and left medial canthal fullness but no external skin lesion. Biopsy revealed aggressive-growth-pattern BCC (ie, morpheaform, with irregular strands of deeply invading cells) (Figure 1B and C). Following biopsy, magnetic resonance imaging showed a 2.7 × 1.6 × 1.9-cm medial orbital mass (Figure 1A). To avoid exenteration with loss of the eye, medical treatment with vismodegib, 150 mg/d by mouth, was begun 1 month later. During the next 5 months, the patient reported occasional nausea and diarrhea and progressively worsening muscle spasms—all known adverse effects of vismodegib therapy.4 Magnetic resonance imaging after 4 months of treatment showed reduction in tumor size to 0.7 × 0.7 × 0.5 cm (Figure 1D). Because of painful muscle spasms, the patient opted for surgical excision instead of continued vismodegib therapy. En bloc excision of the residual orbital mass was performed along with medial rectus muscle release using frozen-section control. Postfixation histopathologic evaluation revealed all margins to be clear of tumor. Vismodegib was discontinued at surgery. The patient has done well, with complete resolution of treatment adverse effects, including the muscle spasms, within 2 months of treatment cessation.

Place holder to copy figure label and caption
Figure 1.
Treatment With Vismodegib Results in Reduction in the Size of a Left Medial Orbital Basal Cell Carcinoma

Before vismodegib treatment, magnetic resonance imaging shows a left medial orbital basal cell carcinoma (arrows) (A and inset of A), and hematoxylin-eosin staining (original magnification ×40) (B) and immunohistochemistry with K903 antibody staining (original magnification ×40) (C) for high-molecular-weight keratin show tumor cell content. Following vismodegib treatment, magnetic resonance imaging reveals a reduction in size (D), while hematoxylin-eosin staining (original magnification ×40) (E) and immunohistochemistry with K903 antibody staining (original magnification ×40) (F) reveal reduction in tumor cell content.

Graphic Jump Location

The excised tumor was submitted in toto and fully analyzed in sequential sections. The original, highly cellular, aggressive-growth-pattern BCC, with areas of squamous differentiation, stained positive for high-molecular-weight cytokeratin. The excised, treated mass revealed a reduction in tumor load (Figure 1B and C vs Figure 1E and F) with the vast majority of tissue composed of fibrotic and fibrovascular tissue with mild, scattered acute and chronic inflammation (Figure 2A and B). Single or small clusters of cytokeratin-positive cells with squamous differentiation, vesicular or smudged nuclei, and abundant eosinophilic cytoplasm were scattered multifocally in the fibrous matrix (Figure 2D). Foci of degenerating squamous cell clusters infiltrated by histiocytes (Figure 2E) and clusters of tumor ghost cells lacking nuclei (Figure 2C) were also present. Many infiltrating leukocytes were immunoreactive for the macrophage marker CD68 (Figure 2F). Importantly, the residual squamous cells not only exhibited degenerative cytologic features but also failed to exhibit nuclear immunoreactivity for the proliferation marker Ki-67 (Figure 2I), suggesting virtual loss of tumor cell proliferation (mitotic index <1%) following vismodegib treatment, in stark contrast to the original BCC (Figure 2G).

Place holder to copy figure label and caption
Figure 2.
Histologic and Immunohistochemical Analysis of the Excised Residual Tumor

Histologic analysis of the excised residual tumor with hematoxylin-eosin staining reveals predominant pattern fibrosis (original magnification ×40 [A] and ×100 [B]) and degenerative nests (original magnification ×200) (C) with a lymphocytic infiltrate (original magnification ×200) (D). Leukocyte phagocytosis of degenerated cells is noted on hematoxylin-eosin staining (original magnification ×100) (E) and CD68 immunohistochemistry (original magnification ×100) (F). In contrast to a high pretreatment proliferative index as indicated by extensive nuclear immunostaining for Ki67 (original magnification ×100) (G), posttreatment tumor shows virtual absence of immunoreactivity (original magnification ×100) (I, representing the only area of the excised tumor with any hint of Ki67 staining). Histologic analysis of corresponding adjacent sections was performed with hematoxylin-eosin staining (original magnification ×100) (H and J).

Graphic Jump Location

Oral vismodegib is a novel therapy for the treatment of metastatic or locally advanced and organ-threatening BCC and may be considered for treatment of eligible patients with eye-threatening orbital BCC. Because the drug is newly approved and is associated with a range of adverse effects and health risks,4 additional experience and study will be required to better assess the risks of treatment and develop optimal treatment criteria. It is troubling to note that we still do not understand the cause of the debilitating muscle spasms that many patients experience, including our patient. To our knowledge, this is the first histopathologic description of the effects of vismodegib treatment of BCC. Tumor cell degeneration and elimination by leukocytes followed by fibrovascular proliferation and fibrosis appear to underlie tumor shrinkage. Although residual cells may have the capacity to reform the tumor if treatment is halted because of treatment adverse effects or if tumor cells develop resistance to vismodegib, it is likely that many of the residual cells are sufficiently damaged so as to have limited proliferative capacity. Nevertheless, en bloc excision with margin control may be prudent when the adverse effects become intolerable to the patient. While we urge caution, our recent experience suggests that vismodegib may be particularly useful as a neoadjuvant treatment, a possibility that warrants further study.

