Head-to-Head in Psoriasis: Brodalumab vs Ustekinumab

It has been unusual for companies to risk direct comparisons of new agents with recent vintage competitors, but that is beginning to happen in the crowded market for biologic agents in psoriasis.  It is also important to note that the trend toward a higher bar for efficacy assessment of treatments for this disease is continuing with a 100% reduction in the psoriasis area-and-severity index score (PASI 100) being used as the benchmark for efficacy.

In two phase III studies (AMAGINE-2 and AMAGINE-3), patients with moderate-to-severe psoriasis were randomized to brodalumab, ustekinumab, or placebo.

The primary aims were to evaluate the superiority of brodalumab over placebo at week 12 with the primary endpoint being the percent of patients achieving at least a 75% reduction in the psoriasis area-and-severity index score (PASI 75) and a static physician’s global assessment (sPGA) score of 0 or 1 (clear or almost clear skin), as well as the superiority of brodalumab over ustekinumab at week 12 with respect to PASI 100.

At week 12, PASI 100 response rates were significantly higher with 210 mg of brodalumab than with ustekinumab (AMAGINE-2, 44% vs 22%; AMAGINE-3, 37% vs 19%; P<0.001).

Rates of neutropenia were higher with brodalumab and with ustekinumab than with placebo and mild or moderate candida infections were more frequent with brodalumab than with ustekinumab or placebo (Lebwohl, 2015).


References

Lebwohl M, Strober B, Menter A, et al. Phase 3 studies comparing brodalumab with ustekinumab in psoriasis. N Engl J Med. 2015;373:1318-28.

Lasers: Red vs Blue in PDT

Its Blue

A study reported late last year was carried out to determine whether prior microneedling would enhance the penetration of topical aminolevulinic acid HCl (Levulan) and thus enhance photodynamic therapy (PDT) and possibly also result in a better cosmetic outcome vs PDT alone in patients with AKs.

In this trial, 20 patients each with ≥4 non-hyperkeratotic AKs on each side of their faces were randomized to receive multiple passes with a microneedling device on one side of their faces, followed by application of aminolevulinic acid HCl to the entire face.

The aminolevulinic acid HCl was allowed to incubate for 1 hour and this was followed by exposure to blue light (Blu U) for 1000 seconds.

For the 19 patients who completed 4 months of follow-up, the mean AK reduction on the microneedling side was 89.3% vs 69.5% on the PDT alone side. In addition, 13 of the 19 patients had a noticeable improved cosmetic appearance on the microneedled side of the face (Spencer, 2016).

No, Its Red

Aminolevulinic acid hydrochloride (BF-200 ALA, Ameluz) was recently approved by the United States Food and Drug Administration for PDT using the BF-RhodoLED lamp, a narrowband, red light illumination source, for lesion-directed and field-directed treatment of AKs of mild-to-moderate severity on the face and scalp.

This approval was based on results from 779 patients with 4-8 mild to moderate AK lesions. The results obtained from these studies demonstrated that BF-200 ALA was significantly superior to the standard of care, with a complete patient response rate of 91% when paired with BF-RhodoLED PDT lamp (CenterWatch, 2017).

In addition, BF-200 ALA showed positive long-term effects with low recurrence over the course of 12 months (Dirschka, 2013).

In a pivotal phase III trial performed on entire treatment fields, BF-200 ALA demonstrated long-lasting skin rejuvenation effects in sun-damaged, but asymptomatic, skin regions (CenterWatch, 2017; Reinhold, 2016).


References

CenterWatch. Ameluz (aminolevulinic acid hydrochloride). 2017. Available at: http://www.centerwatch.com/drug-information/fda-approved-drugs/drug/100150/ameluz-aminolevulinic-acid-hydrochloride

Dirschka T, Radny P, Dominicus R, et al. Long-term (6 and 12 months) follow-up of two prospective, randomized, controlled phase III trials of photodynamic therapy with BF-200 ALA and methyl aminolaevulinate for the treatment of actinic keratosis. Br J Dermatol. 2013;168:825-36.

Reinhold U, Dirschka T, Ostendorf R, et al. A randomized, double-blind, phase III, multicentre study to evaluate the safety and efficacy of BF-200 ALA (Ameluz(®) ) vs. placebo in the field-directed treatment of mild-to-moderate actinic keratosis with photodynamic therapy (PDT) when using the BF-RhodoLED lamp. Br J Dermatol. 2016;175:696-705.

Spencer JM, Freeman SA. Microneedling Prior to Levulan PDT for the Treatment of Actinic Keratoses: A Split-Face, Blinded Trial. J Drugs Dermatol. 2016;15:1072-4.

5-Fluorouracil (5-FU): 4% vs 5% for the Treatment of Actinic Keratosis

While oxymetazoline HCl cream, 1% and bromocriptine gel, 0.33% were not compared in a head-to-head trial, this has been done for 4% 5-FU in an aqueous vehicle cream containing peanut oil (Tolak) vs 5% 5-FU in a vanishing cream (Efudex) in patients with actinic keratosis (AKs).

In a 4-week, double-blind, multicenter non-inferiority study that included 841 subjects, 4% 5-FU cream administered once daily was compared with 5% 5-FU cream twice daily with 100% and 75% clinical clearance of AK’s assessed as the study endpoint.

4% 5-FU achieved 100% clearance in 80% of patients and 75% clearance in 100% of patients compared with 75% and 95%, respectively, with 5% 5-FU.

Skin irritation occurred in 30% of patients treated with 4% 5-FU vs 60% with 5% 5-FU.

It was also noted that the peanut oil component of the 4% 5-FU preparation is safe even in peanut-allergic patients.

Thus, 4% 5-FU is non-inferior to 5% 5-FU with better tolerability and permits once-daily administration which may result in better adherence to therapy (Dohil, 2016).


References

Dohil MA. Efficacy, safety, and tolerability of 4% 5-fluorouracil cream in a novel patented aqueous cream containing peanut oil once daily compared with 5% 5-fluorouracil cream twice daily: meeting the challenge in the treatment of actinic keratosis. J Drugs Dermatol. 2016;15:1218-1224.

Oxymetazoline Hydrochloride 1% Cream for Rosacea

Oxymetazoline hydrochloride (HCl) cream, 1% (RHOFADE), an alpha-1A-adrenoceptor agonist and a partial agonist at the alpha-2 receptor, was approved in January of 2017 and is indicated for the treatment of persistent facial erythema associated with rosacea in adults. Nasal sprays containing a lower concentration of oxymetazoline HCl have been used off-label to treat rosacea for many years, and oxymetazoline hydrochloride (HCl) cream, 1% is the first approved treatment using this compound (Smith, 2017).

In two clinical trials, once-daily application of oxymetazoline hydrochloride (HCl) cream, 1% reduced persistent facial erythema associated with rosacea through 12 hours.  After 29 days of treatment, patients achieving clinical success at 12 hours were 15% vs 6% for placebo in one study and 12% vs 6% in the second trial (RHOFADE PI, 2017).

Oxymetazoline HCl cream, 1% is not the first adrenergic agent approved for the treatment of rosacea. Brimonidine topical gel, 0.33% (MIRVASO) is an alpha-adrenergic agonist indicated for the topical treatment of persistent facial erythema of rosacea in adults that has been available since 2013 (MIRVASO PI, 2016).

Which of these two preparations is a better choice for your patient?  There is no head-to-head comparison of these treatments, so it is hard to know. Combined assessment of results from different studies (for example, with network meta-analyses) has now become a fairly common approach for comparing treatments that have never been tested vs each other, but that has not been accomplished for these drugs.  A look at the labels for the two agents suggests that effect sizes for oxymetazoline HCl cream, 1% and bromocriptine gel, 0.33% are very similar, but that application site erythema may occur more often with bromocriptine gel, 0.33% than with oxymetazoline HCl cream, 1% (RHOFADE PI, 2017; MIRVASO PI, 2016).


References

MIRVASO (brimonidine) topical gel. 2016. Available at: http://www.galdermausa.com/PI/MirvasoPI.pdf

RHOFADE (oxymetazoline hydrochloride) cream, for topical use. 2017. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208552s000lbl.pdf

Obiltoxaximab: A Monoclonal Antibody for Cutaneous Anthrax

You should certainly hope that you will never have to use it, but it is still important to know about obiltoxaximab (Anthim), a monoclonal antibody administered by injection, that has been approved for treating inhalational anthrax due to Bacillus anthracis in combination with appropriate antibacterial drugs in adult and pediatric patients.

It is also approved for prophylaxis of inhalational anthrax when alternatives are not available or appropriate (Kaufman, 2016).

Why should dermatologists care? Because the most common type of human anthrax is the cutaneous form. Other forms of human anthrax (gastrointestinal, inhalational, or injectional) are rare (Kajfasz, 2014).

It is expected that the main use of obiltoxaximab is likely to be in the setting of bioterrorism, but it might also be effective for the rare patient in your practice with cutaneous anthrax.


References

Kaufman MB. Pharmaceutical Approval Update. P T. 2016;41:355-6.

Kajfasz P, Bartoszcze M, Borkowski PK, Basiak W. Retrospective review of the case of cutaneous anthrax-malignant pustule from 1995 in 15-year old girl. Przegl Epidemiol. 2014;68:657-9.

Crisaborole: New Treatment for Atopic Dermatitis

Crisaborole (EUCRISA) is a novel non-steroidal topical ointment for mild to moderate atopic dermatitis (AD, eczema) that was approved in December of 2016. Topical agents are the mainstay of AD therapy and current guidelines recommend both corticosteroids, and topical calcineurin inhibitors (Eichenfield, 2014).

Agents in both of these classes are effective, but may be limited by application reactions and safety concerns with extended use.  Crisaborole is a phosphodiesterase 4 inhibitor (PDE-4) inhibitor with a mechanism of action that has been described for apremilast (Otezla), the oral drug used to treat psoriasis (Moustafa, 2014).

Two identical, vehicle-controlled, double-blind studies showed that crisaborole was significantly more effective than vehicle in achieving ≥2-grade improvements in Investigator’s Static Global Assessment (ISGA) scores in patients with AD (P<0.05 for both studies).

Crisaborole also provided significantly more rapid relief from itch than vehicle. As you know, this is a very important consideration for patients with AD since itch is generally the most bothersome symptom in this common disease.  In addition, itch typically results in scratching which can promote lesion formation and/or transformation to a chronic lichenified state (Turner, 2014).

The majority of treatment-related adverse events with crisaborole were application site pain, primarily reported as burning or stinging. This pain was the only treatment-related adverse events that occurred in ≥1% of patients (Paller, 2016).  Perhaps the main advantage of crisaborole over available topical therapies is avoidance of the potential long-term risks associated with these agents (Zane, 2016).


References

Eichenfield LF, Tom WL, Berger TG, et al. Guidelines of care for the management of atopic dermatitis: section 2. Management and treatment of atopic dermatitis with topical therapies. J Am Acad Dermatol. 2014;71:116-32.

Moustafa F, Feldman SR. A review of phosphodiesterase-inhibition and the potential role for phosphodiesterase 4-inhibitors in clinical dermatology. Dermatol Online J. 2014;20:22608.

Turner MJ, Zhou B. A new itch to scratch for TSLP. Trends Immunol. 2014;35:49-50.

Recognizing Unusual Tumors Part 3: Sebaceous Lesions and Carcinoma

George H. Martin

Sebaceous neoplasms have long been a source of confusion to dermatologists and there are disagreements regarding nomenclature, classification, and best approaches to management.  These lesions include hamartomas, hyperplasias, and benign tumors, as well as highly malignant neoplasms.  Specific sebaceous lesions include sebaceous hyperplasia, nevus sebaceous of Jadassohn, sebaceous adenoma, seboacanthoma, sebaceous epithelioma, sebaceoma, mantleoma, basal cell carcinoma with sebaceous differentiation, sebomatricoma (sebomatrixoma), and sebaceous carcinoma (Eisen, 2009).

Sebaceous Gland Carcinoma (SGC)

SGC is an uncommon adnexal neoplasm with a well-documented capacity for regional and distant metastasis. Historically, SGC has been associated with high rates of recurrence after excision (Kyllo, 2015).  This tumor is thought to arise from sebaceous glands in the skin and, thus, may occur anywhere on the body where these glands are present.  About three-fourths of these tumors arise in the periocular region, an area rich in sebaceous glands (Wu, 2016).

SGC: Eyelid

This tumor accounts for 1-5% of eyelid malignancies, it occurs more frequently in women than men, and arises most often in the 6th-7th decade of life.  It exhibits an aggressive clinical course, with a significant tendency for both local recurrence and distant metastasis.  It usually appears as a painless, slowly enlarging nodule that is yellowish to pink/red color. Diagnosis of ocular SGC is often significantly delayed because it mimics several benign eye conditions, including chalazion, keratoconjunctivitis, blepharoconjunctivitis, and ocular pemphigoid (Wali, 2010).

Suspect SGC when you see:

  • Non resolving chalazion:
    • Inflammation of the Meibomian glands or glands of Zeis
    • Painless granulomatous inflammation
    • Most common misdiagnosis of sebaceous carcinoma
  • Loss of cilia
  • Yellow streaks on conjunctiva
  • Increased vascularity
  • Chronic unilateral inflammation

Extraorbital SGC

Despite the widespread anatomic distribution of sebaceous glands, extraorbital SGC is very rare comprising only 25% of all reported cases for these tumors (Mathur, 2010). Extraocular SGCs most commonly involve the head and neck region, in which sebaceous glands are most plentiful, followed by external genitalia, the parotid and submandibular glands, the external auditory canal, the trunk and upper extremity, sole, the dorsum of the great toe, and laryngeal or pharyngeal cavities (Mathur, 2010). The most frequent clinical presentation is a painless subcutaneous nodule, but it can also present as pedunculated lesions, an irregular mass, or diffuse thickening of the skin. This variable presentation often results in confusion with benign tumors or inflammatory conditions, including basal cell carcinoma (BCC), cutaneous cell carcinoma, squamous cell carcinoma, ceratoacanthoma, cornu cutaneum and Bowen’s disease, as well numerous other malignant and benign lesions thereby leading to delay in diagnosis, inappropriate treatment, increased morbidity, and mortality (Natarajan, 2011; Bolm, 2015).

Muir-Torre Syndrome

Muir-Torre syndrome (MTS) is a rare autosomal dominant genodermatosis that predisposes individuals to skin tumors and visceral malignancies. MTS is very rare, with only about 200 cases reported. Males are more commonly affected, with a male to female ratio of 3:2, and individuals can present at any age. Sebaceous tumors precede visceral malignancy diagnosis in 22% of patients, occur simultaneously in 6%, and develop subsequently in 56% of reported MTS cases (Bhaijee, 2014). MTS-related sebaceous tumors include sebaceous adenoma, sebaceoma/sebaceous epithelioma, sebaceous carcinoma, keratoacanthoma with sebaceous differentiation, BCC with sebaceous differentiation, and cystic sebaceous neoplasms (Bhaijee, 2014).

This cancer is potentially very aggressive and close cancer surveillance is required in individuals with MTS and their families (John, 2016).  The majority of MTS is caused by a mutation in one of the mismatch repair gene (MHL1, MLH2, or MHL3) (Bhaijee, 2014).  However, a newly described subtype of MTS does not demonstrate microsatellite instability and may be inherited in an autosomal recessive pattern. In addition, MTS may be unmasked in transplant recipients taking specific immunosuppressant drugs or other immunosuppressed patients (John, 2016).

Patients can be screened for Muir-Torre Syndrome:

  • Testing sebaceous lesions for microsatellite instability
  • Immunohistochemical staining for mismatch repair genes

Merkel Cell Carcinoma

Merkel cell carcinoma (MCC) was originally described by Toker in 1972 as trabecular carcinoma of the skin. Other names for this malignancy include Toker tumor, primary small cell carcinoma of the skin, primary cutaneous neuroendocrine tumor, and malignant trichodiscoma (NCI, 2015). MCC is an aggressive neuroendocrine carcinoma arising in the dermo-epidermal junction.  It was initially thought to be a sweat gland tumor until electron microscopic studies revealed cytoplasmic secretory granules in tumor cells (Munde, 2013). In Surveillance, Epidemiology and End Results Program data from 1986 to 2001, the age-adjusted United States annual incidence of MCC tripled from 0.15 to 0.44 per 100,000, an increase of 8.08% per year.  This rate of increase is faster than any other skin cancer including melanoma and the reason for it is not known (NCI, 2015).

Etiology

The etiology of MCC is not fully understood, but in 2008, a novel polyomavirus (Merkel cell polyoma virus, MCPyV) was first reported in MCC tumor specimens. High levels of viral DNA and clonal integration of the virus in MCC tumors have also been reported. It has been suggested that there may be two independent pathways for the development of MCC: one driven by the presence of MCPyV and the other driven primarily by sun damage (Saini, 2015; Tothill, 2015).

Presentation

MCC lesions are blue or red, firm, non-tender, solitary, dome-shaped nodules.

Occasional plaque-like or subcutaneous masses may also be observed.  Lesions are typically <2 cm, but they may reach 20 cm in size. MCC occurs most frequently in sun-exposed areas of skin, particularly the head and neck, followed by the extremities, and then the trunk with >25% of cases on the face (NCI, 2015). MCC can infiltrate locally via dermal lymphatics, resulting in multiple satellite lesions. Because of its nonspecific clinical appearance, MCC is rarely suspected prior to biopsy (NCI, 2015).

Histopathology/Immunocytochemistry

Histopathologically, monomorphic dermal and/or subcutaneous nodes are found consisting of round or oval medium sized cells with a vesicular nucleus and sparse cytoplasm. The neoplastic cells of MCC express cytokeratin (CK) 20 with a dot-like perinuclear accentuation. In addition, pan-CK, neuroendocrine markers (e.g., chromogranin A and synaptophysin), neurofilament proteins, CD56, CD57, Bcl-2, terminal deoxynucleotidyl transferase (TdT), and PAX-5 are immunohistochemically positive. CM2B4, an antibody against MCPyV is also positive in most tumors (Fried, 2014). Expression of p63 has been observed in some of the cases of MCC and has been associated with a poorer prognosis (Asioli, 2011).  It has also been shown that Ki-67 staining predicts poor outcomes in patients with MCC (Vujic, 2015). In contrast, overall survival is higher in patients with Bcl-2-positive tumors vs those with negative tumors (Sahi, 2012)

Sentinel Lymph Node Biopsy (SLNB)

Sentinel lymph node positivity is strongly predictive of high short-term risk for recurrence or metastasis in patients with MCC. A study carried out about 15 years ago indicated that therapeutic lymph node dissection appears effective in preventing short-term regional nodal recurrence and aggressive adjuvant treatment should be considered for patients with positive sentinel lymph nodes (Mehrany, 2002).  A more recent study that included 153 patients with localized MCC indicated that SLNB identifies occult nodal metastases in 29% of patients with localized MCC. Predictors of SLNB positivity are tumor size and presence of lymphovascular invasion (Fields, 2011).  Most recently, a record review for 161 patients with MCC treated at a single institution indicated that SLNB identified micrometastases in 33% of 27 early-stage patients. Recurrence developed in 56% of SLNB-positive vs 39% of SLNB-negative patients (Santamaria-Barria, 2013).

Immunohistochemical assessment of SLNBs from 10 patients with MCC indicated that all micrometastatic foci stained strongly for CK-20.  The authors of this study noted examination of hematoxylin and eosin (H&E) sections alone is insufficient for excluding micrometastatic MCC in sentinel lymph nodes and that staining for CK-20 has high sensitivity and specificity (Su, 2002).

Treatment

Multidisciplinary treatment is essential to deliver optimal care to patients with MCC. Surgery involves a wide local excision with or without adjuvant therapy depending on the size of the primary lesion and stage of disease. There is controversy regarding the ideal margin width, and the National Comprehensive Cancer Network guidelines recommend 1–2 cm margins when feasible (NCCN, 2016). Mohs micrographic surgery has been employed as an alternative to wide local excision. Among the benefits of this approach are tissue conservation and identification of tumors that would otherwise require extremely wide excision margins (Boyer, 2002). Nevertheless, surgical resection of MCC with negative margins is the preferred primary modality of therapy when possible (Saini, 2015).

Radiation therapy can be considered for primary therapy in patients who are not surgical candidates. Postsurgical adjuvant radiation is often indicated in the treatment of MCC and is shown to improve outcomes (Saini, 2015).  However, data are conflicting as to whether there is any survival benefit from adjuvant primary site or regional nodal irradiation, partly due to the lack of prospective clinical trials (Prewett, 2015).  Chemotherapy is currently used in advanced stage MCC and as palliative therapy. There is no standard choice of chemotherapeutic agent (Saini, 2015).

Recent work also suggests that immunotherapy targeting the programmed cell death receptor 1/programmed cell death ligand 1 (PD-1/PD-L1) checkpoint holds great promise in treating advanced MCC and may provide durable responses in a portion of patients (Cassler, 2016). First-line therapy with pembrolizumab in 26 patients with advanced MCC was associated with an objective response rate of 56%. Responses were observed in patients with virus-positive and –negative tumors (Nghiem, 2016).

A treatment approach for patients with MCC:

  • Wide local excision (2 cm margins) or Mohs surgery
  • Sentinel lymph node biopsy with anti-CK20 antibody if H&E eosin is negative
  • For positive node:
    • Therapeutic node dissection
    • Adjuvant radiation and/or chemotherapy
  • Consider immunotherapy in patients with advanced disease

References

Asioli S, Righi A, de Biase D, et al. Expression of p63 is the sole independent marker of aggressiveness in localised (stage I-II) Merkel cell carcinomas. Mod Pathol. 2011;24:1451-1461.

Bhaijee F, Brown AS. Muir-Torre syndrome. Arch Pathol Lab Med. 2014;138:1685-1689.

Bolm I, Babaryka G, Moergel M, Al-Nawas B, Kämmerer PW. Multifocal metastasizing extra-ocular facial sebaceous carcinoma as diagnostic challenge: case report and systematic review. J Maxillofac Oral Surg. 2015;14 (Suppl 1):331-337.

Boyer JD, Zitelli JA, Brodland DG, D’Angelo G. Local control of primary Merkel cell carcinoma: review of 45 cases treated with Mohs micrographic surgery with and without adjuvant radiation. J Am Acad Dermatol. 2002;47:885-892.

Cassler NM, Merrill D, Bichakjian CK, Brownell I. Merkel Cell Carcinoma Therapeutic Update. Curr Treat Options Oncol. 2016;17:36.

Eisen DB, Michael DJ. Sebaceous lesions and their associated syndromes: part I J Am Acad Dermatol. 2009;61:549-560.

Fields RC, Busam KJ, Chou JF, et al. Recurrence and survival in patients undergoing sentinel lymph node biopsy for Merkel cell carcinoma: analysis of 153 patients from a single institution. Ann Surg Oncol. 2011;18:2529-2537.

Fried I, Cerroni L. Merkel cell carcinoma. Pathologe. 2014;35:467-75.

John AM, Schwartz RA. Muir-Torre syndrome (MTS): An update and approach to diagnosis and management. J Am Acad Dermatol. 2016;74:558-566.

Kyllo RL, Brady KL, Hurst EA. Sebaceous carcinoma: review of the literature. Dermatol Surg. 2015;41:1-15.

Mathur SK, Singh S, Rajni Y, Amrita R, Rajeev S. Extraocular sebaceous carcinoma – a rare tumour at a rare site. Egypt Dermatol Online J. 2010;6:14.

Mehrany K, Otley CC, Weenig RH, Phillips PK, Roenigk RK, Nguyen TH. A meta-analysis of the prognostic significance of sentinel lymph node status in Merkel cell carcinoma. Dermatol Surg. 2002;28:113-117.

Munde PB, Khandekar SP, Dive AM, Sharma A. Pathophysiology of Merkel cell. J Oral Maxillofac Pathol. 2013;17:408-412.

Natarajan K, Rai R, Pillai SB. Extra ocular sebaceous carcinoma: a rare case report. Indian Dermatol Online J. 2011;2:91-93.

National Comprehensive Cancer Network. Merkel Cell Carcinoma. Version I. 2016. Available at: https://www.nccn.org/professionals/physician_gls/pdf/mcc.pdf.

National Cancer Institute. PDQ Adult Treatment Editorial Board. Merkel Cell Carcinoma Treatment (PDQ®): Health Professional Version. 2015 Apr 9. PDQ Cancer Information Summaries [Internet]. Bethesda (MD): National Cancer Institute (US); 2002-. Available at: http://www.ncbi.nlm.nih.gov/books/NBK65713/

Nghiem PT, Bhatia S, Lipson EJ, et al. PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma. N Engl J Med. 2016;374:2542-2552.

Prewett SL, Ajithkumar T. Merkel Cell Carcinoma: Current Management and Controversies. Clin Oncol (R Coll Radiol). 2015;27:436-444.

Sahi H, Koljonen V, Kavola H, et al. Bcl-2 expression indicates better prognosis of Merkel cell carcinoma regardless of the presence of Merkel cell polyomavirus. Virchows Arch. 2012;461:553-559.

Saini AT, Miles BA. Merkel cell carcinoma of the head and neck: pathogenesis, current and emerging treatment options. Onco Targets Ther. 2015;8:2157-2167.

Santamaria-Barria JA, Boland GM, Yeap BY, Nardi V, Dias-Santagata D, Cusack JC Jr. Merkel cell carcinoma: 30-year experience from a single institution. Ann Surg Oncol. 2013;20:1365-1373.

Tothill R, Estall V, Rischin D. Merkel cell carcinoma: emerging biology, current approaches, and future directions. Am Soc Clin Oncol Educ Book. 2015:e519-526.

Vujic I, Marker M, Posch C, et al. Merkel cell carcinoma: mitoses, expression of Ki-67 and bcl-2 correlate with disease progression. J Eur Acad Dermatol Venereol. 2015;29:542-548.

Wali UK, Al-Mujaini A. Sebaceous gland carcinoma of the eyelid. Oman J Ophthalmol. 2010;3:117-121.

Wu W. Dermatologic manifestations of sebaceous carcinoma. Medscape. 2016. http://reference.medscape.com/article/1101433-overview.

Recognizing Unusual Tumors Part 2: Disruptive Technologies for Skin Cancer: Electronic Brachytherapy and Superficial Radiation

Hayes B. Gladstone

As noted in previous sections, a wide range of treatment modalities are available for patients with basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC).  Surgical options include curettage with electrodessication, Mohs micrographic surgery, and surgical excision; and they provide high control rates and generally satisfactory cosmetic results. However, some patients are not suitable candidates for surgery and some cases of non-melanoma skin cancer (NMSC) may not be optimally treated with surgery due to the potential for disfigurement.

Radiation Therapy

Radiation therapy, including external beam and brachytherapy techniques, has been used as primary and post-surgical adjuvant therapy for NMSC and results from published studies have indicated local control ranging from 84-97% with good tolerability (Khan, 2014).

Electronic Brachytherapy

Electronic brachytherapy (EBT) is the administration of high dose rate brachytherapy without the use of a radioactive isotope and with minimal shielding requirements due to the low energies utilized with this system.  This novel approach has been demonstrated to be effective in a large series of 187 patients with 277 NMSC lesions.  At a mean follow-up of 13 months (range = 1-51 months) there were no recurrences. The most frequent acute effects were rash in 90 (44.1%), pruritus in 9 (4.4%) and hyperpigmentation in 4 (2.0%) of 204 lesions evaluated at 1 month after treatment. The most frequent late effects were hypopigmentation in 17 (10.1%) and alopecia in 4 (2.4%) of 168 lesions evaluated at 1 or more years after treatment. Cosmesis at 3 years was excellent for 25 (89.3%) and good for 3 (10.7%) of 28 evaluable lesions; and at 4 years, was excellent for all 6 (100%) evaluable lesions Bhatnagar, 2014).

How would EBT fit into your practice?

  • Personnel:
    • Radiation oncologist
    • Radiation therapist
    • Physicist
  • Treatment:
    • Patient comes into room; portable shield (lead walls not required); machine calibrated and dose parameters set
    • Patient treated
    • Visit takes about 15 minutes twice per week for 8-12 treatments
    • Currently, can be performed in office or at a center

Superficial Radiation: a Different Model

Superficial x-ray therapy (SXRT) has been used by dermatologists for many years and it differs from modern electron beam radiotherapy in that light is the energy source rather than a charged particle. The beam in SXRT is very focused with less collateral tissue damage than EBRT; and the treatment duration is 90 seconds. A retrospective analysis performed on 1715 histologically confirmed primary cutaneous BCC and SCC 2000 and 2010 indicated cumulative recurrence rates for all tumors at 2 and 5 years of 1.9% and 5.0%, respectively.  The recurrence rates for BCC at these evaluations were 2% and 4.2% respectively; and those for SCC were 1.8% and 5.8% (Cognetta, 2012). This approach to treatment for NMSC is appropriate for patients with larger tumors in very cosmetic sensitive areas, those receiving anticoagulants, frail/elderly patients who may not tolerate surgery, and those who refuse surgical intervention.

