Fellow-in-Training Perspectives

Each annual Fellow-in-Training Board Observer also serves as a member of the ACMS Newsletter Committee in order to participate in discussion of, and provide valuable perspective on, College activities and news for other Fellows-in-Training. Below are their contributions.

Spring 2022: Precision Medicine in Cutaneous Oncology
Winter 2021: Through the Confocal Lens: Peering into the Future of Mohs Surgery
Spring 2021: Efficacy in Mohs surgery is dependent on slide preparation and quality
Winter 2020: Pursuing Progress in a Pandemic
Summer 2020: Non-Melanoma Skin Cancer Risk Factors, Cellular Pathways, and Immunosuppression Board Review
Spring 2020: Immunochemistry for Mohs
Winter 2019: Light and Shadows: A Shared Focus of Artists and Mohs Surgeons
Summer 2019: Complexities Surrounding Use of Streaming Music Services in the Office Setting
Spring 2019: Patient-Reported Outcome Measures
Winter 2018: Use of Digital Patient Photography for Surgical Site Identification
Summer 2018: A Roadmap to Navigate the Year of Fellowship Training
Spring 2018: What Fellows-in-training Should Know About the Transition from Trainee to Independent Practitioner
Winter 2017: Staging of Melanoma and SCC in the AJCC 8th Edition Cancer Staging Manual
Summer 2017: Tools and Resources for Continuing Education
Spring 2017: Words of Wisdom: Advice from Successful Mohs Surgeons
Winter 2016: Did You Know? ACMS Resources Available to Fellows-in-Training

 

Spring 2022

Precision Medicine in Cutaneous Oncology

By Kalee Shah, MD • 2021-22 FIT Board Observer

The Human Genome Project, completed in 2003, was a massive international effort to sequence and map the human genome and create a genetic blueprint of the human species. This endeavor has had an immense impact on human health and medical research, from the identification of the genetic basis of many diseases, to the development of targeted therapies, and the advancement of high-throughput sequencing technology that made it faster and cheaper to obtain genetic information. Precision medicine has specifically revolutionized cancer therapeutics through the advent of targeted therapies. In the last 10 years, we have seen major advances in the treatment of advanced skin cancer such as the development of BRAF inhibitors for melanoma, hedgehog pathway inhibitors for basal cell carcinoma, and the tyrosine-kinase inhibitor imatinib for unresectable dermatofibrosarcoma protuberans. 

While we continue to improve our ability to treat patients with tumor-specific therapies, a new area of precision oncology is emerging that may help us better diagnose, risk-stratify, and ultimately, prevent advanced disease. The current paradigm for the evaluation of skin cancer that we use as dermatologists is physical examination, histopathologic evaluation, and clinical/pathological risk stratification. However, these tools may fail to adequately capture cases that go on to develop poor outcomes, as evidenced by the significant number of deaths in patients with T1 melanoma and the low predictive value of staging systems for metastasis in cutaneous squamous cell carcinoma (cSCC). Perhaps genomics can help us segment patients more effectively.

There are two major genomic approaches to supplement diagnostics and prognostication: tumor tissue-based and liquid biopsy-based techniques. The gene expression profile (GEP) test is a tumor tissue-based approach that measures the expression of specific genes that may shed light on prognosis via tumor biology characteristics. GEP tests have been developed for melanoma and cSCC and are currently available for clinical use. The goal of these commercial testing platforms is to stratify patients into high-risk and low-risk cohorts which may impact clinical management including decisions surrounding sentinel lymph node biopsy, adjuvant therapy, and intensity of post-treatment surveillance. Several retrospective and prospective studies have been performed on GEP tests in melanoma and cSCC, however the utility of the currently available tests remains controversial. Routine use is currently not recommended by the National Comprehensive Cancer Network (NCCN) or the Melanoma Prevention Working Group (MPWG) until large prospective studies demonstrate the added clinical value in high-risk patients and the minimal harm in low-risk patients, as well as address the tests' cost-effectiveness.

Liquid biopsy is a non-invasive approach that identifies circulating biomarkers for early cancer detection and therapeutic surveillance. The technology was originally developed to study circulating tumor cells (CTCs) that are released into circulation by the primary tumor and/or metastasis. It has now expanded to include circulating tumor DNA (ctDNA) – small fragments of DNA released from apoptotic tumor cells – microRNA, antibodies, and tumor-derived exosomes. Early data suggests that CTCs and ctDNA can predict response to immunotherapy and targeted therapy in advanced melanoma. In Merkel cell carcinoma, CTCs and anti- MCPyV-antibodies have been correlated to tumor burden, disease outcomes, and response to therapy. The use of liquid biopsy in high-risk cSCC is a significant research interest, though it faces several disease-specific challenges such as high-mutational burden and frequent occurrence of multiple cSCC that may confound results.

It is hard to believe that the human genome was fully sequenced only 20 years ago. We have already seen the ways in which genomics have shaped therapeutics and led to significant advances in patient care. While we may not yet be ready to use these tools in our everyday practice for diagnostics and prognostication, they offer a significant amount of novel information that could help shape the future of our practice if studied in an appropriate and comprehensive manner.