Corresponding Author: Alon Kahana, MD, PhD, Department of Ophthalmology and Visual Sciences, 243 Kellogg Eye Center, 1000 Wall St, Ann Arbor, MI 48105 (akahana@med.umich.edu).

Published Online: August 1, 2013. doi:10.1001/jamaophthalmol.2013.4430.

Author Contributions:Study concept and design: All authors.

Acquisition of data: Kahana, Elner.

Analysis and interpretation of data: Kahana, Elner.

Drafting of the manuscript: Kahana.

Critical revision of the manuscript for important intellectual content: All authors.

Obtained funding: Kahana.

Administrative, technical, and material support: Kahana, Elner.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was supported by a Career Development Award from Research to Prevent Blindness (Kahana), by grant K08 EY018689 from the National Eye Institute, and in part by the University of Michigan Cancer Center Support Grant P30 CA046592 from the National Institutes of Health, Vision Research Core Grant P30 EY007003 from the National Eye Institute, and an unrestricted departmental grant from Research to Prevent Blindness. Kahana is supported by the Helmut F. Stern Career Development Endowed Professorship in Ophthalmology and Visual Sciences. Elner is supported by the Ravitz Foundation Professorship in Ophthalmology and Visual Sciences.

Role of the Sponsors: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript.

Leibovitch  I, McNab  A, Sullivan  T, Davis  G, Selva  D.  Orbital invasion by periocular basal cell carcinoma. Ophthalmology. 2005;112(4):717-723.
PubMed   |  Link to Article
Iuliano  A, Strianese  D, Uccello  G, Diplomatico  A, Tebaldi  S, Bonavolontà  G.  Risk factors for orbital exenteration in periocular basal cell carcinoma. Am J Ophthalmol. 2012;153(2):238-241, e1.
PubMed   |  Link to Article
Lear  JT.  Oral hedgehog-pathway inhibitors for basal-cell carcinoma. N Engl J Med. 2012;366(23):2225-2226.
PubMed   |  Link to Article
Sekulic  A, Migden  MR, Oro  AE,  et al.  Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012;366(23):2171-2179.
PubMed   |  Link to Article
Tang  JY, Mackay-Wiggan  JM, Aszterbaum  M,  et al.  Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome. N Engl J Med. 2012;366(23):2180-2188.
PubMed   |  Link to Article
US Food and Drug Administration. Vismodegib. http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm289571.htm. Accessed October 16, 2012.

Figures

Place holder to copy figure label and caption
Figure 1.
Treatment With Vismodegib Results in Reduction in the Size of a Left Medial Orbital Basal Cell Carcinoma

Before vismodegib treatment, magnetic resonance imaging shows a left medial orbital basal cell carcinoma (arrows) (A and inset of A), and hematoxylin-eosin staining (original magnification ×40) (B) and immunohistochemistry with K903 antibody staining (original magnification ×40) (C) for high-molecular-weight keratin show tumor cell content. Following vismodegib treatment, magnetic resonance imaging reveals a reduction in size (D), while hematoxylin-eosin staining (original magnification ×40) (E) and immunohistochemistry with K903 antibody staining (original magnification ×40) (F) reveal reduction in tumor cell content.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
Histologic and Immunohistochemical Analysis of the Excised Residual Tumor

Histologic analysis of the excised residual tumor with hematoxylin-eosin staining reveals predominant pattern fibrosis (original magnification ×40 [A] and ×100 [B]) and degenerative nests (original magnification ×200) (C) with a lymphocytic infiltrate (original magnification ×200) (D). Leukocyte phagocytosis of degenerated cells is noted on hematoxylin-eosin staining (original magnification ×100) (E) and CD68 immunohistochemistry (original magnification ×100) (F). In contrast to a high pretreatment proliferative index as indicated by extensive nuclear immunostaining for Ki67 (original magnification ×100) (G), posttreatment tumor shows virtual absence of immunoreactivity (original magnification ×100) (I, representing the only area of the excised tumor with any hint of Ki67 staining). Histologic analysis of corresponding adjacent sections was performed with hematoxylin-eosin staining (original magnification ×100) (H and J).

Graphic Jump Location

Tables

References

Leibovitch  I, McNab  A, Sullivan  T, Davis  G, Selva  D.  Orbital invasion by periocular basal cell carcinoma. Ophthalmology. 2005;112(4):717-723.
PubMed   |  Link to Article
Iuliano  A, Strianese  D, Uccello  G, Diplomatico  A, Tebaldi  S, Bonavolontà  G.  Risk factors for orbital exenteration in periocular basal cell carcinoma. Am J Ophthalmol. 2012;153(2):238-241, e1.
PubMed   |  Link to Article
Lear  JT.  Oral hedgehog-pathway inhibitors for basal-cell carcinoma. N Engl J Med. 2012;366(23):2225-2226.
PubMed   |  Link to Article
Sekulic  A, Migden  MR, Oro  AE,  et al.  Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012;366(23):2171-2179.
PubMed   |  Link to Article
Tang  JY, Mackay-Wiggan  JM, Aszterbaum  M,  et al.  Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome. N Engl J Med. 2012;366(23):2180-2188.
PubMed   |  Link to Article
US Food and Drug Administration. Vismodegib. http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm289571.htm. Accessed October 16, 2012.

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections