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.

Infectious Disease 2016: Chikungunya

Dr. Sheila Fallon-Friedlander

Dr. Sheila Fallon-Friedlander

Dr. Sheila Fallon-Friedlander

Chikungunya: Dengue-lite?

Chikungunya is an arthropod-borne virus (arbovirus) endemic to West Africa that causes acute febrile polyarthralgia and arthritis. The name chikungunya is derived from a local language of Tanzania meaning “that which bends up” or “stooped walk” because of the incapacitating arthralgia caused by the disease. Chikungunya in neonates is a very rare entity and a diagnostic challenge. Newborns with this infection generally require admission to pediatric intensive care, and related support, due to severe clinical manifestations, which include respiratory distress, sepsis, necrotizing enterocolitis, meningoencephalitis, myocarditis, edema, bullous dermatitis and pericarditis. The case fatality rate for congenital Chikungunya virus infection has been reported to be >30%.

In the acute stage, diagnosis is possible with reverse transcription polymerase chain reaction or serology. Anti-Chikungunya virus IgM antibodies are detectable after an average of 2 days (range = 1-12 days) by enzyme-linked immunosorbent assay and remains positive for several weeks to 3 months.

Infectious Disease 2016: MRSA

Dr. Theodore Rosen

Dr. Theodore Rosen

Dr. Theodore Rosen

Smoking and treatment of methicillin-resistant Staphylococcus aureus (MRSA): apparently cigarette smoke isn’t deadly for all living creatures

Results from a recent study have shown that cigarette smoke may make MRSA more virualent. Researchers at the University of California in San Diego infected macrophages with MRSA that were grown normally or with exposure to cigarette smoke extract. While macrophages were equally able to take up the two bacterial populations, smoke-exposed MRSA were more resistant to killing by reactive oxygen species (i.e., the macrophage oxygen burst). In addition, the smoke-exposed MRSA were more resistant to killing by naturally produced antimicrobial peptides and more adherent to keratonocytes. Additional in vivo experiments in mice showed pneumonia resulting from that smoke-exposed MRSA pneumonia was associated with higher mortality (40% vs 10%) and increased bacterial burden compared to control MRSA-infected mice

Dr. Aditya K Gupta

Infectious Disease 2016: Onychomycosis

Dr. Aditya K Gupta

Dr. Aditya K Gupta

Dr. Aditya K Gupta

Onychomycosis is an infection of the nail plate that is prevalent among the ageing population. Onychomycosis is difficult to treat with low initial cure rates, high rates of relapse, and reinfection. Changing demographic characteristics, such as the relative aging of the population, the increasing prevalence of diabetes and peripheral vascular disease, widespread iatrogenic immunosuppression, and changes in lifestyle (e.g., earlier and greater participation in sports), are likely to lead to an increased prevalence of onychomycosis in both adults and children. Mixed infections of dermatophytes and nondermatophyte molds are increasing in patients with onychomycosis. One recent case series indicated the presence of mixed infections in 41% of patients.

There have been a number of important advances in the treatment of onychomycosis.

New topical agents approved in the US for the treatment of onychomycosis are solutions with lower viscosity and increased nail penetration characteristics. These agents penetrate through the transungual route and via the space between the nail plate and the nail bed. The subungual route partially circumvents the thickness of the nail plate. Laser therapy has been promoted as one of the most promising device-based therapies for onychomycosis. Clinical trial and anecdotal results to date have varied greatly and the specific mechanism of action for this intervention has not been well-elucidated. Overall, this therapy provides cosmetic improvement, but is does not appear to treat the underlying disease. Combining nail drilling with antimycotic treatment has recently been shown to be effective for the treatment of onychomycosis. Treatment with holes plus topical terbinafine produces significantly greater improvement in toenails’ appearance and higher mycological cure rates compared to treating the dorsal aspect of the nail plate with topical terbinafine alone. Overall, early treatment is the path to cure in patients with onychomycosis. The chance of success is better when you treat early.

Recurrence (relapse or re-infection) occurs in 10% to 53% of patients of patients with onychomycosis. However, data on recurrence is limited by the fact that clinical studies have followed patients beyond 12 months. Although a number of factors have been suggested to play a role in recurrence, only the co-existence of diabetes has been shown to have a significant impact. A small study showed that amorolfine prophylaxis may delay recurrence, but prophylaxis may need to be continued for up to 3 years for optimal effect. Treating tinea pedis and any immediate family members may also decrease risk for recurrence; and other preventative strategies include avoiding communal areas where infection can spread and decontaminating footwear.

Dr. Aditya K Gupta

Infectious Disease 2016: HIV/AIDS

Dr. Aditya K Gupta

Dr. Mark Jacobson

Dr. Mark Jacobson

Antiretroviral therapy (ART) for the treatment of HIV infection has improved steadily since the advent of potent combination therapy in 1996 and it has transformed HIV infection into a manageable chronic condition. However, fewer than one-third of HIV-infected individuals in the United States have suppressed viral loads, mostly due to undiagnosed HIV infection and failure to link or retain diagnosed patients in care.

The period of acute HIV infection is particularly problematic with respect to transmission of the disease. Acute HIV infection may have no signs at all or can present itself as a nonspecific viral illness within 2-6 weeks of infection. This is also the most infectious phase of the disease and is often undiagnosed. After exposure to HIV, it can take as many as 3-4 weeks for antibodies to be detectable. Advanced fourth-generation HIV tests (also known as “combo tests”) have been developed to detect HIV during the acute window period before antibody is detectable and during established HIV.

There has been a progressive shift toward earlier initiation of ART in patients with HIV infection. It is well recognized that the key to successful ART in maintaining viral suppression is adherence to the prescribed regimen. Evidence indicates that drug resistance and consequent loss of viral suppression occurs more frequently in individuals who initiate therapy later in the course of infection than in those who initiate ART earlier. Initiation of ART is now recommended for all HIV-infected individuals, regardless of CD4 cell count, to reduce the morbidity and mortality associated with HIV infection and to prevent HIV transmission. More than 25 antiretroviral (ARV) drugs in 6 mechanistic classes are approved for treatment of HIV infection. These include nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), a fusion inhibitor (FI), a CCR5 antagonist, and integrase strand transfer inhibitors (INSTIs). In addition, two drugs (pharmacokinetic [PK] enhancers or boosters) are used to improve the PK profiles of some ARV drugs. The initial ARV regimen for a treatment-naive patient generally consists of two NRTIs, usually abacavir plus lamivudine or tenofovir disoproxil fumarate plus emtricitabine, plus a drug from one of three drug classes: an INSTI, an NNRTI, or a PK-enhanced PI.

Pre-exposure prophylaxis (PrEP) should be considered for individuals who are HIV-negative and at very high risk for HIV infection. When taken every day, PrEP with the combination of tenofovir and emtricitabine has been shown to reduce the risk of HIV infection in people who are at high risk by >90%. A recent study also suggests that “on demand” PrEP is also effective; in this scenario, a drug dose is taken three times: 2-24 hours before anticipated unprotected sex, and then at 24 and 48 hours afterwards. This “on demand” regimen reduced HIV acquisition by nearly 90%.

Dr. Sheila Fallon-Friedlander

Infectious Disease 2016: Pediatric Infected Atopic Dermatitis

Dr. Sheila Fallon-Friedlander

Dr. Sheila Fallon-Friedlander

Dr. Sheila Fallon-Friedlander

A major aggravating factor associated with atopic dermatitis is the presence of microorganisms on the patient’s skin surface. S aureus and Streptococcus pyogenes can exacerbate chronic skin inflammation. S aureus can colonize the skin or the respiratory tract in healthy patients and become pathogenic under conditions such as skin barrier breakdown and diminished immunity. Atopic dermatitis patients are highly susceptible to staphylococcal skin infections. Studies have shown that between 80% and 100% of patients with atopic dermatitis have nasal or skin colonization by S aureus vs 5% to 30% in individuals without atopic dermatitis. First and second generation cephalosporins are suitable for treatment of patients infected with methicillin-susceptible S aureus and MRSA is best treated with clindamycin and trimethoprim/sulfamethoxazole. Antimicrobial therapy should be tailored on the basis of local resistance patterns. Streptococcal infections may be treated with clindamycin and cephalexin.

Eczema herpeticum, also known as a form of Kaposi varicelliform eruption caused by viral infection, usually with the herpes simplex virus (HSV), is an extensive cutaneous vesicular eruption that arises from pre-existing skin disease, usually atopic dermatitis. Children with atopic dermatitis have a higher risk of developing eczema herpeticum, in which HSV type 1 is the most common pathogen. Patients with this condition may be treated with acyclovir.

Eczema cocksackium may also occur in patients with atopic dermatitis. In one case series, 51% of patients diagnosed with Eczema cocksackium had a history of atopic dermatitis. This enterovirus-associated exanthem is characterized by fever, stomatitis of the oral mucosa, and a vesicular rash affecting the hands, feet, and occasionally the buttocks. About one-third of infants <1 year of age may also present with bullae. Symptoms are strikingly similar to eczema herpeticum caused by HSV type 1. Patients with eczema cocksackium have been successfully treated with wet wrap therapy and low-dose corticosteroids. Bleach baths are also effective for both killing of pathogens and decreasing inflammation.

 

Infectious Disease 2016: Zika

Dr. Theodore Rosen

Dr. Theodore Rosen

Dr. Theodore Rosen

Zika virus: what is relevant for dermatologists?

Zika virus disease is a disease caused by Zika virus that is spread to people primarily through the bite of an infected Aedes species mosquito. The most common symptoms of Zika are fever, rash, joint and muscle pain, headache and conjunctivitis. The illness is usually mild with symptoms lasting for several days to a week after being bitten by an infected mosquito. Once a person has been infected, he or she is likely to be protected from future infections. The virus was first discovered in 1947 and is named after the Zika forest in Uganda. In 1952, the first human cases of Zika were detected and since then, outbreaks of Zika have been reported in tropical Africa, Southeast Asia, and the Pacific Islands. A stream of recent case report studies as well as a small number of case control and cohort studies initially suggested an association between Zika and both microcephaly and Guillain-Barré syndrome.

In May 2015, the Pan American Health Organization issued an alert regarding the first confirmed Zika virus infection in Brazil and on February 1, 2016, the World Health Organization declared Zika virus a public health emergency of international concern. In April, 2016, the CDC concluded that Zika virus is, indeed, a teratogen, associated with microcephaly, intracranial calcification in the newborn, and other neonatal brain abnormalities. Cases have now been widely reported throughout Central and South America and the Caribbean. Puerto Rico has been especially hard hit, with nearly 700 confirmed cases to date, including 8 cases suspected of being transmitted sexually. Of the cases confirmed in the continental United States, all have been acquired during travel to regions where mosquito-borne Zika virus infection is prevalent. However, some projections suggest that competent mosquito vectors within the United States will acquire the virus and that s significant Zika epidemic could emerge this summer. For this reason, the FDA just approved for wide distribution a Quest Diagnostics Zika blood test based on RNA detection. Heretofore, the only approved tests (IgM-based ELISA and RT-PCR) were only offered by the CDC and CDC-approved regional laboratories.

The rash associated with Zika virus is maculopapular, either morbilliform or scarlatiniform. It starts on the face on the first day of illness and spreads all over the body. It begins to fade within 2-3 days and is gone completely within a week.

Dr. Sheila Fallon-Friedlander

Infectious Disease 2016: Pemphigus Syphiliticus

Dr. Sheila Fallon-Friedlander

Dr. Sheila Fallon-Friedlander

Dr. Sheila Fallon-Friedlander

Persistent sniffles and a rash? Pemphigus syphiliticus is a possible answer.

Congenital syphilis is increasing and it is important to be aware of symptoms in neonates. Mucosal features may include rhinitis that develops at 1 week and worsens. Mucus is initially clear then progressively purulent and blood stained. Mucous ‘patches’ are seen on palate and lips along with perioral and perianal condylomata. Cutaneous features include maculopapular eruption over buttocks and lower torso, palms, and soles; and bullous eruptions that mimic staphylococcal infection.