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Advanced Skin Cancer
A Case-Based Approach

Senior Editors
Debjani Sahni, MD
G. Robert Baler Endowed Professor of Dermatology
Director, Cutaneous Oncology Program
Department of Dermatology
Boston University School of Medicine

Adam Lerner, MD
Professor of Medicine
Section of Hematology/Oncology
Department of Medicine
Boston University School of Medicine

Junior Editor
Bilal Fawaz, MD
Assistant Professor of Dermatology
Department of Dermatology
Boston University School of Medicine
With a Foreword by
Rhoda M. Alani, MD
Herbert Mescon Endowed Professor and Chair
Department of Dermatology
Boston University School of Medicine
Dermatologist-in-Chief
Boston Medical Center
First edition published 2022
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DOI: 10.1201/9780429026683

Typeset in Times
by codeMantra
Contents

Foreword .................................................................................................................................................. vii

Preface ...................................................................................................................................................... ix
Acknowledgments...................................................................................................................................... x
Editors ....................................................................................................................................................... xi
Contributors .............................................................................................................................................xii

1 Melanoma .......................................................................................................................................... 1
Ali Al-Haseni and Debjani Sahni

2 Squamous Cell Carcinoma ............................................................................................................ 37

Ali Al-Haseni and Debjani Sahni

3 Basal Cell Carcinoma .....................................................................................................................61

Ali Al-Haseni and Debjani Sahni

4 Cutaneous Lymphoma ................................................................................................................... 83

Bilal Fawaz and Debjani Sahni

5 Kaposi’s Sarcoma ..........................................................................................................................115

Bilal Fawaz and Debjani Sahni

6 Dermatofibrosarcoma Protuberans ............................................................................................131

Bilal Fawaz and Debjani Sahni

7 Merkel Cell Carcinoma ................................................................................................................143

Allene S. Fonseca, Song Park, and Paul Nghiem

8 Rare Cancer Presentations...........................................................................................................155

Bilal Fawaz, Heather A. Edwards, Monica Rosales Santillan, Debjani Sahni,
Connor O’Boyle, and Daniel L. Faden

Index .......................................................................................................................................................169

v
Foreword

Advanced Skin Cancer: A Case-Based Approach provides case-based examples of the personalized,
multidisciplinary approach to complex skin cancer management utilized at premier tertiary care cancer
centers in the United States. This team-based care allows for collaborative input to inform best practices
for patients with complex skin cancers. The majority of the patient cases presented in this book were
seen at Boston Medical Center. As the largest safety-net hospital in New England, Boston Medical
Center provides exceptional care to a diverse population of patients with unique medical needs which
are often complicated by complex social determinants that greatly impact their care and outcomes. The
Department of Dermatology at Boston Medical Center is the entry point for a large number of patients
who present with advanced primary or metastatic skin cancers. The authors possess unique expertise
in the evaluation and management of advanced cutaneous malignancies, and discuss interesting and
informative cases that have presented to our dermatology care team initially, but which require a mul-
tidisciplinary approach given the complexities of cutaneous malignancy and other medical and social
challenges.
The past decade has seen a tremendous expansion of personalized approaches to the treatment of can-
cers, with specific targeted therapies being developed for driver events in a variety of malignancies. For
skin cancers, notable advances in targeted therapies for melanoma have drawn the attention of the inter-
national medical community with enthusiasm over early successes being dampened by near-universal
innate or acquired resistance to such therapies. These novel therapies have been widely studied both in
patients and in research laboratories, and their complex role in the management of patients with advanced
melanoma continues to evolve. In addition, recent advances in the development of immunotherapies, par-
ticularly immune checkpoint inhibitors (IHIs), for a wide range of cancers have shown particular efficacy
in aggressive types of cutaneous malignancies. These treatments have significantly enhanced the thera-
peutic armamentarium for patients with complex cutaneous malignancies and advanced disease, and are
examined within the context of the cases presented here.
The unique perspectives of the editors and authors of this book have evolved from decades of clinical
practice and research within complex healthcare systems which inform their decision making. This book
is designed to share a pragmatic approach to complex skin cancer management that may serve as a guide
for providers around the world, particularly those that care for patients with diverse social and medi-
cal needs. The text reflects state-of-the-art practices as well as team-based decision making to afford
the best possible personalized care to each patient and their unique clinical and social circumstances.
This book will be of particular value to any physicians caring for patients with cutaneous malignancies,
either as primary care physicians or as specialty care providers. The cases presented and management
through team decision making will be especially valuable to medical oncologists, surgical oncologists,
dermatologists, radiation oncologists, plastic surgeons, head and neck surgeons, and nursing staff that
care for patients with complex cutaneous malignancies. Case discussions will have particular relevance
for physicians and advanced-practice providers who care for patients within underserved communities
to demonstrate best practices when treating patients who present to healthcare providers with advanced-
stage cutaneous malignancies.
Finally, the new era of personalized cancer therapeutics has also informed the critical need for a
team-based approach to the treatment of patients with advanced skin cancers. Each case presented
here illustrates the importance of diverse medical teams for the effective treatment of advanced skin

vii
viii Foreword

cancers as well as the inclusion of ancillary service team members to support patients through their
treatment and recovery. Such a team-based approach is particularly important in the setting of safety-
net care for vulnerable populations and is critical to ensuring the best possible outcomes for these
disadvantaged communities.

Rhoda M. Alani, MD
Herbert Mescon Endowed Professor and Chair
Department of Dermatology
Boston University School of Medicine
Dermatologist-in-Chief
Boston Medical Center
Boston, Massachusetts
Preface

We are fortunate to be living in a period of “oncology renaissance,” an era where major advances in
science and medicine have culminated in an explosion of novel therapies that are decisively making
meaningful differences to the lives of cancer patients. This is certainly true for cutaneous oncology,
where advanced disease states such as metastatic melanoma can finally be met with a choice of drugs
that can lead to a real survival benefit in patients for whom care was previously palliative. It is becom-
ing increasingly apparent that the most effective care of advanced cutaneous oncology patients occurs
through a multidisciplinary approach utilizing evidence-based national guidelines for best practice,
which considers both tumor-specific and patient-specific factors. It is discernable that there is no “one-
size-fits-all” approach for the care of cutaneous oncology patients, but instead, a range of potential thera-
peutic options and solutions. Patient management is dictated by a combination of medical and social
considerations including nuances of the cancer in question, patient co morbidities, social circumstances,
access to healthcare, immediate support network, and medical healthcare coverage. Thus, the final deci-
sion in the course of management becomes personalized to each patient.
A multidisciplinary cutaneous oncology team facilitates the coordinated care between numerous spe-
cialties. This enables the appropriate expertise of each specialty to be utilized in the most effective and
efficient way for the patient. A “one-stop” multidisciplinary clinic where patients can be reviewed by
faculty from various specialties at the same time is more practical for the patient, while additionally
allowing better communication among specialist providers, a key component of excellence in patient
care. A multidisciplinary cutaneous oncology tumor board panel implements the academic review of
patient- and tumor-specific factors, distinct aspects of the tumor pathology, and prevailing national
guidelines to help determine the best care for patients. It also provides an important educational oppor-
tunity for trainees to observe how providers outside of their specialty arrive at decisions in patient care.
The series of cases in this book reflects the coordinated care and expertise of the multidisciplinary
cutaneous oncology team at Boston Medical Center, including a chapter dedicated to patients with
Merkel cell cancer managed by the cutaneous oncology team from the University of Washington Medical
Center. The editors aim to illustrate the relevant contributions from each of the specialties that culminate
in the final decision plan for each patient.

Debjani Sahni
Adam Lerner
Bilal Fawaz

ix
Acknowledgments

All three editors wish to thank Rhoda Alani, MD, Chair of the Boston University School of Medicine,
Department of Dermatology, for her foresight and support in the development of the Cutaneous Oncology
Program in which most of the patients described in this book were seen. We are grateful to her for pro-
posing the composition of this book and for advocating for us throughout this mammoth task.
I am fortunate to work with a highly skilled and supportive group of colleagues, the multidisciplinary
cutaneous oncology team at Boston Medical Center. I would not be able to deliver excellent care to our
patients without them, and they graciously contributed their talent to the book. At the start of this project,
it became quickly apparent that I could not showcase the work in this book without inviting and equally
involving Adam Lerner, MD, who co-manages complex patients with me. His guidance and mentorship
have been invaluable. It is fortuitous that we both think alike in our patient care, but more importantly,
that we listen to each other. Similarly, it would have been impossible to produce this book without the
cooperation of an intelligent, organized, and patient colleague, Bilal Fawaz, MD. He was essentially my
right-hand man for this task.
My final words of acknowledgment go to my family, in particular, my parents, brother, and sister
who have been a part of my journey throughout. Most importantly, I am grateful to my husband Anik,
and my two daughters, Sophia and Neve, who have been so patient and supportive and made everything
worthwhile.

Debjani Sahni, MD

Dr. Lerner would like to acknowledge the support of his family throughout his career as an oncologist,
particularly his wife, Beth Warach.

Adam Lerner, MD

I have to start by thanking my parents, Hussein and Hana, for their endless support, not only through my
fellowship, but throughout my entire educational endeavor. I couldn’t have done it without you.
I would also like to thank my outstanding mentors, Dr. Sahni, Dr. Lerner, and Dr. Alani, for providing
me with this opportunity. This experience was invaluable in my personal and professional development.

Bilal Fawaz, MD

x
Editors

Debjani Sahni, MD, is the G. Robert Baler Endowed Professor and Director of the multidisciplinary
Cutaneous Oncology Program at Boston University School of Medicine and Boston Medical Center, where
she specializes in the medical management of advanced skin cancers. She completed her medical school
training at the United Medical and Dental Schools of Guy’s and St Thomas’ Hospitals in London, UK.
After acquiring membership of the Royal College of Physicians (MRCP), she completed her dermatol-
ogy residency at the St John’s Institute of Dermatology in London. She subsequently undertook a cutane-
ous oncology fellowship at Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard
Medical School, Boston. Dr Sahni serves as the Director of the Cutaneous Oncology Fellowship Program
and the Director of the unique and highly respected International Graduate Program in Dermatology
(IGPD). First established in 1988, the IGPD offers international postgraduate doctors the opportunity to
train in dermatology, utilizing state-of-the-art facilities and therapies available in the United States. Her
academic interests include teaching and mentoring for which she is the recipient of several teaching awards
and an external examiner for postgraduate dermatology training exams internationally. Dr Sahni’s clinical
research interests focus on the epidemiology and treatment of skin cancers, and she is the author of multiple
scientific papers, and editor and co-author for the dermatology textbook, Melanoma in Clinical Practice.

Adam Lerner, MD, is a Professor in the Section of Hematology/Oncology, Department of Medicine, at

Boston University School of Medicine and Boston Medical Center. His clinical practice focuses on the
care of patients with cutaneous and hematologic malignancies as well as sarcomas. His research focuses
on cyclic nucleotide phosphodiesterase and focal adhesion complex signaling in human cancer biology.

Bilal Fawaz, MD, is an Assistant Professor in the Department of Dermatology at Boston University
School of Medicine and Boston Medical Center. His notable contributions to research have been in
cutaneous oncology, specifically revolving around optimizing patient outcomes and quality of life. He is
the recipient of the American Society for Dermatologic Surgery’s Cutting-Edge Research Grant in 2018
for his work on improving the quality of life for patients with skin cancer. He is the author of several
book chapters in well-known dermatology textbooks such as Treatment of Skin Disease and Melanoma
in Clinical Practice.

xi
Contributors

Ali Al-Haseni, MD Waleed Ezzat, MD, FACS

Department of Dermatology Plastic and Reconstructive Surgery
Boston University School of Medicine Department of Otolaryngology – Head and Neck
Boston, Massachusetts Surgery
Boston University School of Medicine
Sara Al Janahi, MD, MSc Boston, Massachusetts
Department of Dermatology
Boston University School of Medicine Daniel L. Faden, MD, FACS
Boston, Massachusetts Department of Otolaryngology – Head and Neck
Surgery
Harvard Medical School
Michael R. Cassidy, MD and
Department of Surgery Massachusetts Eye and Ear
Division of Surgical Oncology Massachusetts General Hospital
Boston University School of Medicine Boston, Massachusetts
Boston, Massachusetts
Bilal Fawaz, MD
Malathi Chittireddy, MD, MSc Department of Dermatology
Department of Dermatology Boston University School of Medicine
Boston University School of Medicine Boston, Massachusetts
Boston, Massachusetts
Allene Fonseca, MD
Department of Dermatology
Emily Coleman, MD
University of Washington
Department of Dermatology
Seattle, Washington
Boston University School of Medicine
Boston, Massachusetts
Sarah Ann Kam, MD
Department of Dermatology
Yasin Damji, MD Boston University School of Medicine
Department of Dermatology Boston, Massachusetts
Boston University School of Medicine
Boston, Massachusetts Iman Fatima Khan, MS, MPH
Boston University School of Medicine
Michael A. Dyer, MD Boston, Massachusetts
Department of Radiation Oncology
Boston Medical Center Hannah Kopelman, DO
Boston University School of Medicine Department of Dermatology
Boston, Massachusetts Boston University School of Medicine
Boston, Massachusetts

Heather A. Edwards, MD Adam Lerner, MD

Department of Otolaryngology – Head and Neck Section of Hematology/Oncology
Surgery Department of Medicine
Boston University School of Medicine Boston University School of Medicine
Boston, Massachusetts Boston, Massachusetts

xii
Contributors xiii

Hannah E. Mumber, BS Elizabeth T. Rotrosen, AB

Boston University School of Medicine Boston University School of Medicine
Boston, Massachusetts Boston, Massachusetts

Paul Nghiem, MD, PhD Tatchai Ruangrattanatavorn, MD, MSc

Department of Dermatology Department of Dermatology
University of Washington Boston University School of Medicine
Fred Hutchinson Cancer Research Center Boston, Massachusetts
Seattle, Washington

Bichchau Michelle Nguyen, MD, MPH Teviah E. Sachs, MD, MPH

Department of Dermatology Department of Surgery
Boston University School of Medicine Division of Surgical Oncology
Boston, Massachusetts Boston University School of Medicine
Boston, Massachusetts
Connor O’Boyle, MD
Massachusetts Eye and Ear Debjani Sahni, MD
Massachusetts General Hospital Department of Dermatology
Harvard Medical School Boston University School of Medicine
Boston, Massachusetts Boston, Massachusetts

Song Park, MD Monica Rosales Santillan, MD

Division of Dermatology Department of Dermatology
University of Washington Boston University School of Medicine
Seattle, Washington Boston, Massachusetts

Shreya Patel, MD Shawn Shih, MD

Department of Dermatology Department of Dermatology
Boston University School of Medicine Boston University School of Medicine
Boston, Massachusetts Boston, Massachusetts

Nicole Patzelt, MD Marguerite Sullivan, MD

Department of Dermatology Department of Dermatology
Boston University School of Medicine Boston University School of Medicine
Boston, Massachusetts Boston, Massachusetts

Sarah Phillips, MD Minh T. Truong, MD

Department of Dermatology Department of Radiation Oncology
Boston University School of Medicine Boston University School of Medicine
Boston, Massachusetts Boston, Massachusetts
1
Melanoma

Ali Al-Haseni and Debjani Sahni

CONTENTS
Introduction ................................................................................................................................................ 1
Epidemiology ............................................................................................................................................. 1
Pathogenesis and Risk Factors ................................................................................................................... 2
Clinical Presentation and Histological Subtypes ....................................................................................... 2
Treatment and Prognosis ............................................................................................................................ 3
References .................................................................................................................................................. 3
Case 1.1 ...................................................................................................................................................... 5
Case 1.2 ...................................................................................................................................................... 9
Case 1.3 .................................................................................................................................................... 13
Case 1.4 .....................................................................................................................................................16
Case 1.5 .................................................................................................................................................... 20
Case 1.6 .................................................................................................................................................... 24
Case 1.7 .................................................................................................................................................... 28
Case 1.8 .................................................................................................................................................... 33

Introduction
Melanoma is a skin cancer originating from melanocytes that are most commonly located in the skin.
Melanoma can less commonly also arise from the eye or mucosal surfaces of the head and neck, urogeni-
tal tract, and gastrointestinal surfaces.1 Melanoma is responsible for more than 90% of deaths related to
skin cancer, with incidence increasing by 270% from 1973 to 2002 in the United States.2,3

Epidemiology
The incidence of melanoma has been increasing steadily by 3%–4% annually.2 The estimated current
lifetime risk of melanoma in the United States is 1 in 63, with an incidence rate of 20.1 per 100,000
persons for the period between 2003 and 2007. This compares to 41.1–55.8 per 100,000 persons in
Australia.3 This increased incidence over the past five decades has been attributed to multiple factors,
including increased exposure to ultraviolet (UV) radiation from sun or tanning bed use and enhanced
screening leading to increased diagnosis.2 Melanoma tends to affect middle-aged adults, with a median
age of 57 years at diagnosis. In young adults (<55 years), it is more common in females, representing the
sixth most common cancer in women, while for adults over the age of 55 years, it is seen more commonly
in males, constituting the fifth most common cancer in men.3,4

