Received: 26 February 2017
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Revised: 21 April 2017
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Accepted: 2 May 2017
DOI: 10.1111/dth.12509
THERAPEUTIC HOTLINE: SHORT PAPERS
Inoperable infiltrative basal cell carcinoma successfully treated with vismodegib Omid Zargari1 | Seyyede Zeinab Azimi2
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Siamak Geranmayeh3
1
Dana Clinic, Rasht, Iran
2
Department of Dermatology, Guilan University of Medical Sciences, Rasht, Iran 3
Sina Pathobiology Laboratory, Rasht, Iran
Correspondence Seyyede Zeinab Azimi, Department of Dermatology, Razi Hospital, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran. Email:
[email protected]
Abstract Basal cell carcinoma (BCC) is the most common skin cancer but usually has a good prognosis. However, there is a subset of BCC cases with a less favorable prognosis. For patients with locally advanced, recurrent or metastatic BCCs who are not suitable for surgery or radiotherapy, small-molecule drug inhibitors of hedgehog pathway are a new therapeutic opportunity. Here, we present a case of infiltrative BCC with multiple recurrences. Wide excision with reconstructive plastic surgery was performed initially with adjuvant radiotherapy. Due to multiple recurrences afterward, radiotherapy, topical imiquimod and oral itraconazole were used but were not effective. Finally, the patient was treated with vismodegib which led to a complete response. Moreover, the patient’s symptoms due to the locally diffused cancer resolved. KEYWORDS
basal cell carcinoma, hedgehog pathway, vismodegib
1 | INTRODUCTION
Unfortunately, the pathologic examination of the excised tumor revealed that the excision was not complete and the patient was
Basal cell carcinoma (BCC) is the most common cutaneous malignancy
referred to a radiotherapist by the plastic surgeon.
(Puig & Berrocal, 2015). BCCs are divided into histologic subtypes ranging
In July 2009, he developed new BCC lesions on the nasal skin,
from less aggressive such as nodular and superficial to more-aggressive
adjacent to the site of previous one (Figure 1). Given the size of the
forms such as infiltrative, micronodular, basosquamous, and sclerosing or
new lesion and anticipated large deformity caused by a second surgery,
morphea form (Lewin & Carucci, 2015). Surgery and radiation therapy are
surgical treatment was deferred and he was offered radiotherapy. He
the main treatments for localized BCC. Despite surgical excision being the
was informed of possible side effects of the treatment. The patient at
gold standard of care, non-surgical techniques have gained attention
the time agreed to the proposed treatment. The patient received local
due to less comorbidity and better cosmetic outcomes (Fellner, 2012).
radiation therapy, a total of 50 Gy over a series of 24 treatments.
2 | CASE PRESENTATION
which got better after 4-month administrations of Imiquimod cream
In August 2011, new suspicious lesions were detected on his nose, and the, remaining crusts were removed with curettage. A 48-year-old man was seen in March 2016 in the dermatology outpa-
In January 2015, he developed severe edema and inflammation on
tient clinic because of an extensive tumor on the nose. Initially, he pre-
the nasal and right periorbital areas with crust formation. Systemic anti-
sented with a large, pigmented ulcerative plaque on the right lateral
biotic and then curettage of the crusts alleviated the lesions.
nose in 2006. Results of a pathological examination confirmed the
Four months later he underwent biopsy of a recurrent lesion
diagnosis of an infiltrative BCC. The craniofacial computed tomography
(Figure 2). The biopsy was consistent with a BCC which had infiltrated
performed at that time, revealed no erosive changes of bony struc-
the whole the nose with loss of tissue on the right side. Recurrences of
tures. The posterior fossa, nasopharynx, larynx, para nasal sinuses, and
the disease caused severe ptosis leading to visual limitation on the
cervical esophagus, all appeared normal. There was no family history of
same side eye. The patient then was referred for ophthalmology
skin cancers. No other suspicious lesions were detected on physical
assessments. Eye exam showed no evidence of visual impairment.
examination. The tumor was widely excised by a plastic surgeon.
Systemic itraconazole, as an antagonist of the Hedgehog (Hh) signaling
Dermatologic Therapy. 2017;e12509. https://doi.org/10.1111/dth.12509
wileyonlinelibrary.com/journal/dth
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F I G U R E 1 (a) New BCC lesions on the nasal skin, beside the site of the previous one, radiotherapy was suggested. (b) High power view of specimen demonstrates focal infiltrative BCC with desmoplastic stroma (*400)
pathway was started for him in September 2015. He continued itraco-
significant number of the patients with BCC in Iran, are those who had
nazole twice a day for four months with minimal effects.
had radiation therapy for treating their tinea capitis (Zargari, 2015).
Finally, treatment with vismodegib 150 mg per day was started for
Although the prognosis for patients with BCC is generally good, a small
him on March 2016. After three consecutive cycles (28 days for each
subset of cases poses a challenge for clinical management. Such cases
cycle) of treatment with vismodegib, the lesion responded dramatically
include locally advanced tumors, aggressively recurrent tumours and
to treatment with a significant decrease in size. Within one month of
rare cases of metastatic BCC (Lear et al., 2014). Particularly, BCCs
treatment initiation, there was remarkable improvement, with a visible
located on the ear, nose, eyelid, and lip, also called as “H” zone, have
decrease in tumor size and signs of healing in the periphery of the
higher recurrence rate and local invasion, resulting in tissue injury to
lesion. The patient’s condition improved and he reported improved vis-
vital structures (Zargari, 2015).
ual movement (Figure 3). No significant side effects of vismodegib
The Hedgehog (Hh) pathway is activated abnormally in both spo-
occurred. Eight months after the treatment, no signs of recurrence
radic and inherited BCCs (Gorlin syndrome) (Lear et al., 2014).
were found and another skin biopsy showed no evidence of residual
Normally, Patched homologue 1 (PTCH1) inhibits smoothened (SMO)
BCC. He was satisfied with the cosmetic outcome.
signaling. Alterations in inhibition of SMO, induces transcription factors that promote basal cells’ proliferation and growth. Hedgehog plays key
3 | DISCUSSION
role in the cell proliferation of BCC by inhibiting PTCH1, and removal of the inhibition of SMO (Epstein, 2008). Vismodegib is a synthetic, small-molecule inhibitor of SMO, a key
BCC is the most common skin malignancy (Lear et al., 2014). Ultraviolet exposure is the major risk factor for developing BCC, however, a
component of intracelluar hedgehog pathway which had obtained FDA’s approval in 2012 (Erivedge, Genentech) (Fellner, 2012). When surgery is unsuitable and additional radiation therapy cannot be used, in conditions such as metastatic BCC or locally advanced BCC that has recurred after surgery, Hh pathway inhibitors can be considered as a potentially useful treatment option (Fellner, 2012; Lear et al., 2014; Lewin & Carucci, 2015; Puig & Berrocal, 2015; Zargari, 2015). Up to now, three clinical trials in metastatic BCC and locally advanced BCC with vismodegib have been published (Basset-Seguin et al., 2015; Sekulic et al., 2012; Von Hoff et al., 2009). Locally advanced BCC have been defined as lesions larger than 1 cm and inappropriate for surgery, and also for cases which radiotherapy was contraindicated or unsuitable. The ERIVANCE trial reported overall response rates of 48.5% in metastatic BCCs and 60.3% in locally advanced BCCs. The median duration of responses were 14.8 months in metastatic BCC and 26.2 months in locally advanced BCCs. Eight weeks after initiation of therapy, the first clinical evaluation of patients was conducted, and most of them showed evidence of tumor
FIGURE 2
Recurrent BCCs, candidate for itraconazol
shrinkage at that time (Sekulic et al., 2012). The STEVIE clinical trial
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FIGURE 3
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Eight months after treatment with vismodegib
reported an interim analysis in 500 patients with metastatic BCC or
4 | CONCLUSIONS
locally advanced BCC, where the patients received 150 mg of oral vismodegib on a continuous basis in a 28-day cycle with a response rate
This case draws attention to the role of vismodegib for treatment of
of 64.9% (Basset-Seguin et al., 2015).
inoperable and infiltrative cases of BCC. Regarding the high cost of vis-
The most common adverse effects, reported in the phase I trial, experienced by patients taking vismodegib, consisted of muscle
modegib, pulse therapy could be considered as another option for such cases.
spasms, fatigue, alopecia, dysgeusia, and nausea. Other rare side effects mentioned were hyponatremia, pyelonephritis, anxiety, and hyperglycemia, cough, back pain, and vomiting (Von Hoff et al., 2009). Perhaps, the most important side effect of vismodegib is
CONFLIC T OF I NTE RE ST The authors have no conflict of interests.
developing new malignancies. Recent studies have shown that there is a significant risk of second malignancies, specifically cutaneous
OR IGINAL PUBLICATION
squamous cell carcinoma (SCC), with vismodegib therapy (Mohan et al.,
This manuscript contains original unpublished work and is not being
2016). Until now, at least two cases of keratoacanthoma and five cases
submitted for publication elsewhere at the same time.
of squamous cell carcinoma has been reported following treatment with vismodegib (Aasi, 2013; Iarrobino et al., 2013; Orouji et al., 2014;
ET HICS
Saintes et al., 2015). Interestingly in all of these cases, the new tumors
The patient has provided informed consent for participation in this
appeared soon after vismodegib initiation. Therefore, a careful
report.
surveillance through regular follow-ups, particularly within the first year of vismodegib initiation, is recommended for all patients (Mohan et al., 2016; Saintes et al., 2015). One study about the use of vismodegib in the basal cell nevus syndrome reported that over half of treated patients, discontinued the drug administration due to its side effects (Tang et al., 2012). Also, some studies reported discontinuation of drug due to the cost of vismodegib (Lewin & Carucci, 2015). Fortunately, our case did not experience any serious side effects. Our patient received an oral dosage of 150 mg vismodegib daily for three months, which resulted in a dramatic shrinkage of tumor and correction of secondary lid ptosis. Interestingly enough, the improvement persisted even after the discontinuation of vismodegib. This observation suggests that administrating the drug as a pulse therapy may be as effective as continuous therapy. This case was a unique case of a patient with infiltrative BCC followed by for more than a decade and who underwent different treatments. To our knowledge, no previous clinical report had been published about effectiveness of vismodegib in infiltrative BCC. A significant benefit was achieved by treatment with vismodegib in our patient; his symptoms improved and treatment produced complete remission with a three month drug administration.
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How to cite this article: Zargari O, Azimi SZ, Geranmayeh S. Inoperable infiltrative basal cell carcinoma successfully treated with vismodegib. Dermatologic Therapy. 2017;e12509. https:// doi.org/10.1111/dth.12509