References:

1. National Human Genome Research Institute: https://www.genome.gov/human-genome-project
2. Wang JY, Sarin KY. Dermatology advances into an era of precision medicine. JAMA Dermatol. 2021 Jul 1;157(7):770–2.
3. Geidel G, Heidrich I, Kött J, Schneider SW, Pantel K, Gebhardt C. Emerging precision diagnostics in advanced cutaneous squamous cell carcinoma. NPJ Precis Oncol. 2022 Mar 23;6(1):17.
4. Grossman D, Okwundu N, Bartlett EK, Marchetti MA, Othus M, Coit DG, et al. Prognostic gene expression profiling in cutaneous melanoma: identifying the knowledge gaps and assessing the clinical benefit. JAMA Dermatol. 2020 Sep 1;156(9):1004–11
5. Arron ST, Wysong A, Hall MA, Bailey CN, Covington KR, Kurley SJ, et al. Gene expression profiling for metastatic risk in head and neck cutaneous squamous cell carcinoma. Laryngoscope Investig Otolaryngol. 2022 Feb;7(1):135–44.
6. Boyer M, Cayrefourcq L, Dereure O, Meunier L, Becquart O, Alix-Panabières C. Clinical relevance of liquid biopsy in melanoma and merkel cell carcinoma. Cancers (Basel). 2020 Apr 13;12(4):E960.
7. Fattore L, Ruggiero CF, Liguoro D, Castaldo V, Catizone A, Ciliberto G, et al. The promise of liquid biopsy to predict response to immunotherapy in metastatic melanoma. Front Oncol. 2021 Mar 18;11:645069.

 

 Winter 2021

Through the Confocal Lens: Peering into the Future of Mohs Surgery

By Kalee Shah, MD • 2021-22 FIT Board Observer

Confocal microscopy is a high-resolution imaging technology that is used for non-invasive in vivo and ex vivo visualization of the skin. While traditional histopathology remains the gold standard for diagnosis of skin neoplasms, confocal microscopy has emerged as a helpful adjunct to general dermatologists and dermatologic surgeons in complex clinical scenarios. The following are only a few scenarios in which confocal imaging has the potential to augment and improve current diagnostic and therapeutic management options.

• Pre-biopsy imaging to reduce benign biopsy burden in a patient with dysplastic nevus syndrome
• Surgical margin mapping for ill-defined lentigo maligna on a cosmetically sensitive area
• Surveillance of skin cancers such as basal cell carcinoma and extramammary Paget disease treated with non-invasive therapy

In vivo reflectance confocal microscopy (RCM) was first developed in the 1990s and has been refined over the last 30 years. RCM emits 830-nm monochromatic coherent light onto the skin surface, which is subsequently reflected and captured by a detector. The technology harnesses the refractile indices of cellular structures and organelles to produce a grayscale, en face image of the tissue. By adjusting the objective lens in relation to the skin surface, users can visualize the epidermis, dermo-epidermal junction, and the papillary dermis with high resolution (30X) that is comparable to histopathologic examination. This resolution diminishes at a depth greater than 200 m, therefore visualization of thicker tissue (such as palmoplantar skin) and the deep dermis is not possible. Backscatter from hair (such as on the scalp), hyperkeratosis, and dense pigment may compromise image quality.

There are currently two commercially available and FDA-cleared RCM devices: the wide-probe Vivascope 1500® and the handheld Vivascope 3000® (Caliber Imaging & Diagnostics, Inc). The wide-probe RCM requires fixed contact between the skin and the device achieved through a metal tissue ring that is magnetically coupled to the RCM probe. Only flat surfaces may be imaged with a wide-probe RCM device. The device obtains multiple minute images which are combined to create a mosaic representation up to 8 x 8 mm. Larger lesions require multiple images or a focus on the most clinically suspicious area. In contrast to the wide-probe RCM, the handheld RCM does not require direct fixation. Instead, the handheld probe slides across the surface of the skin which allows for imaging of convex and concave anatomic sites. However, the field of view is limited to 0.75 x 0.75 mm2. The wide-probe RCM is usually used to obtain three mosaic images: suprabasilar epidermis, basilar epidermis/DEJ, and superficial dermis. Image sets from both devices are saved and stored as would be glass slides, and the interpretation formatted into a standardized written report as a pathology report would be.

In 2016, the Centers for Medicare & Medicaid Services defined and valued RCM CPT codes so that imaging services can be submitted to insurance companies for reimbursement commensurate to skin biopsy and pathology services. CPT code 96931 is used when image acquisition, interpretation, and report of a single skin lesion is performed by the same provider. If different providers are acquiring and interpreting images, CPT code 96932 is used for image acquisition and 96933 is used for interpretation and reporting services. Additional skin lesions are reported under codes 96934-96936. For the first skin lesion, the average RVU for image acquisition is 3.57 and for image interpretation and reporting is 1.30. Only services rendered with the wide-probe Vivascope 1500® are covered under these codes as the handheld Vivascope 3000® does not produce mosaic images. Skin biopsies that are performed on the same day after RCM imaging remain a billable service.

Clinical applications for in vivo RCM imaging include diagnosis of benign and malignant neoplasms, biopsy site selection in large or ill-defined clinical lesions, margin mapping to aid in surgical planning, and surveillance for tumor recurrence or persistence following non-invasive treatment. A body of literature has demonstrated the sensitivity and specificity of RCM for BCC, SCC, melanoma, EMPD, and benign keratinocytic and melanocytic neoplasms.

Lesion Type	Sensitivity	Specificity
BCC	92 - 100%	75-93%
SCC	79 - 100%	78 - 100%
Melanoma	82 - 100%	68 - 98%
Lentigo maligna	80 -93%	81 - 89%
Amelanotic or hypomelanotic melanoma	67%	89%
EMPD	75%	100%
All skin cancer types	94%	83%

Ex vivo confocal microscopy (EVCM) is an emerging imaging technique that allows for real-time microscopic analysis of fresh tissue (without rapid freezing or chemical fixation), making it an exciting tool for rapid margin assessment during Mohs surgery. This technology bypasses the time-consuming process of tissue processing, embedding, and sectioning and produces digital images of fresh tissue within minutes. An additional benefit is that the excised tissue can be subsequently processed as frozen or formalin-fixed tissue without compromising the quality of traditional histopathologic evaluation with H&E and immunostains.

The Vivascope 2500® (Caliber Imaging & Diagnostics, Inc) is the only commercially available device for EVCM. It uses two lasers (488 nm and 785 nm) to produce greyscale images similar to in vivo RCM (reflectance mode) or green-fluorescent images (reflectance + fluorescent mode). Freshly excised tissue is briefly submerged in a nuclear contrast agent, most commonly acridine orange. The tissue is then flattened between two glass slides and placed on the microscope stage for imaging. The microscope creates mosaics of en face sections of tissue and can image tissue up to 20 x 20 mm in horizontal dimension and 200 m in depth. Image mosaics can then be digitally “stained” to mimic H&E. The digitally stained EVCM images and typical H&E-stained Mohs frozen sections are remarkably similar, thereby reducing the learning curve for Mohs surgeons to interpret EVCM images (Image 1). Several studies have demonstrated the high sensitivity and specificity for the detection of BCC and SCC on Mohs surgery specimens and additional work is being done to assess the feasibility of EVCM in DFSP, EMPD, nail tumors, and melanocytic tumors.

Other non-invasive imaging technologies in development for use in cutaneous oncology are optical coherence tomography (OCT) and two-photon non-linear microscopy (NLM). OCT is an in vivo imaging device that emits coherent light waves onto tissue and measures the delay and the intensity of the echo. It produces greyscale en face and cross-sectional images of the skin. While the resolution of OCT is less than RCM, it has the capability of imaging the skin to a depth of 2 mm. Current research suggests application for in vivo visualization of keratinocyte carcinoma, as well as melanoma; with highest success when combined with RCM. NLM is being studied for ex-vivo visualization of keratinocyte carcinoma on Mohs margins. NLM uses a laser to excite fluorophores (commonly acridine orange and sulforhodamine 101) in fresh tissue and produces a mosaic image analogous to H&E-stained frozen sections. The appearance of normal skin anatomy, BCC and SCC are similar between NLM and frozen section histology (Image 2) with only slight variation in color hue. The average reported acquisition speed for mosaic images is about 8.3 minutes per cm2 of tissue and expected to improve with instrument redesign.

While further research, device and protocol optimization, and cost reduction is needed for mainstream adoption of non-invasive imaging in clinical practice, these technologies give us an exciting glimpse of the future of our specialty.

Image 1: BCC captured on EVCM (A) compared with traditional Mohs frozen sections (B). Images courtesy of Dr. Manu Jain and Dr. Rajadhyaksha.

Image 2: BCC captured on 2-photon NLM (A and C) compared with traditional Mohs frozen section (B and D). Images courtesy of Dr. Sherrif Ibrahim and Dr. Michael Giacomelli.

References:

1. Shahriari N, Grant-Kels JM, Rabinovitz H, Oliviero M, Scope A. Reflectance confocal microscopy: Principles, basic terminology, clinical indications, limitations, and practical considerations. Journal of the American Academy of Dermatology. 2021;84(1):1-14.
2. Guida S, Arginelli F, Farnetani F, et al. Clinical applications of in vivo and ex vivo confocal microscopy. Applied Sciences. 2021;11(5):1979.
3. Levine A, Markowitz O. In vivo reflectance confocal microscopy. Cutis. 2017;99(6):399-402.
4. Ahlgrimm-Siess V, Laimer M, Rabinovitz HS, et al. Confocal microscopy in skin cancer. Curr Derm Rep. 2018;7(2):105-118.
5. Pezzini C, Kaleci S, Chester J, Farnetani F, Longo C, Pellacani G. Reflectance confocal microscopy diagnostic accuracy for malignant melanoma in different clinical settings: systematic review and meta‐analysis. J Eur Acad Dermatol Venereol. 2020;34(10):2268-2279
6. Bayan C ‐A. Y, Khanna T, Rotemberg V, Samie FH, Zeitouni NC. A review of non‐invasive imaging in extramammary Paget’s disease. J Eur Acad Dermatol Venereol. 2018;32(11):1862-1873.
7. Cinotti E, Perrot JL, Labeille B, Cambazard F, Rubegni P. Ex vivo confocal microscopy: an emerging technique in dermatology. Dermatol Pract Concept. 2018;8(2):109-119.
8. Malvehy J, Pérez‐Anker J, Toll A, et al. Ex vivo confocal microscopy: revolution in fast pathology in dermatology. Br J Dermatol. 2020;183(6):1011-1025.
9. Bini J, Spain J, Nehal K, Hazelwood V, DiMarzio C, Rajadhyaksha M. Confocal mosaicing microscopy of human skin ex vivo: spectral analysis for digital staining to simulate histology-like appearance. J Biomed Opt. 2011;16(7):076008.
10. Peters N, Schubert M, Metzler G, Geppert JP, Moehrle M. Diagnostic accuracy of a new ex vivo confocal laser scanning microscope compared to H&E-stained paraffin slides for micrographic surgery of basal cell carcinoma. J Eur Acad Dermatol Venereol. 2019;33(2):298-304.
11. Mu EW, Lewin JM, Stevenson ML, Meehan SA, Carucci JA, Gareau DS. Use of digitally stained multimodal confocal mosaic images to screen for nonmelanoma skin cancer. JAMA Dermatol. 2016;152(12):1335-1341
12. Giacomelli MG, Faulkner-Jones BE, Cahill LC, Yoshitake T, Do D, Fujimoto JG. Comparison of nonlinear microscopy and frozen section histology for imaging of Mohs surgical margins. Biomed Opt Express. 2019;10(8):4249-4260.
13. Caliber I.D. - Imaging & Diagnostics, Inc. www.caliberid.com

 

Spring 2021

Efficacy in Mohs surgery is dependent on slide preparation and quality

By Harib H. Ezaldein, MD • 2020-21 FIT Board Observer

I have come to appreciate the unique opportunity of access to full-time technicians who share the vision of helping to educate the fellows. Successful Mohs surgery is dependent on frozen tissue slide preparation and quality of tissue interpretation. Therefore, inconsistency in standards for Mohs surgical tissue processing may compromise the practice of Mohs surgery and hence patient care.

At our clinics in fellowship and residency, we had two full-time histotechnicians with a large dedicated laboratory space that included tissue processing equipment and multi-headed microscopes. The benefits of this setup include consistent slide quality, daily feedback to laboratory personnel, and a close familiarity with surgeon preferences.

On days when my fellowship director was out of town, I worked closely with our technicians to learn how to cut tissue and troubleshoot problems in the laboratory. We did research together and developed improvements for immunostaining protocols. Freeze artifacts, missing epidermis, tumor dropout, or inconsistent thickness or staining of the sections all present diagnostic problems and have taught me the importance of troubleshooting my own slides. By overseeing the technicians and developing a long-term collaborative relationship, I am able to learn about the dozens of moving parts that form the histologic part of our Mohs technique. Every slide is inspected together and hence there is an educative dialogue and feedback loop that is critical for fellowship and high-quality Mohs surgery.

Another benefit of full time technicians during fellowship training is guidance regarding CLIA regulations that govern most Mohs laboratories. These regulations are in place to ensure quality slide preparation and documentation, such as a frozen section logs, the peer review process, proper equipment function and quality control. Our technicians have been very helpful in explaining the documentation and daily maintenance necessary. Additionally, histotechnicians are knowledgeable regarding the makes and models of reliable cutting and staining equipment- representing an invaluable perspective when considering the various equipment options that exist. Thus, it is important for all fellowships to provide this educational opportunity for trainees so that when they set up their own laboratory, they have this basic knowledge.

Continuity of feedback and long-term oversight of one’s technicians are effective strategies for achieving success with Mohs surgery. The Mohs College recognizes the importance of maintaining slide quality in their affiliation with the American Society of Mohs Histotechnicians. This relationship fosters unique opportunities to comprehensively train one’s technicians with hand-on learning with updated equipment, in both groups or individually. Our college also contains numerous resources such as a frozen section manual, immunostaining protocols, and access to slide review for the purposes of improvement. Our goal is to preserve the integrity of Mohs surgery and ensure our patients receive the highest quality of care.

Winter 2020

Pursuing Progress in a Pandemic

By Harib H. Ezaldein, MD • 2020-21 FIT Board Observer

“It’s time to cancel everything.”

Days after the Los Angeles mayor pleaded for residents to stay at home, the county faces its deadliest week since the beginning of the pandemic, equipped with no more than 80 available ICU beds.

What a time to be in fellowship training!

As physicians on the frontlines, we battle the downstream consequences from the desperate political battles outside our clinics aiming to control a pandemic that nobody fully comprehends.

Despite the seemingly bleak narratives on fellows attaining minimum Mohs layer and reconstructive requirements, the setting of the ongoing pandemic may serve as an unparalleled opportunity for a fellow to learn and grow. On a daily basis, the dynamic and reactionary measures taken by our institutions allow fellows to focus on learning how to provide safer patient care. Efforts to battle COVID-19 created improvements in containment practices, virtual surgical consultations and rationing of resources such as protective equipment, all of which serve as educational examples of clinical adaptation.

As we remodel to the evolution of COVID-related national policies and progress, several practices are also experiencing the inevitable “V-shaped recovery” with respect to case numbers. Whether this is a result of prior delayed treatment or patients’ expectancy of future lockdowns remains debatable. However, the augmented surgical volume is accompanied with increasingly complicated pathology, advanced reconstructions, unresectable tumors, and multidisciplinary care. These consequences invariably result in additional unique surgical conundrums, learning opportunities, and impactful clinical experience for fellows.

The unique clinical circumstances we are facing could define the perspectives and practice patterns of an entire generation of dermatologic surgeons, but also, our patients. Let us not forget that the physician-patient relationship is now socially-distant and obscured by masks, which may last indefinitely. These changes contribute to a heightened sense of trepidation and apprehension that becomes our responsibility to recognize and allay, especially as we move forward in clinical practice. Fellows tend to be the first to meet with patients therefore we have a significant opportunity to shape the narrative for the encounter. Whether the outcome is a single-stage tumor clearance or an unresectable tumor requiring further workup, fellows have the power to improve the patient experience by virtue of awareness and compassion.

The ongoing COVID-19 pandemic cements the concept that regardless of what transpires outside of our clinics, we should define our experience by focusing on the silver-lining. We are in an extremely privileged situation to train, grow and flourish our technical skills, fund of knowledge, and our responsibility to comfort patients- all without facing the managerial and administrative stresses that might befall our fellowship directors. This was a tremendously difficult year for most, but it is really quite impressive that many of our practices and patients managed to continue weathering the storm. We will certainly emerge from this fellowship year stronger, more resilient and better equipped to adapt for future crises.

Summer 2020

Non-Melanoma Skin Cancer Risk Factors, Cellular Pathways, and Immunosuppression Board Review

By Col. Eduardo Vidal, MD • 2019-20 FIT Board Observer

Basal cell skin cancer
Basal cell skin cancer (BCC) accounts for 75-80%^2,3 of all non-melanoma skin cancers (NMSC).⁴ In fact, it is the most common cancer known to man. It is the most common skin cancer in Caucasian, Hispanic, Chinese and Japanese populations, and is it the second most common skin cancer in African American and Asian Indian populations.^5,6 Risk factors for BCC include intense episodic UVR exposure, ionizing radiation exposure, arsenic ingestion and immune suppression.⁷ Individuals with Basal cell nevus syndrome⁸ (BCNS) or Gorlin’s syndrome, are genetically predisposed to development of multiple BCCs early in life. The overwhelming majority of BCCs are the result of uncontrolled activation of the Sonic Hedgehog (SHH) pathway, through mutational loss of the tumor suppressor Patched1 (PTCH1) (73-90%), or gain of function of the G protein-coupled receptor Smoothened (SMO) (10-20%).^7,9,10 The second most common mutation occurring in BCC are ultraviolet radiation induced mutations in tumor protein P53 (approximately 60%).¹⁰ Additional mutations associated with the development of BCC include: MYCN, PPP6C, STK19, LATS1, ERBB2, PIK3CA, NRAS/KRAS/HRAS, PTPN14, RB1, and FBXW7.¹¹ An aggressive form of BCC known as Basosquamous carcinoma, contains features of both BCC and squamous cell carcinoma (SCC), is caused by SHH pathway mutations followed by ARID1A mutations, and the RAS/MAPK pathway activation with subsequent squamatization.^9,12,13

Squamous cell carcinoma
Squamous cell carcinoma (SCC), is the most common skin cancer among African Americans.^5,6,14 SCC has an overall 0.3–5% metastatic rate on sun exposed sites, that increases from 9-11% if located on the ear, 14% if located on the lips, and in non-sun exposed sites such as anogenital regions, the metastatic rate ranges from 15-74%.^15,16,17 Perineural invasion is associated with local recurrence rates of 47% and metastatic rates of 35-47%.¹⁷
Despite the fact that individuals with skin of color as have lower rates of NMSC, they experience higher rates of morbidity and mortality.^5,18,19 For African Americans, chronic inflammatory lesions and scarring present the greatest risk factors for the development of SCC cancer, accounting for 20-40% of SCCs, with a much higher metastatic rate of 20-74%.^5,15,20,21 In contrast, the greatest risk factor for SCC in Caucasians is UV exposure which has an associated metastatic rate of only 1-4%. Risk factors for the development of SCC include: UVR exposure, ionizing radiation, chronic lymphocytic leukemia, autoimmune disease, immunosuppression, Human Papilloma Virus, chronic inflammatory lesions, and scarring. Mutations in the following tumor suppressor genes are associated with SCC: TP53, CDKN2a, NOTCH1 and NOTCH2, as are alterations in RAS/RAF/MEK/ERK and P13K/AKT/mTOR pathways.²²

Actinic keratoses (AK) are premalignant lesions known to progress to SCC. Actinic keratoses share similar pathogenesis with SCC via chronic UVB radiation exposure leading to the development of thymidine dimers in tumor suppressor gene TP53 and loss of gene function. The progression of AK to SCC ranges is not well understood. The progression rate is approximately 10% in untreated lesions over a 10 year period, with an overall malignant transformation rate ranging from 0.025% to 16%.^23,24 Traditionally, the progression of AK to invasive SCC was thought to progress systematically from atypia localized to the basal cell layer to full thickness atypia prior to transformation in to invasive SCC. However, there is evidence that invasive SCC can result directly from AK’s with limited basal cell atypia.²⁵ Therefore, all AK’s should be treated appropriately.

Immune Suppression
Chronic ultraviolet radiation (UVR) exposure results in chronic immune suppression.^26,27 There is no known adaptive response in humans to counteract the immunosuppressive effects of UVR exposure.²⁸ This has important implications as over 90% of NMSCs are related to UVR exposure.²⁹ BCC is associated with intense intermittent UVR exposures whereas SCC is associated with cumulative lifetime UVR exposure.³⁰ BCC outnumbers SCC by a ratio of 4:1.³¹ However, in the presence of immunosuppression, the ratio is reversed to a ratio of 1:3.15 For example, solid organ transplant patients have a 200 to 250-fold overall risk for cutaneous SCC in comparison to age-matched immunocompetent populations, with BCC demonstrating much lower 10-fold increase.^32,33 Other NMSC’s such as Merkel cell carcinoma have an 5 to 50-fold increased incidence in the presence of immunosuppression.³³ The greater the immune suppression, the higher the incidence of NMSC. Heart transplant patients, who receive the highest level of immunosuppression amongst solid organ transplant patients, have the highest rates of NMSC.³³ Furthermore, the longer the immunosuppression, the higher the incidence, with incidence rates of 7% for NMSC after 1 year, increasing to 45% after 11 years of chronic immunosuppression.³ Having a history of NMSC prior to organ transplantation leads to an almost 3-fold increased incidence of NMSC in comparison to those patients without a history of NMSC.^33,34

Immunosuppression as a result of systemic disease also poses an increased risk of cutaneous SCC with chronic lymphocytic leukemia having an 8-fold increased risk, and patients with non-Hodgkin lymphoma and patients on thiopurines for inflammatory bowel disease both having a 5-fold increased risk.^32,33,35-38 HIV infection increases the risk of BCC and SCC by 2-fold and 5-fold respectively.³³ A diagnosis of rheumatoid arthritis doubles the risk for SCC in comparison to the general population.³⁹ There is also evidence that treatment of diseases such as rheumatoid arthritis, psoriasis, and inflammatory bowel disease with tumor necrosis factor inhibitors can potentially increase the risk of NMSC, but further studies are needed to clarify the actual risk.³³

Merkel cell carcinoma
Merkel cell carcinoma (MCC) is a rare aggressive tumor with a generally poor prognosis as evidenced by a 5-year survival rate⁴⁰ as low as 40%.⁴¹ It typically occurs on the head and neck of Caucasian males over the age of 70 years old. At least 6-16% of cases are in advance stages and have metastasized at the time of diagnosis.⁴² MCC is caused by exposure to the merkel cell polyomavirus (MCPyV)40 or less commonly from ultraviolet light exposure.^43,44 Testing for exposure to the merkel cell polyomavirus involves detection of antibodies to capsid proteins or oncoprotein. Antibodies MCPyV capsid proteins are associated with a favorable prognosis when elevated, however they do not correlate with tumor burden and cannot be used to access response to therapy.⁴⁵ In contrast, antibodies to MCPyV oncoprotein, do correlate with tumor burden.⁴⁵ MCPyV oncoprotein seronegative patients may have an elevated risk of recurrence.⁴⁵ MCC polyomavirus oncoprotein antibodies may be considered as part of an initial workup.⁴⁶ The exact pathway by which the MCPyV virus leads to MCC is unknown, however, UV-induced viral-negative MCC is associated with mutations in TP53 and RB1.⁴⁷

Sebaceous carcinoma
Sebaceous carcinoma (SC) is an uncommon tumor located on the head and neck. It accounts for one out of every 2,000 cutaneous malignancies and has an annual incidence of 0.41 cases per million.^48,49 It occurs in individuals aged 60-79 years of age with a male predominance. However, ocular sebaceous occurs more frequently in women.⁵⁰ SC is classified as either ocular or extraocular, with lesions occurring most commonly on the upper eyelid. Targeted screening for patients diagnosed with SC for Muir–Torre syndrome (cutaneous SC and keratoacanthomas) should be based on clinical criteria.⁵¹ For initial localized disease, Mohs micrographic surgery (MMS) is the preferred treatment.^52-54 Risk factors for SC include: age > 60 years old, history of radiation therapy to the head and neck, Asian heritage, immunodeficiency, Muir-Torre syndrome. Activation of the Sonic Hedgehog (SHH) pathway is associated with SC (and BCC), with mutations in the CTNNB1 gene.^55,56

Microcystic adnexal carcinoma
Microcystic adnexal carcinoma (MAC) is a rare skin tumor of the head and neck with only a few hundred reported cases in the literature. As such, its true etiology remains a mystery. Risk factors for development of MAC include UV radiation exposure, immunosuppression, and exposure to ionizing radiation.⁵⁷ This tumor tends to remain locally invasive and rarely metastasizes to lymph nodes.⁵⁸ The overall 5-year survival rate is approximately 90%.

Atypical fibroxanthoma
Atypical fibroxanthoma (AFX) is a relatively rare tumor that most commonly occurs on the head and neck of elderly males. Histologically, AFX is often characterized as a more superficial and controversially⁵⁹ less aggressive variant of pleomorphic dermal sarcomas. Risk factors include UV radiation exposure, immunosuppression, and exposure to ionizing radiation.⁵⁹ UV-induced mutations in PIK3CA and TP53, as well as mutations in TERT, CDK6, KRAS, MDM2, ATM, PTEN, and CDKN2A have been discovered.^60,61

Dermatofibromasarcoma Protuberans
Dermatofibromasarcoma Protuberans (DFSP) is a rare dermal soft tissue sarcoma. Risk factors include immunodeficiency disorders (X-linked agammaglobulinemia, adenosine deaminase-deficient severe combined immune deficiency, ataxia telangiectasia syndrome, and HIV).⁶² The majority of DFSPs (90%) are caused by supernumerary ring chromosomes (chromosome 17 and 22), or chromosomal translocation t(17;22) (q22;q13), which lead to the fusion of collagen type 1-alpha and platelet-derived growth factor beta (PDGFβ), leading to PDGFβ over-expression and Akt-mTOR pathway activation.⁶²

Extramammary Paget’s Disease
Extramammary Paget’s Disease (EMPD) is a malignant slow-growing intraepithelial uncommon cancer located on the perineum, genitalia, anus, or axilla. Primary EMPD is associated with postulated apocrine cell origin, whereas secondary EMPD (21-29%)⁶³ arises from an underlying adenocarcinoma or other carcinoma from rectum or urogenital sites.⁶⁴ Risk factors identified for vulvar EMPD include postmenopausal status, history of ionizing radiation exposure, obesity. EMPD has been associated with the mTOR signaling pathway and MSI1 ectopic overexpression.⁶⁵

Angiosarcoma
Angiosarcoma is a rare malignancy derived from vascular endothelial cells in elderly patients. Risk factors include chronic sun exposure, Chronic lymphedema (i.e. Stewart-Treves syndrome, filariasis), ionizing radiation exposure, carcinogens (i.e. vinyl chloride, thorium dioxide and arsenic), and immunosuppression.⁶⁶ The molecular pathogenesis of angiosarcoma is not fully understood, but evidence points to involvement of UV-induced TP53 gene amplification, or amplification of MYC and FLT4 genes.

Cutaneous leiomyosarcoma
Cutaneous leiomyosarcoma (LMS) is a rare dermal tumor arising from the erector pili muscles of hair follicles. Potential risk factors for cutaneous LMS include trauma to the affected site, ionizing radiation exposure, immunocompromise in association with Epstein-Barr virus, and exposure to chemicals such as vinyl chloride.⁶⁷ The cause of cutaneous LMS is not known, but LMS has been associated with mutations in RB1, TP53, IGF1R, and PTEN. Also, LMS has been reported at least twice in association with Birt-Hogg-Dubé syndrome.⁶⁸

References
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36. Jensen AO, Olesen AB, Dethlefsen C, Sorensen HT, Karagas MR. Chronic diseases requiring hospitalization and risk of non-melanoma skin cancers--a population based study from Denmark. J Invest Dermatol. 2008;128(4):926-931.
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38. Hagen JW, Pugliano-Mauro MA. Nonmelanoma Skin Cancer Risk in Patients With Inflammatory Bowel Disease Undergoing Thiopurine Therapy: A Systematic Review of the Literature. Dermatol Surg. 2018;44(4):469-480.
39. Raaschou P, Simard JF, Asker Hagelberg C, Askling J, Group AS. Rheumatoid arthritis, anti-tumour necrosis factor treatment, and risk of squamous cell and basal cell skin cancer: cohort study based on nationwide prospectively recorded data from Sweden. BMJ. 2016;352:i262.
40. Lee AY, Berman RS. The Landmark Series: Non-melanoma Skin Cancers. Ann Surg Oncol. 2020;27(1):22-27.
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49. Muqit MM, Foot B, Walters SJ, Mudhar HS, Roberts F, Rennie IG. Observational prospective cohort study of patients with newly-diagnosed ocular sebaceous carcinoma. Br J Ophthalmol. 2013;97(1):47-51.
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53. Knackstedt T, Samie FH. Sebaceous Carcinoma: A Review of the Scientific Literature. Curr Treat Options Oncol. 2017;18(8):47.
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55. Bladen JC, Moosajee M, Tracey-White D, Beaconsfield M, O'Toole EA, Philpott MP. Analysis of hedgehog signaling in periocular sebaceous carcinoma. Graefes Arch Clin Exp Ophthalmol. 2018;256(4):853-860.
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Spring 2020

Immunochemistry for Mohs

By Col. Eduardo Vidal, MD • 2019-20 FIT Board Observer

Mohs micrographic surgery (MMS), the "gold standard for excision of keratinocyte carcinomoas, owes its effectiveness on the ability to interpret frozen sections¹, tumor mapping techniques, and complete circumferential peripheral and deep margin assessment (CCPDMA). However, hematoxylin and eosin (H & E) frozen sections produce processing artifacts that can sometimes make interpretation difficult, especially for melanocytic carcinomas. Advances in immunohistochemistry (IHC) have made it possible to use immunohisochemistry, without the use of immunofluorescence and specialized microscopes, and in a rapid fashion, making IHC a useful adjunctive technique to increase the effectiveness of MMS. ^1-3  Despite numerous advantages, utilization of IHC in the Mohs community is still limited. ^4,5

There are several advantages to the use of IHC with MMS. The ability of IHC to highlight and detect residual tumor and therefore reduce recurrence is the most compelling reason to implement IHC. Identification of residual tumor in frozen sections can be extremely difficult when there is single cell spread of tumor, poorly differentiated tumor cells, tumor cells are within a dense inflammatory infiltrate ⁶, when perineural invasion occurs, when tumors track down nerves, vessels, or fascial planes, or in the presence of scar or dense fibrotic tissue. ^3,7 When the proper antibodies are used, (Table 1) IHC is able to clearly differentiate tumor from non tumor cells, unmasking hidden tumor cells that may missed with H&E stains. ^7,8  Frozen sections are also less likely to lose IHC antigens during processing in comparison to formalin-fixed and paraffin-embedded tissue. This is especially true for cytoplasmic and cell membrane staining antigens as formalin fixation can disrupt cell membranes.² Malignant melanoma can be very difficult to interpret on frozen sections as it is often difficult to distinguish melanocytes from keratinocytes, especially with single cell spread, pagetoid spread, or in the presence of diffuse actinic damage (actinic keratoses).³  For malignant melanoma, IHC allows for rapid identification of melanocytes, allowing for accurate diagnosis and microscopic margin evaluation.⁹  The use of Pan cytokeratin antibodies is particularly useful for keratinocyte carcinomas when evaluating areas where keratinocytes are not routinely encountered such as perineurally and within deep subcutaneous tissue. The use of IHC can potentially decrease the number of Mohs stages by providing surgeons with the ability to clear keratinocyte carcinoma in areas of dense inflammation that would normally require additional stages because of uncertainty.³

 There are some potential challenges to the use of IHC as well.  Displacement of soluble antigens, and prolonged incubation times for staining are well-known issues.¹ Using of higher antibody titers – as well as other methods to boost the IHC signal – can decrease incubation times. However, boosting the IHC signal can increase background noise (labeling). Therefore, use of positive and negative controls on archived tissue is highly recommended. 

The ability to reliably distinguish tumor from non-tumor allows for reductions in the number of Mohs stages, the potential to uncover hidden tumors, reductions in tumor recurrence, and greater confidence in clearance of surgical margins. It’s important to realize that there are no tumor-specific markers, as the usefulness of IHC rests on the ability of the examiner to identify abnormal patterns, when highlighted cells are present in areas they are not commonly found, and distinguishing between inflammatory cells and tumor cells. AS the champions of the "gold standard" surgical modality for skinc cancer, all Mohs surgeons should be familiar with IHC techniques.

References:

1. Sroa N., Campbell S., Ravitsky L. Immunohistochemistry in Mohs Micrographic Surgery: A Review of the Literature. J Clin Aesthet Dermatol. 2009;2(7):37-42
2. El Tal A.K., Abrou A.E., Stiff M.A., Mehregan D.A. Immunostaining in Mohs Micrographic Surgery: A Review. Dermatol Surg. 2010;36(3):275-290.
3. Miller C.J., Sobanko J.F., Zhu X., Nunnciato T., Urban C.R. Special Stains in Mohs Surgery. Dermatol Clin. 2011:29(2):273-286, ix
4. Trimble J.S., Cherpelis B.S. Rapid Immunostaining in Mohs: Current Applications and Attidutes. Dermatol Surg. 2013;39(1 Pt 1):56-63
5. Robinson J.K. Current histologic preparation methods for Mohs Micrographic Surgery. Dermatol Surg.201:27(6):555-560
6. Jimenez F.J., Grichnik J.M., Buchanan M.D., Clark R.E. Immunohistochemical Techniques in Mohs Micrographic Surgery: Their Potential Use in the Detection of Neoplastic Cells Masked by Inflammation. J Am Acad Dermatol. 1995;32(1):89-94.
7.  Stranahan D., Cherpelis B.S., Glass L.F., Ladd S., Fenske N.A. Immunohistochemical Stains in Mohs Surgery: A Review. Dermatol Surg. 2009;35(7):1023-1034.
8. Zachary C.B., Rest E.B., Furlong S.M., Arcedo P.N., McGeorge B.C., Kist D.A. Rapid Cytokerating Stains Enhance the Sensitivity of Mohs Micrographic Surgery for Squamous Cell Carcinoma. J Dermatol Surg Oncol. 1994;20(8):530-535.
9. Cherpelis B.S., Moore R., Ladd S., Chen R., Glass L.F. Comparison of MART-1 Frozen Sections to Permanent Sections Using a Rapid 19-Minute Protocol. Dermatol Surg. 2009;35(2):207-213.
10. Beaulieu D., Faithi R., Srivastava D., Nijhawan R.I. Current Perspectives on Mohs Micrographic Surgery for Melanoma. Clin Cosmet Investig Dermatol. 2018;11:309-320.
11. Iwamoto S., Burrows R.C., Agoff S.N., Piepkorn M., Bothwell M., Schmidt R. The p75 Neurotrophin Receptor, Relative to Other Schwann Cell and Melanoma Markers, is Abundantly Expressed in Spindled Melanomas. Am J Dermatopathol. 2001;23(4):288-294.

Winter 2019

Light and Shadows:  A Shared Focus of Artists and Mohs Surgeons

By Col. Eduardo Vidal, MD • 2019-20 FIT Board Observer

Since the 15th century, artists have used lighting and shadows to add realism to their art.  In much the same way, Mohs surgeons intuitively use these same visual clues to plan and execute both facial and non-facial cutaneous reconstructions. Current reconstruction paradigms (i.e. Relaxed Skin Tension Lines and Cosmetic Subunits) guide reconstructive surgery. But there are times when our artistic vision violates existing tenets of these paradigms.

The use of light and shadow in paintings originated in the 1400’s and reached its pinnacle in the Renaissance period. One of the most influential artists of this time, Leonardo da Vinci, popularized the technique of using of light and shadows known as “Chiaroscuro” (Italian light-dark)¹. Light was used not only to convey a sense of realism, but to highlight elements, and to evoke dramatic tension.  Light and shadows were further expanded into three-dimensional (3D) space by contemporary artist James Turrell, who used light and sculptural curved forms to create stunning visual experiences and a sense of physical presence.² Light and shadows were also studied in architecture through Sciography, an old mathematical discipline, used projected shadows to calculate linear perspective in two dimensional drawings.³  Computer algorithms in the 1960-70’s led to the first commercially released 3D computer program in 1978, that allowed for shading of objects in a virtual 3D space. In the 1990’s, Persistence of Vision Ray Tracer (POV-Ray) software made casting shadows off shiny 3D objects possible.⁴  POV-Ray would go on to become the first ray-tracing program to render a computer-generated image in orbit on the International Space Station, in 2002.⁵ These early software algorithms eventually led to more complex shading systems such as radiosity, with reflected and scattered light algorithms. In the entertainment industry, 3D digital artists rely heavily on lighting techniques to convey realism and a sense of proportion (See above figure).

Mohs surgeons intuitively use lighting and shadows as visual cues in the design and execution of their reconstructions, applying many of the same principles used by artists.⁶ However, instead of creating realism, Mohs surgeons seek to achieve an aesthetic outcome. Knowledge of surgical anatomy and these visual cues are combined with two well established paradigms (i.e. relaxed skin tension lines and cosmetic subunits) to form the basis of surgical reconstruction planning. Surgeons pinch relaxed facial skin to reveal a furrow or fold in the skin known as relaxed skin tension lines (RSTL). RSTL’s delineate areas of maximal extensibility and are oriented perpendicular to the direction of maximum tension.^7,8 This concept proposes that wound tension is minimized when the axis of closure is oriented along an RSTL. Presumably, this in turn results in a better aesthetic outcome. Cosmetic subunits^9,10 are perceived as well-defined components of the face joined at distinct boundary lines. These cosmetic subunits are similar to artistic planes of the head.⁶ Artistic planes of the head have been used by artist’s since the early 1500’s¹¹, and intuitively by surgeons for centuries, underscoring the importance of light and shadow in both art and surgery.

Current surgical reconstructive paradigms of RSTL and cosmetic subunits do not account for the surgeon’s artistic visualization of a closure. This is can be most readily appreciated when a closure is performed that bridges between adjacent cosmetic subunits or when the suture line is not parallel to RSTL’s, yet a wonderfully aesthetic result is achieved. Mohs Surgeon, Dr. Wentzell, notes that an S-plasty violates RSTL tenets, but the cosmetic outcome is superior to a straight-line closure that strictly follows the RSTL.   In this case, optimum surgical reconstruction prioritizes maintenance of the surface contours over adherence to the RTSL and cosmetic subunit paradigms.  Anatomy-defining interplay of light and shadow, through preservation of surface contour, is thereby preserved.

At the 2019 American College of Mohs Surgery 51th Annual Meeting, Mike Wentzell introduced a new paradigm that focuses on preservation of contours and preventing contour deformities. This paradigm is termed the Radius of Curvature Zones (ROC Zones) paradigm.  The ROC Zone paradigm may help to define and formalize artistic vision. Afterall, preservation of contours is the attempted goal of both the RSTL and Cosmetic Subunit paradigms. Wentzell’s ROC Zone paradigm describes the surface contours of the body as composed of curvatures that have an associated arc when visualized in cross-section. Each arc has a unique radius of curvature. The topology of facial contours is then described as several radii of curvature zones or ROC zones separated by narrow transitions. The guiding principal of the ROC paradigm is that surgical reconstruction should preserve the radius of curvature that defines the contoured surface. Contour deformities are thereby averted. Contours revealed by light and shadow are thus preserved. Therefore, at its core, the ROC Zone paradigm is a focus on contour preservation as can only be revealed through careful visualization of light and shadows that define these contours.

The use of light and shadows by both surgeons and artists outlines a shared aesthetic focus.  A comprehensive system for surgical reconstruction incorporates this artistic vision with functional anatomy and elements of the RSTL and cosmetic subunit paradigms.  In this regard, newer paradigms, such as the ROC Zone paradigm, may serve as the template for a systematic way to put into words what surgeons and artists have been doing for centuries.

References:

1. Shah U. Conceptualizing Light- Light and Shadow in Renaissance and Baroque Art. . In. Intro to renaissance Vol 2019: Worldpress.com; 2015
2. Shaub N. How Caravaggio, Turrell, and 3 Other Artists Revolutionized the Use of Light in Art. In. Artsy for Education. 4 September 2015 ed2015
3. Baxandall M. Shadows and enlightenment. New Haven: Yale University Press; 1995
4. Buck D. 1.1.5 The Early History of POV-Ray. In. Persistence of Vision2001
5. Reach for the stars. In. Oyonale - 3D art and graphic exp