Dermatologists should be leaders in the use of radiation therapy for the treatment of NMSC.  How do we get there?

  • Develop a method where dermatologists can independently perform EBT and SXRT:
    • Dermatologists are skin cancer experts
    • Dermatologists have historically performed external beam radiotherapy for skin conditions
    • Some dermatologists are currently performing EBT
  • There is a Task Force of Conference of Radiation Control Program Directors:
    • Dermatology is represented
    • Develop guidelines and recommend training for dermatologists in either an independent or hybrid system

 

If we aren’t proactive in advances in skin cancer treatment, then other
specialties will and patients will look elsewhere

 

References

Bhatnagar A. Electronic brachytherapy for the treatment of nonmelanoma skin cancer: results up to 4 years. Int J Radiation Oncol. 2014;90:S756.

Cognetta AB, Howard BM, Heaton HP, Stoddard ER, Hong HG, Green WH. Superficial x-ray in the treatment of basal and squamous cell carcinomas: a viable option in select patients. J Am Acad Dermatol. 2012;67:1235-1241.

Khan L, Breen D, Zhang L, et al. Predictors of recurrence after radiotherapy for non-melanoma skin cancer. Curr Oncol. 2014;21:e326-329.

 

Recognizing Unusual Tumors Part 1: Defining and Managing High-risk Basal Cell and Cutaneous Squamous Cell Carcinoma

Dr. Suneel Chilukuri and Dr. Neil A. Swanson

Basal Cell Carcinoma

Despite the fact that treatment for basal cell carcinoma (BCC) is curative in the vast majority of cases, some patients are at high risk of recurrence and, in a few patients, lesions can progress to a point where local therapy is not possible and the prognosis is quite poor (Puig, 2015).

Characteristics of High-risk Disease

Treatment decisions in patients with BCC are usually made on the basis of estimated risk for recurrence. Aggressive, infiltrating tumors are frequently ulcerated and have ill-defined margins; ulcerated BCC is usually larger than non-ulcerated tumors and may be locally destructive. Risk associated with tumor size varies with location and is defined as >6 mm for the mask area, >1 cm for the cheek, forehead, scalp, and neck, and >2 cm in other body areas. Histological subtype should also be considered in assessing risk for relapse. Morpheaform, sclerosing, infiltrating, desmoplastic, micronodular, basosquamous, keratotic, and metatypical subtypes are associated with higher risk vs superficial and the nodular forms of BCC. Perineural invasion is also associated with a higher risk of relapse; but vascular invasion does not appear influence long-term outcomes.  Importantly, more than 30% of BCCs have mixed pathology, combining less and more aggressive subtypes (e.g., nodular BCC with areas of infiltrating BCC) (Marzuka, 2015; Puig, 2015; Proceddu, 2015).

There is no agreement on the prognostic significance of other factors, such as a previous history of radiotherapy, in patients with BCC.

Squamous Cell Carcinoma

Cutaneous squamous cell carcinoma (cSCC) represents 20% of all non-melanoma skin cancer, and has the ability to metastasize to any organ in the body. It is estimated that cSCC is diagnosed at a rate of 15-35 per 100,000 people and this is expected to increase 2-4 % per year (Burton, 2016).

Risk and Staging cSCC

Although most sSCC are easily cured, there is a high-risk subset with an increased risk of metastasis and death (Karia, 2014). Factors believed to be associated with higher risk cSCC include location on the ear, lip, or genitalia; poorly differentiated, acantholytic desmoplastic, or adenoid squamous histology; perineural invasion; and clinical features that include rapid growth, pain, paresthesias, invasion to bone, and cranial nerve involvement.

Despite identification of individual factors associated with higher risk cSCC, there is no consensus definition of high-risk disease and there is limited published information on best approaches to treatment.  At present, these high-risk patients are typically managed with a multidisciplinary approach decided on a case-by-case based on tumor board discussions. Several clinical and histologic risk factors are associated with increased risk of recurrence, metastasis, and death in patients with cSCC, but high-risk cSCC has not been consistently defined, nor has associated prognosis been estimated (Karia, 2014).  There are multiple staging systems for SCC, including those from the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) and a more recently developed system developed at the Brigham and Women’s Hospital (BWH) (Jambusaria-Pahlajani, 2013; Karia, 2014). A comparison of these systems indicated that current UICC and AJCC tumor (T) staging fail to identify high-risk sSCC because the majority of poor outcomes occur in low T stages and heterogeneous tumors with diverse risk profiles. Conversely, the BWH system has four statistically distinct stages and enhanced ability to appropriately upstage high-risk tumors from low to high stages (Karia, 2014).

What to do in defining risk in your patients with BCC or cSCC:

  • Consider clinical presentation and histology
  • Be aware of a new validated approach to staging patients with SCC.

