Melanoma in Clinical Practice

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Rhoda M. Alani • Debjani Sahni
Editors

Melanoma in Clinical
Practice
Editors
Rhoda M. Alani Debjani Sahni
Department of Dermatology Department of Dermatology
Boston University School of Medicine Boston University School of Medicine
Boston Medical Center Boston Medical Center
Boston, MA Boston, MA
USA USA

ISBN 978-3-030-82638-3    ISBN 978-3-030-82639-0 (eBook)

https://doi.org/10.1007/978-3-030-82639-0

© Springer Nature Switzerland AG 2021

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Preface

Of the three commonest skin cancers, malignant melanoma is the most lethal,
with increasing worldwide incidence over the past 50 years. It is notable that
melanoma is one of the most common cancers in the 15–30 year age group with
preventable risk factors, and its survival is significantly impacted by the stage at
clinical presentation. Prevention and early detection, therefore, remain powerful
tools in curbing this disease. Differentiating atypical, pigmented lesions from
benign versus neoplastic can be challenging, given the large variety of melano-
cytic tumors with benign, intermediate, and malignant biological behavior, as
well as overlapping clinical and histopathological features between the entities.
Over the years, melanoma staging has developed with improved prognos-
tication to better guide the management of patients. Surgery is the mainstay
of treatment for early-stage disease. Data from landmark clinical trials have
impacted practice guidelines in recent decades, moving away from prior
extensive and morbid surgeries of the primary lesion and regional nodes to
more optimized surgeries that provide a better balance of the risk–benefit
ratio for the patient.
During the past decade, with an improved understanding of the genetic drivers
of melanoma development and progression and the immunologic basis of host
responses to cancers, oncologists have seen an explosion of novel treatments for
metastatic melanoma which has enabled them to offer patients effective therapies
that significantly improve patient survival and quality of life. Despite these giant
steps in melanoma therapy, there is still much room for optimizing therapies to
extend the survival benefit to a greater number of patients, with better predict-
ability of response, and for a longer duration. The breakthroughs afforded by
these remarkable new therapies are a testament to decades of basic and transla-
tional research and meaningful collaborations between academia and industry to
forge advances in patient care through a streamlined process.
This book provides a comprehensive review of clinical, basic, and transla-
tional research in melanoma, current standards for the diagnosis and treat-
ment of localized, regional, and advanced disease, and forward-looking

v
vi Preface

remarks on what may be expected in the field in the near future. Specific
chapters are dedicated to melanoma epidemiology, melanoma biology, and
disease prevention, diagnosis, and treatment in a detailed yet readable format
highlighted by inclusion of key study data. Specific attention is also paid to
rarer variants of melanoma and melanoma of specific populations such as
children that may have atypical clinical presentations and behaviors.

Boston, MA, USA  Rhoda M. Alani, MD

Boston, MA, USA Debjani Sahni, MD
Acknowledgments

The editors would like to acknowledge the valuable time, thoughtful discus-
sions, and outstanding contributions of our colleagues and coauthors that
have promoted the development of this book. This project was an immense
collaborative effort of melanoma thought leaders from across the USA and
beyond during the difficult time of the COVID-19 pandemic. We are truly
grateful for the tremendous dedication of our colleagues to prepare this com-
prehensive and state-of-the-art body of work despite the challenges encoun-
tered throughout this journey.

Rhoda M. Alani, MD and Debjani Sahni, MD

To my husband Philip Cole and children, Hannah and Matthew Cole, for
their tremendous support throughout my career. You bring me so much joy
and always inspire me to be my best self. To my colleagues, teachers, men-
tors, trainees, and patients who have taught me greatly about science, medi-
cine, and life. To Debjani Sahni, MD, who was the driving force behind this
awesome endeavor and whose brilliance, kindness, tenacity, and dedication
never cease to amaze me.

Rhoda M. Alani, MD

I am grateful to my family in getting me to where I am today. In particular,

I am thankful to my two very patient children, Sophia and Neve, who had to
sacrifice their time with me during the composition of this book, and to my
husband Anik, for his ongoing support.
I would like to thank Rhoda Alani, MD, who is an exceptional mentor to
me, for giving me the opportunity to coedit this book with her, and for always
encouraging and supporting me to take on the next step in my career
pathway.

Debjani Sahni, MD

vii
Contents

Part I Understanding Melanoma: Background,

Etiology and Histologic Diagnosis

1 Melanoma Prevention����������������������������������������������������������������������   3

Elizabeth J. R. Orrin, Pamela B. Cassidy, Rajan P. Kulkarni,
Elizabeth G. Berry, and Sancy A. Leachman
2 Epidemiology of Melanoma������������������������������������������������������������ 31
Debjani Sahni, Suephy Chen, Erica S. Tarabadkar,
Rhoda M. Alani, and George Atteh
3 Pathogenesis of Melanoma�������������������������������������������������������������� 47
James M. Kilgour and Kavita Y. Sarin
4 The Histopathology of Melanocytic Nevi and
Malignant Melanoma���������������������������������������������������������������������� 71
Zena Willsmore and Alistair Robson

Part II Evaluation and Staging of Disease

5 Aids to Detecting Melanoma ���������������������������������������������������������� 123

Jette V. C. Hooper and Jane M. Grant-Kels
6 Evolution of Melanoma Staging ���������������������������������������������������� 139
Candice E. Brem and Lynne J. Goldberg

Part III Melanoma Management: Treatment of the Primary Lesion

7 Lentigo Maligna Melanoma������������������������������������������������������������ 157

Sara Snyder Phillips and Michelle Nguyen
8 Surgical Treatment of Primary Melanoma������������������������������������ 163
Brendin Beaulieu-Jones and Michael R. Cassidy
9 Evolution of Neoadjuvant Therapy in Melanoma������������������������ 175
Bilal Fawaz, Gordana Rasic, and Teviah E. Sachs

ix
x Contents

Part IV Melanoma Management: Treatment of Regional Disease

10 Sentinel Lymph Node Biopsy and Nodal Surgery������������������������ 185

Brendin Beaulieu-Jones and Michael R. Cassidy
11 Adjuvant Systemic Therapy for Stage III Melanoma������������������ 199
Adam Lerner and Debjani Sahni
12 Adjuvant Radiation Therapy for Stage III Melanoma���������������� 203
Sonny Batra, Justin Park, and Minh Tam Truong

Part V Melanoma Management: Treatment of Systemic Disease

13 Systemic Therapy of Advanced Melanoma ���������������������������������� 219

Adam Lerner, Vanessa Furtado, and Debjani Sahni
14 Radiation Therapy in Advanced Melanoma���������������������������������� 239
Michael A. Dyer, Christa M. Lam, Muhammad M. Qureshi,
and Minh Tam Truong

Part VI Melanoma Management: Future of Melanoma Management

15 Novel Therapies in Melanoma�������������������������������������������������������� 271

Bilal Fawaz, Debjani Sahni, and Adam Lerner
16 Predictive Biomarkers of Melanoma���������������������������������������������� 285
Ailish Hanly, Frederick Gibson, and Rhoda M. Alani

Part VII Melanoma Subtypes in Targeted Populations

17 Acral Melanoma������������������������������������������������������������������������������ 303

Bilal Fawaz, Hannah Kopelman, and Debjani Sahni
18 Mucosal Melanoma�������������������������������������������������������������������������� 309
Sanghee Lim, Ali Al-Haseni, and Debjani Sahni
19 Melanoma in Pediatric Patients������������������������������������������������������ 323
Hilary Haimes, Lisa Y. Shen, and Margaret S. Lee
20 Melanoma in Skin of Color ������������������������������������������������������������ 335
Nicole Patzelt and Neelam A. Vashi
21 Melanoma in Pregnancy������������������������������������������������������������������ 343
Alexander M. Cartron, Jane M. Grant-Kels,
and Marcia S. Driscoll
Index���������������������������������������������������������������������������������������������������������� 357
About the Editors

Rhoda M. Alani, MD, serves as the Herbert Mescon Endowed Professor

and Chair of Dermatology at the Boston University School of Medicine and
Boston Medical Center. She received her MD degree with Honors and
Distinction in Research from the University of Michigan Medical School and
completed her internship in internal medicine at Yale-New Haven Hospital
and a residency in dermatology at Harvard Medical School followed by post-
doctoral training at Harvard Medical School and Memorial Sloan-Kettering
Cancer Center. From 1999 to 2009, Dr. Alani was the director of the
Laboratory of Cutaneous Oncology at the Johns Hopkins University School
of Medicine where she also served as the director of the Melanoma and
Pigmented Lesion Clinics in Dermatology. Dr. Alani’s research focus is in
understanding the molecular basis of melanoma development and progres-
sion with the aim of translating her laboratory findings to improve the preven-
tion, detection, diagnosis, and treatment of melanoma. Her current research
efforts seek to understand the epigenetic basis for melanoma development
and progression and are supported by the National Institutes of Health,
Department of Defense, and the Melanoma Research Alliance. Dr. Alani is a
member of Phi Beta Kappa and Alpha Omega Alpha Honor Societies, the
American Academy of Dermatology, the Society for Investigative
Dermatology, the Society for Melanoma Research, and the American
Association for Cancer Research and was elected to the American Society for
Clinical Investigation in 2005 and to the American Dermatological Association
in 2011. She is the author of numerous scientific publications and is the owner
of several US patents related to melanoma biomarkers, novel melanoma ther-
apies, and imaging systems for improved melanoma detection.

xi
xii About the Editors

Debjani Sahni, MD, is the G. Robert Baler Endowed Professor and Director
of the multidisciplinary Cutaneous Oncology Program at the Boston
University School of Medicine and Boston Medical Center, where she spe-
cializes 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 her
Membership of the Royal College of Physicians (MRCP), she completed der-
matology residency at the St John’s Institute of Dermatology in London. She
subsequently undertook a cutaneous 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 avail-
able in the USA. Her academic interests include teaching and mentoring for
which she is the recipient of several teaching awards and an external exam-
iner 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.
 Part I
Understanding Melanoma: Background,
Etiology and Histologic Diagnosis
 Melanoma Prevention
1
Elizabeth J. R. Orrin, Pamela B. Cassidy,
Rajan P. Kulkarni, Elizabeth G. Berry,
and Sancy A. Leachman

1.1 Introduction In the United States, mortality has recently fallen

significantly and it is unclear whether this is due
Cutaneous melanoma inflicts a heavy global to increased use of novel targeted- and immuno-
health burden. It continues to increase in inci- therapies, better detection, or a combination of
dence worldwide, and deaths from the disease the two. Prevention of lethal melanoma, includ-
occur primarily in the United States (18%) and ing early detection, is an important component in
Europe (45%) (http://gco.iarc.fr). In the United our arsenal to control and overcome this too fre-
States alone, the current melanoma mortality rate quently fatal disease.
stands at 2.1 deaths per 100,000 every year [1]
with estimated annual treatment costs of $3.3 bil- Definitions: Primary, Secondary, and Tertiary
lion [2]. Late diagnosis confers a particularly Prevention
high mortality rate [3]. The five-year survival of There are three categories of intervention
patients with localized melanomas is almost 99% designed to reduce the burden of melanoma: pri-
but drops to 25–50% for those with distant metas- mary, secondary, and tertiary prevention. As the
tases [4]. Early excision leading to cure has name implies, primary prevention targets the root
become increasingly frequent, yet overall mortal- cause of the disease. In the case of cancer, and
ity has continued to increase in many countries. specifically melanoma, the primary cause is

Knight Cancer Institute, Oregon Health and Science

E. J. R. Orrin
University, Portland, OR, USA
Department of Dermatology, Oregon Health and
Science University, Portland, OR, USA Department of Biomedical Engineering, Oregon
Health and Science University, Portland, OR, USA
King’s College Hospital, London, UK
Department of Radiation Oncology, Oregon Health
P. B. Cassidy · S. A. Leachman (*)
and Science University, Portland, OR, USA
Department of Dermatology, Oregon Health and
Science University, Portland, OR, USA Division of Operative Care, Portland VA Medical
Center (PVAMC), Portland, OR, USA
Knight Cancer Institute, Oregon Health and Science
University, Portland, OR, USA Cancer Early Detection and Advanced Research
e-mail: [email protected] Center (CEDAR), Portland, OR, USA
R. P. Kulkarni E. G. Berry
Department of Dermatology, Oregon Health and Department of Dermatology, Oregon Health and
Science University, Portland, OR, USA Science University, Portland, OR, USA

© Springer Nature Switzerland AG 2021 3

R. M. Alani, D. Sahni (eds.), Melanoma in Clinical Practice,
https://doi.org/10.1007/978-3-030-82639-0_1
4 E. J. R. Orrin et al.

mutations that lead to a stepwise progression to (therapy, drug, natural product) to intervene in the
malignancy [5]. Because ultraviolet radiation process of tumorigenesis in the primary, second-
(UV) exposure is the best characterized, estab- ary, or tertiary setting, and can sometimes target
lished, and modifiable environmental cause of more than one category of prevention.
mutations in melanoma, most primary prevention Categorization as a primary, secondary, or tertiary
for melanoma aims to block or ameliorate the preventive therapeutic (or multi-category) depends
effects of UV-induced mutagenic insults in other- on the mechanism of action. If the agent prevents
wise healthy individuals. normal skin from transforming into a pre-lethal
state, it is a primary preventive and if it prevents
Secondary prevention of melanoma consists progression of an existing pre-lethal primary
of interventions that are effective when the trans- lesion, it is a secondary preventive. If the agent has
formation to malignancy has already occurred (or preventive effects on both normal and pre-lethal
is imminent) and prevention depends on both lesions, it can be classified as both a primary and a
detecting and removing the early cancer before it secondary preventive therapeutic agent.
attains metastatic or lethal potential. Secondary
prevention can also involve stopping the progres- Melanoma Risk Factors
sion of transformed cells to lethal cancers. Because prevention interventions can lead to
Because most melanoma is visible on the surface unintended harms, the risk of any intervention
of the skin prior to the development of metastatic should be appropriate for the level of risk in the
potential, melanoma early detection (secondary individual and/or population. Stratifying risk in
prevention) can include skin screening by patients different individuals and populations aids in
and providers with the naked eye and with more assessing the suitability of a particular interven-
advanced tools designed to improve detection. tion. The Fitzpatrick skin type (or phototype) is
These tools include dermoscopy, reflectance one of the best characterized and most utilized
in vivo confocal microscopy, and a myriad of scales for assessing an individual’s response to
burgeoning molecular diagnostic and prognostic ultraviolet radiation and risk for melanoma
tests. Less clear within the field of secondary pre- (Fig. 1.1 and Table 1.1). The scale is as follows:
vention is the question of whether atypical nevi, Type I (very white skin, often freckled) always
which are non-obligate precursors of melanoma burns, and never tans; Type II (white skin) usu-
[6], have progressed sufficiently towards malig- ally burns and minimally tans; Type III (cream-­
nancy to be considered pre-lethal, and should white to light brown skin) sometimes mildly
therefore be excised. In various contexts, a pre-­ burns and tans uniformly; Type IV (dark olive to
lethal melanocytic lesion may be defined as an moderate brown skin) burns minimally and
atypical or dysplastic nevus, melanoma in situ, or always tans well; Type V (dark brown skin) very
invasive melanoma. For the purposes of this rarely burns and tans very easily; and Type VI
chapter, a broad definition is applied. Any form (very dark brown to black skin) never burns [15].
of screening for melanoma is considered second- Skin types I and II are associated with approxi-
ary prevention based upon the intent to remove mately double the risk of developing melanoma
an existing lesion that appears to be dangerous. relative to skin type IV. Despite its widespread
Tertiary prevention aims to reduce recurrence use in assessing skin vulnerability to UV damage
and further spread of metastases, usually follow- and skin cancer, reproducibility of the scale, even
ing successful treatment of a melanoma that has when performed by dermatologists, can be chal-
already metastasized to the lymph nodes or other lenging without standardization [16].
distant organs. Tertiary prevention modalities A notable gap in current data-based guidelines
such as the use of adjuvant therapy or radiation is the lack of definition of the level of risk that
therapy will not be discussed in this chapter. warrants routine screening by providers. Several
Chemoprevention, also known as therapeutic risk calculators have been published and some
prevention, entails the use of an exogenous agent are available online [17–25]. However, to date,
1 Melanoma Prevention 5

I Very white skin, highly sensitive to II White skin, very sun sensitive, usually
sun, almost always burns, almost never tans burns, tans to a light brown

III Cream white to olive skin, sun IV Dark olive to moderate brown skin,
sensitive, occasionally burn, tans to a minimally sun sensitive, burns minimally,
medium brown tans to a dark brown

V Dark brown skin, sun insensitive, very VI Deeply pigmented skin (dark
rarely burns, tans easily brown/black skin), sun insensitive, never
burns

Fig. 1.1 Fitzpatrick phototypes. Figure provided courtesy of the War on Melanoma™

none have been widely applied to national screen- summary of literature concerning the relative risk
ing programs or studied with respect to risk or (RR), of developing melanoma. This study exam-
cost benefit. Johnson et al. [26] have published a ines genetic, iatrogenic, and environmental risk
6 E. J. R. Orrin et al.

Table 1.1 Risk levels for melanoma as determined by risk factors—Reference population for relative risk is a general
population without the risk factor except as noted
Melanoma risk (RR
Risk level Melanoma risk factors except as noted)a
Moderate risk Total common nevi >15 [1] 1.5
Total common nevi 41–60 versus <15 [1] 2.2
1 atypical nevus 1.5
2 atypical nevi 1.5
High density of freckles vs low 2.1
Blue eye color vs dark [2] 1.5
Hazel eye color vs dark [2] 1.5
Green eye color vs dark [2] 1.6
Light brown hair vs dark [2] 1.6
Blond hair vs dark [2] 2.0
Fitzpatrick I phototype 2.1
Fitzpatrick II phototype 1.8
History of sunburn [4] 2.0
Indoor tanning use in any gender [7] 1.7c
High risk Total common nevi 61–80 vs < 15 [1] 3.3
3 atypical nevi [1, 4] 3.0
4 atypical nevi [1, 4] 4.4
Red hair vs dark [2] 3.6
Family history of melanoma in one or two first-degree relatives [2, 8] 1.7–3
History of AK and/or KC [2] 4.3
CLL [9] 3.9b
Indoor tanning use in women aged 30–39 years [7] 4.3
Transplant recipient [10, 11] 2.2–4.6b
Ultra-high risk Total common nevi 101–120 vs <15 [1] 6.9
5 atypical nevi [1] 6.4
Personal history of melanoma [12] 8.2–13.4
CDKN2A mutation carrier [13] 14e–28f
3 or more relatives on the same side of the family affected [8] Up to 35–70
Indoor tanning use in women aged <30 years [7] 6.0c
MC1R R/R genotyped and ≥20 nevi >5 mm vs wildtype MC1R and 0–4 25.1c
nevi [14]
AK actinic keratosis, KC keratinocyte carcinoma, CLL chronic lymphocytic leukemia
a
RR = relative risk
b
Standardized incidence ratio (SIR)
c
Odds ratio (OR)
d
Patients with loss-of-function mutations commonly associated with the red hair phenotype in both alleles of the MC1R
gene
e
Absolute risk by age 50
f
Absolute risk by age 80

factors. They recommended assignment of risk 1.2 Primary Prevention

factors into moderate, high, and ultra-high-risk (Table 1.2)
categories (Table 1.1). Petrie et al. have extended
this concept of risk categories to include different Ultraviolet radiation (UV) is currently the most
outreach and screening methodologies by risk important modifiable risk factor for melanoma
class and provider specialty [27]. development and is classified as a group 1 car-
1 Melanoma Prevention 7