DOI: 10.1201/9780429026683-1 1
2 Advanced Skin Cancer

Pathogenesis and Risk Factors

Melanoma is a multifactorial disease that results from the interaction of environmental factors in geneti-
cally predisposed individuals.3 It is associated with a high somatic mutation burden when compared to
many other human cancers. However, most of these mutations eventually lead to activation of two main
pathways: The mitogen-activated protein kinase (MAPK) and the phosphoinositol-3 kinase (PI3K/AKT)
pathways. MAPK is responsible for cellular proliferation, differentiation, and survival, while PI3K is
responsible for cellular homeostasis. Approximately 90% of all melanomas show MAPK pathway activa-
tion. The most common mutation in the MAPK pathway is a mutation in the BRAF gene, with 80%–90%
of the mutations being a missense mutation resulting in valine to glutamate substitution (V600E). This
mutation is found in ~40%–60% of melanomas arising in intermittently sun-exposed skin. The second
most common mutation in the MAPK pathway is an activating mutation in NRAS found in 15%–30% of
melanomas, followed by neurofibromin 1 (NF1) tumor-suppressor gene mutation, present in 10%–15%
of melanomas. However, NF1 mutations are usually associated with chronic sun exposure.4 The receptor
tyrosine kinase KIT mutations are found in 2%–8% of melanomas and are usually present in acral mela-
nomas and in melanomas arising from intermittent sun exposure. A number of other gene mutations are
involved in melanoma development; some examples include telomerase reverse transcriptase (TERT)
promoter mutations, cyclin-dependent kinase inhibitor-2A (CDKN2A) mutations, and phosphatase and
tensin homolog (PTEN) mutations.4
The most important environmental risk factor for the development of melanoma is UV radiation from
sun light.3,4 Specifically, intense intermittent sun exposure (sun burns) carries a higher melanoma risk
when compared with chronic continuous exposure. Other risk factors include fair skin type, red hair,
blue eyes, numerous freckles, UV-A exposure (therapeutic or tanning bed use), immune suppression,
multiple melanocytic nevi, and a personal or family history of melanoma.3,4 The white population has
a tenfold higher risk of developing cutaneous melanoma when compared with people of color (Black,
Asian, or Hispanics). However, the rate of acral melanoma, which is not correlated with UV damage, is
equal between Whites and Blacks (though it is the most common subtype of melanoma in the Black pop-
ulation). In the case of non-cutaneous melanomas (i.e., mucosal melanoma), although higher numbers are
detected in the white population, they make up a higher proportion of melanoma subtype in patients of
color compared to Whites.5 There is a sevenfold increased risk of melanoma in patients with more than
100 melanocytic nevi, 32-fold increased risk with more than 10 atypical nevi, and 2%–5% increased risk
with large congenital nevi (>20 cm in size). Despite this, only 25%–30% of melanomas arise from pre-
existing nevi, with the vast majority occurring de novo on normal skin.3,4,6–8 Familial cases are rare and
are usually related to mutations in CDKN2A or cyclin-dependent kinase-4 (CDK4).3,4

Clinical Presentation and Histological Subtypes

Melanoma presents classically as a changing brown, black, or pink pigmented skin lesion. If left untreated,
it can ulcerate and/or bleed. The education campaigns targeted for early melanoma recognition by physi-
cians and the public launched the “ABCD” criteria in 1985, with subsequent addition of the letter “E”.
They stand for Asymmetry, Border irregularity, Color variation, Diameter > 6 mm, and Evolution. This
can help patients considerably during regular self-skin exams, which has a sensitivity of 57%–90% for
melanoma detection. Dermatoscopic findings of an atypical pigment network, irregular dots/globules/
streaks, regression, or blue-white veil raise the suspicion of melanoma.3 Melanomas are most commonly
located on the back of men and the legs of women. The mortality rate of melanoma showed an initial
increase of 1.4% annually between 1977 and 1990. However, a downtrend of 0.3% annually was subse-
quently observed for the period between 1990 and 2002.3
Historically, cutaneous melanomas were divided into several subtypes based on clinical factors or
histopathological growth patterns. Superficial spreading melanoma accounts for 70% of cases with an
early radial growth phase in the epidermis followed by a vertical growth phase in the dermis. Nodular
melanoma, which accounts for 5% of cases, presents as a rapidly growing, often ulcerating, brown-black