Interventions in cSCC and BCC

Retinoids for Prevention Treatment of Skin Cancer

Systemic retinoids have been shown to be effective for the prevention of skin cancer (Tilley, 2015); and initiation of prophylaxis is indicated to prevent morbidity from multiple primary tumors and to decrease the risk of death from high-risk tumors.  Candidates for retinoid administration include patients with xeroderma pigmentosum, basal cell nevus syndrome, or severe sun damage; and patients who are immunosuppressed for solid organ transplantation or with chronic lymphocytic leukemia (Reilly, 2004).

Delivering retinoids for skin cancer prevention – practical considerations:

  • Start Low: 10 mg/day
  • Gradually increase the dose to 20-30 mg/day
  • Titrate the dose to prevent/manage side effects (chelitis, skin peeling, scalp alopecia, hyperotosis, hyperlipidemia)
  • Understand that this is potentially life-long treatment and educate your patient
  • Drug holidays may help to treat transient side effects
  • Try to decrease immunosuppression in conjunction with this treatment
  • Be aware of risk for elevations in triglycerides and hepatic transaminases

Smoothened Inhibitors in the Treatment of BCC and Risk for cSCC

The smoothened inhibitors, vismodegib and sonidegib, have been shown to be highly effective for the treatment of patients with advanced BCC (e.g., Sekulic, 2012; Migden, 2015); and many new agents from this class (e.g., saridegib, CUR61414, BMS-833923, LEQ506, PF-04449913, TAK-441) are in development for the treatment of BCC and other cancers. However, extensive use of vismodegib in patients with BCC has been associated with increased risk for the development of cSCC.  Case reports have described emergence of new-onset keratoacanthomas and cSCCs in patients with advanced BCCs during vismodegib therapy (Aasi, 2013; Orouji, 2014); and results from a recent case-control study carried out at the Stanford Medical Center which included 180 patients indicated that treatment of BCC with vismodegib was associated with a >6-fold increase in the risk for cSCC (Mohan, 2016).  The mechanism(s) underlying this phenomenon are not understood, but it has been suggested that smoothened inhibition may inadvertently activate the RAS/MAPK pathway, thereby promoting tumorigenesis (Zhao, 2015).

What to remember and what to do:

  • BCC with apparent resistance to vismodegib may actually be newly developed cSCC
  • Perform new biopsies whenever in doubt about new and/or progressive skin lesions in patients receiving hedgehog pathway inhibitors
  • Patients with advanced BCCs who are considering vismodegib should be advised that this treatment seems to increase the risk for subsequent cSCC

References

Aasi S, Silkiss R, Tang JY, et al. New onset of keratoacanthomas after vismodegib treatment for locally advanced basal cell carcinomas: a report of 2 cases. JAMA Dermatol. 2013;149:242-243.

Burton KA, Ashack KA, Khachemoune A. Cutaneous squamous cell carcinoma: a review of high-risk and metastatic disease. Am J Clin Dermatol. 2016 Jun 29. [Epub ahead of print].

Jambusaria-Pahlajani A, Kanetsky PA, Karia PS, et al. Evaluation of AJCC tumor staging for cutaneous squamous cell carcinoma and a proposed alternative tumor staging system. JAMA Dermatol. 2013;149:402-410.

Karia PS, Jambusaria-Pahlajani A, Harrington DP, Murphy GF, Qureshi AA, Schmults CD. Evaluation of American Joint Committee on Cancer, International Union Against Cancer, and Brigham and Women’s Hospital tumor staging for cutaneous squamous cell carcinoma. J Clin Oncol. 2014;32:327-334.

Marzuka AG, Book SE. Basal cell carcinoma: pathogenesis, epidemiology, clinical features, diagnosis, histopathology, and management. Yale J Biol Med. 2015;88:167-179.

Migden MR, Guminski A, Gutzmer R, et al. Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised, double-blind phase 2 trial. Lancet Oncol. 2015;16:716-728.

Mohan SV, Chang J, Li S, Henry AS, Wood DJ, Chang AL. Increased risk of cutaneous squamous cell carcinoma after vismodegib therapy for basal cell carcinoma. JAMA Dermatol. 2016;152:527-532.

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 carcinomas. Br J Dermatol. 2014;171:431-433.

Porceddu SV. Prognostic factors and the role of adjuvant radiation therapy in non-melanoma skin cancer of the head and neck. Am Soc Clin Oncol Educ Book. 2015:e513-518.

Puig S, Berrocal A. Management of high-risk and advanced basal cell carcinoma. Clin Transl Oncol. 2015;17:497-503.

Reilly P, DiGiovanna JJ. Retinoid chemoprevention in high-risk skin cancer patients. Dermatol Nurs. 2004;16:117-120, 123-126; quiz 127.

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.

Zhao X, Ponomaryov T, Ornell KJ, et al. RAS/MAPK activation drives resistance to Smo inhibition, metastasis, and tumor evolution in Shh pathway-dependent tumors. Cancer Res. 2015;75:3623-3635.