Table 1.2 What simple primary preventative messages [29]. Elevation, time of day, and season all influ-
should we regularly be giving to patients? ence the distance sunlight travels through the
Clothing atmosphere, which changes the amount and
 • Cover up with clothing. Tighter knit and darker wavelengths of radiation that reach the earth’s
clothes give better ultraviolet protection.
surface. Another source of variation is the degree
 • Some clothes carry a UPF rating; a UPF of 20+
gives good protection. However, good protection to which a particular wavelength is absorbed by
can still be achieved with nonspecialist clothing. the earth’s ozone. UVB (280–315 nm) is
 • UV dyes that increase the UPF of clothing can be absorbed to a greater degree than UVA (315–
effective. 400 nm) (approximately 95% and 5%, respec-
Sunscreen
tively). UVC (100–290 nm) is highly mutagenic,
 • Sunscreen reduces the rate of skin cancer,
including melanoma. but it is almost completely absorbed by the
 • Apply sunscreens before going in the sun. Most earth’s atmosphere and is not relevant to mela-
people underuse sunscreens; one ounce (a full shot noma pathogenesis [28].
glass) is required to cover the entire body covered UVA and UVB affect the human body differ-
only by a swimsuit.
ently due to degree of penetration in the skin, the
 • Use broad-spectrum sunscreens marked as SPF 50
or greater. different energy levels they contain, and the vary-
 • For those concerned about the environmental ing absorption spectra of chromophores in the
impact or safety of chemical sunscreens, we skin [30]. The epidermis of the skin serves as a
recommend physical sunscreens. barrier to UV through absorption by its constitu-
Supplements, antioxidants and vitamin D
ent chromophores and by scattering. For UV
 • There is currently no drug, supplement, or natural
product known to lower melanoma risk. wavelengths <300 nm, amino acids, nucleic
 • Sunscreens are very unlikely to cause vitamin D acids, and melanin are the main chromophores.
deficiency. However, if you are concerned, talk to For UVA the main chromophore is melanin.
your doctor about your individual risk of vitamin Longer wavelengths of UV penetrate deeper into
D deficiency.
the skin [31].
UVA is most effective at causing tanning of
cinogen by the International Agency for Research the skin, while UVB is 1000 times more effective
on Cancer (IARC). UV is a “complete carcino- at producing erythema than an equivalent dose of
gen,” meaning that it is capable of facilitating energy in the UVA portion of the spectrum [32].
both initiation of skin cancers and the progres- Effects of UVA on the skin include immediate
sion of premalignant lesions. Until other environ- pigment darkening, within minutes, and persis-
mental or nutritional risk factors are identified, tent pigment darkening, which may last for a day.
primary prevention for melanoma focuses on Delayed tanning is initiated by a response to
reducing an individual’s exposure and/or sensi- DNA damage in keratinocytes, which initiate the
tivity to UV. synthesis of α-melanocyte-stimulating hormone
(α-MSH) by the p53-driven expression of the
gene encoding its pro-hormone, POMC.
1.2.1 Ultraviolet Radiation Activation of pigment synthesis in melanocytes
Exposure and Effects ensues when α-MSH activates its receptor, the
melanocortin-1 receptor (MC1R) [33].
There is up to a fourfold variance in an individu-
al’s solar UV exposure depending on global
location and time of year [28]. The dose and 1.2.2 UV-Induced DNA Mutagenesis
wavelength of UV exposure can vary in different
climates, elevations, and environments based on Both UVA and UVB are carcinogenic.
how much UV has been absorbed or reflected by UV-induced DNA damage that can result in
the surrounding environment or atmosphere mutations occurs by two main mechanisms: