Transcript Dermatology for the Internist

Dermatology for the Internist
LORIE GOTTWALD, MD
PROFESSOR AND CHIEF
DIVISION OF DERMATOLOGY
UNIVERSITY OF TOLEDO
Objectives
 Review common dermatological conditions
recognizing uncommon variants; why are these
important?
 Distinguish which cases to refer, and to whom
 List emerging therapies
Disclosures
 Speakers Bureau: Amgen, Centicor, Abbott,
Galderma
 Consultant: Abbott
Outline
 Skin Cancers
 Non-Melanoma Skin Cancers (NMSC)--Basal and Squamous
Cell
 Melanoma
 Psoriasis
 Manifestations of Systemic Disease
Skin Cancers
 Why?
 More than 3.5 million skin cancers in 2.5 million patients in
U.S. annually
 Current estimates are that 1 in 5 Americans will develop skin
cancer in their lifetime
 By 2015, in in 50 will develop melanoma
 Melanoma is the most common form of cancer for young
adults aged 25-29, second most common for 15-29
 On average, one person dies from melanoma every hour
Skin Cancers
 Why?
 Basal and squamous cell cancers have cure rates approaching
95% if detected and treated early
 If melanoma is detected early, 5 year survival rates approach
98%
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This decreases to 62% for regional disease, and 15% for distant
spread
In 2004, the direct cost associated with treating nonmelanoma skin cancer was $1.5 billion in the U. S.
The 2010 cost for treating melanoma in the U.S. was $2.36
billion
This is a huge burden!
Non-Melanoma Skin Cancers
Basal Cell Carcinoma
 Basal Cell Carcinoma
 Classic pearly papule with central ulceration, telangectasia
 26 variants exist: nodular, superficial, sclerosing, multifocal,
pigmented, basosquamous, cystic et cetera
 May have history of radiation treatment—i.e. acne
 Comprises 80-85% of skin cancers; most common human
cancer overall
 Usually slow-growing; derived from hair follicle/pilosebaceous
unit
 Treatment via excision, 5-fluorouracil, dessication and
currettage, Mohs surgery, cryosurgery, radiation therapy,
chemical peels, laser, imiquimod , photodynamic therapy,
chemotherapy --vismodegib
Squamous Cell Carcinoma
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Clinical appearance varies: Scaly, keratotic plaque; primary
ulceration; exophytic, eroded plaque
Often a history of tenderness of the lesion
Precursor lesion: actinic keratosis/cheilitis; keratoacanthoma
Sun exposed areas or prior burns/scars; check history for
arsenic or radiation exposure, tobacco use
Arises from keratinocytes
Head and neck areas herald higher metastatic rate
Treatment same as for basal cell carcinoma save not
responsive to imiquimod/vismodegib
Management Caveats—When to Refer
 Histology
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BCC: Sclerosing/morpheaform; multifocal, micronodular,
recurrent/within scar tissue—BAD signs
SCC: Moderately to poorly differentiated; neurotropic, inflitrating;
adenoid/adenosquamous/desmoplastic
 Size
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Anything greater than 20 mm or greater than 6 mm if in a high risk
area
 Location
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Mask areas of face; genitalia; hands/feet; cosmetically sensitive
 Clinical
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Concomitant immunosuppression
Chronic inflammation/ulceration/scarring
Genetic disorders
Emerging Therapies: Basal Cell
 Vismodegib
 Small molecule inhibitor of the hedgehog signaling pathway
 Approved for the treatment of metastatic basal cell carcinoma or locally advanced
disease that has recurred after surgery or for those who are not candidates for
surgery or radiation therapy; recent approval for basal cell nevus syndrome
 150 mg daily oral dosing
 30% response rate in metastatic disease; 43% in locally advanced disease; mean
duration 7.6 mos NEJM 2012; 366: 2171-2179
 Significant side effects: muscle spasms, alopecia, dysgeusia, fatigue, weight
loss—30%
 Cost--$90,000/yr
 Sequential intralesionial interferon therapy
 Mechanism of action similar to imiquimod
 Ingenol mebutate
 In clinical trials; currently only approved for actinic keratoses
 Inducer of cell death; exact mechanism of action unknown
Emerging Therapies: Squamous Cell
 Cituximab
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Monoclonal antibody directed against the human epidermal growth
factor receptor has been approved in combination with radiation
therapy for locally advanced head and neck disease
 Antiangiogenic therapies and tyrosinase kinase
(gefitinib and erlotinib) in clinical trials
 Anti-vascular endothelial growth factor and human
epidermal growth factor vandetanib in clinical trial
 Oral retinoid therapy
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Multiple studies in organ transplant, immunocompetent and –
compromised, and high UV exposure patients
 Ingenol mebutate
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Clinical trials
Melanoma
Risk Factors
 Personal history of melanoma
 Family history of melanoma
 Atypical (>5) or multiple moles (>50)
 Fair skin type
Light eyes
 Red-blonde hair
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 Sunburn—Particularly prior to age 21 or intermittent
 Two outdoor summer jobs as a youth
 Giant congenital nevi (>15 cm)
 Genetic markers and/or syndromes
Risk Factors
 Higher income level
 Tanning Bed Use
Tanning beds can emit UVA and UVB radiation at fifteen
times the strength of the sun
 Int J Cancer 2007—meta-analysis of 19 studies
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RR 1.15 for melanoma with tanning bed use
 RR 1.75 if tanning began prior to age 35
 No protective effect of tanning bed against damage from
subsequent sun exposure
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Definition
 Cancer of melanocytes, the pigment producing cells of
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the skin
Melanocytes reside at the basal cell layer of the skin
Neuroectodermal in origin
Other common areas: retina, Organ of Corti, adrenal
glands, leptomeninges
Multiple variants:
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Superficial spreading, nodular, lentigo maligna melanoma, acral
lentiginous, amelanotic, nevoid, malignant blue nevus, desmoplastic,
clear cell sarcoma type, animal type
Can be very difficult to classify both clinically and pathologically
Self-exam components
 ABCD (and sometimes E!)
 Asymmetry
 Border Irregularity
 Color Irregularity
 Diameter
 Extension or Elevation
 The “Ugly Duckling” sign
 Looking for the “outlying” mole Arch Dermatol 2008
Jan:144(1): 58-64
Assessment
 Breslow level
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Measurement of depth of invasion from granular cell layer
down to last malignant cell
Expressed in millimeters
 Ulceration
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Gross or microscopic
 Mitotic rate
 Histology—Number of dermal mitoses per mm2 (1 mm2=4.5
high power(40x) fileds
 Replaced Clark level for defining T1b subcategory
 N staging
 Micro- (a) or macro- (b) metastasis to one node broken out
Treatment
 Excision
 Breslow level defines margins
In situ—1/2 cm margins
 < or = 1mm—1 cm margins
 > 1mm to 2mm—1-2 cm margins
 > 2mm– 2 cm margins
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 Consideration of SLN biopsy for lesions > 1mm thick
or discordant Clark/Breslow
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Ulceration
High mitotic rate
Survival curves by number of mitoses per millimeter squared.
Thompson J F et al. JCO 2011;29:2199-2205
©2011 by American Society of Clinical Oncology
Survival curves from the American Joint Committee on Cancer Melanoma Staging Database
comparing (A) the different T categories and (B) the stage groupings for stages I and II
melanoma.
Balch C M et al. JCO 2009;27:6199-6206
©2009 by American Society of Clinical Oncology
Treatment
 Sentinel lymph node biopsy
 Status of sentinel lymph node is most important prognostic
indicator for disease-specific survival in patients with primary
cutaneous melanoma
 Impact on overall survival remains unclear
 Not recommended for in situ or T1a
 Not certain of effect of adjuvant interferon therapy—promising
8-9% increased survival for stage III disease—ECOG 1684 trial
 Significant toxicity
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Kaplan-Meier survival for patients undergoing successful lymphatic mapping and SLN biopsy
stratified by SLN status.
Gershenwald J E et al. JCO 1999;17:976-976
©1999 by American Society of Clinical Oncology
Recommendations
Baseline laboratory tests and imaging studies are generally
not recommended in asymptomatic patients with newly
diagnosed primary melanoma of any thickness.
No clear data regarding follow-up interval exist, but at
least annual history and physical examination with
attention to skin and lymph nodes is recommended.
Regular clinical follow-up and interval patient selfexamination
of skin and regional lymph nodes are most
important means of detecting recurrent disease or new
primary melanoma; findings from history and physical
examination should direct need for further studies to
detect local, regional, and distant metastasis.
Surveillance laboratory tests and imaging studies in
asymptomatic patients with melanoma have low yield
for detection of metastatic disease and are associated
with relatively high false-positive rates.
J AM ACAD DERMATOL
VOLUME 65, NUMBER 5
Bichakjian et al 1039
Management Caveats: When to Refer
 American Academy of Dermatology
 All patients with a prior diagnosis of melanoma should be seen
by a Dermatologist annually
 Greater frequency if newly diagnosed based on the staging
 All first degree relatives should be screened
 Regular eye examination
 Multidisciplinary melanoma clinics based on patient,
staging, recurrence
 Safest just to refer
Management Caveats
 When will you get in trouble?
 Resting on the laurels of a “negative” biopsy
 Resting on the laurels of time
 Not listening to patient
 Not undressing patient
 Not counseling patient or family
 Share the responsibility
New and Emerging Therapies
 Vemurafenib
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Inhibitor of mutated BRAF genes; 40-60% of melanomas carry this
mutation—”mutation-specific” therapy
86% ages 20-30
 22% aged 70+
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Pivotal trial versus dacarbazine for stage IIIc or IV disease
At 6 mos, survival 84% in vemurafenib group, 64% dacarbazine
 Median progression free survival in vemurafenib group 5.3 mos versus
1.6 with dacarbazine NEJM 2011; 364: 2507-2516
 Overall still very poor prognostic rates
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Not a durable drug—resistance occurs; anti-sense therapy candidate?
Targets bcl 2 gene expression
Significant side effect of eruptive keratoacanthomata, squamous cell
carcinomata—amongst others
New and Emerging Therapies
 Ipilimumab
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Inhibitor to CTLA4 (inhibits the inhibitor)
3mg/kg every three weeks/ 4 cycles
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Ipilimumab and gp vaccine/ipilimumab alone/vaccine alone Hodi
NEJM 2010; 363:711
10 mos drug and vaccine median survival
 10.1 drug alone
 6.4 vaccine alone
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Ipilimumab 10 mg/kg +dacarbazine v dacarbazine mono Robert
NEJM 2011
Median 11.2 mos for both drugs
 9.1 mos dacarbazine alone
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New and Emerging Therapies
 Ipilimumab: Significant side effects
 Colitis
 Cutaneous
Stevens-Johnson/Toxic Epidermal Necrolysis
 Generalized eruptions
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Autoimmune hepatitis
Endocrine abnormalities
Thyroid
 Pituitary
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Demyleination
Severe or fatal Sea in 10-15% of patients
Cost $120,000 for a 70 kg person
Psoriasis
Psoriasis
 Why?
 Psoriasis affects 2.9 million people in the United States alone;
1.7 million seek treatment
 Average age of onset 28 years; 10% are under 10 years of age
 Skin lesions can antedate arthritic symptoms by ten years; 25%
have arthritis
 400 psoriasis related deaths each year
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Metabolic , treatment-related, suicide
About 25% of patients have moderate to severe disease
Body surface area measurements
 Psoriasis Area and Severity Index (PASI) scores
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Psoriasis
 Psychological burden
 Increased obesity and higher incidence of smoking—Utah
Psoriasis Initiative
 Higher incidence of diabetes, hypertension, hyperlipidemia,
obesity and smoking—EADV
 Greater risk of myocardial infarction—JAMA
2006;296:1735-41
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Independent of co-morbidities
 Increased risk of diabetes mellitus and likelihood of
treatment for such Arch Dermatol 2012;148(9):995-1000
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Independent of co-morbidities
 Inherent risk of lymphoma
Psoriasis Co-Morbidities
Psoriasis Co-Morbidities
Psoriasis can present as all of the following
except:
 A. Erythroderma
 B. Isolated hand/foot disease
 C. Pustules
 D. Without cutaneous disease at all
 E. Only at the groin and axillae
 F. On the mucous membranes
F. On the mucous membranes
Types of Psoriasis
 Plaque
 Most common, 80% of all cases
 Raised, red scaly lesions
 Guttate
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Small, dot-like lesions
 Erythrodermic
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Intense redness, inflammation, some scaling
 Pustular
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Pus-filled lesions, some scaling;
often localized to palms and soles
Photos from the National
Psoriasis Foundation
Types of Psoriasis
 Nail
 Pitting, onycholysis, “oil drop” changes
 Inverse
 Intertriginous areas
 Annular
 Circumferential and sepriginous
 Psoriatic arthritis
Therapies/Emerging Therapies
 Standard
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Topicals: Steroids, vitamin A and D derivatives, tar, anthralin
Systemic: Methotrexate, Acitretin, Cyclosporine, Sulfasalazine’
Mycophenolate mofetil, hydroxyurea
Phototherapy and chemophototherapy
 Biologic
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TNF-alpha blockers: Infliximab, etanercept, adalimumab,
golimumab
IL 12/23 blocker: Ustekinumab
T cell blocker: Alefacept
 Watch for: Infection, heart failure, demyelinization
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Non-melanoma skin cancer, lupus, hematologic
No increase in lymphoma to date with psoriasis use
Emerging Therapies
 Biologic
 TH 17 blockers
 Three finishing phase three trials
 Systemic
 Fumaric acid esterases
Management Caveats
 Referral
 Anyone with moderate to severe disease
 Suspected psoriatic arthritis
 Erythroderma
 Difficult presentation—inverse, pustular
 Screening questions
 Co-morbidities well documented
 Accountability for management
Manifestations of Internal
Disease
(THERE ARE WELL OVER A HUNDRED)
What is your diagnosis?
 A. Stasis dermatitis
 B. Cellulitis
 C. Necrobiosis lipoidica
diabeticorum
 D. Psoriasis
Stasis Dermatitis
 Inflammatory changes of the lower extremities in
association with edema
 Peripheral vascular disease/venous
insufficiency/congestive heart failure
 Acute stages/exacerbations associated with bright
erythema; chronic cases with progressive
lichenification, pigmentation
 Frequently mistaken for cellulitis, vasculitis, venous
thrombosis, diabetic dermopathy
Management of this lesion should include:
 A. Wide surgical
debridement
 B. Oral Vitamin C
supplementation
 C. IV antibiotics
 D. Oral steroids
D. Oral steroids
Pyoderma Gangrenosum
 Erythematous nodules progressing to pustules and
eventually ulcers; heal with characteristic
“cribriform” scarring
 Adults aged 40-60; seen in association with
ulcerative colitis, rheumatoid arthritis, monoclonal
gammopathies, hepatitis, leukemia
 Neutrophilic infiltration of the skin leads to
abscesses and breakdown
Pyoderma Gangrenosum
 Bullous variant recognized, associated with
hematologic disorders
 Differential diagnosis
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Venous ulcers/vascular disease
Infectious processes
Sweet’s syndrome
Erythema nodosum
 Treatment via immunosuppressives and local care;
biologics
What should we screen for in this condition?
 A. ANA
 B. CCP or RA
 C. Blood glucose
 D. Zinc deficiency
C. Blood glucose
Necrobiosis Lipoidica Diabeticorum
 Well-circumscribed, yellow-brown plaques with an
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erythematous border
Progress to atrophic or slcerotic patches
Lower extremities>>upper extremities;
women>>men
Strong association with the development of diabetes
mellitus
Differential diagnosis
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Dermatitidies, Erythema nodosum, Infection
You see these lesions on a patient’s ankle—
where else should you look?
Lichen Planus
 Pruritic, purple, polygonal papules and plaques
 Overlying reticulate scale—”Wickham’s striae”
 Widespread or localized
 Hypertrophic variant recognized—predominately
lower extremities; lichen planus pemphigoides bullous
variant
 Skin and mucous membranes; nails show “angel wing”
deformity; scarring hair loss
 Oral forms can rarely lead to squamous cell carcinoma
Lichen Planus
 Can see as an overlap with lupus erythematosus
 Unknown etiology; association with Hepatitis C,
medications including non-steroidals, beta-blockers,
thiazides, antimalarials, penicillamine, others
 Multiplicity of forms makes differential extensive
What should you do for this patient?
 A. Perform a biopsy for
H and E staining
 B. Begin treatment for
psoriasis
 C. Check an RPR
 D. Counsel not to
worry—this is a self
limited viral infection
A. Perform a biopsy
Sarcoidosis
 Granulomatous disease of uncertain etiology
 Violaceous papules and plaques; favor African-
American women
 Great mimicker—verrucous, ulcerative,
hypopigmented variants; can arise in scars
 Centro-facial involvement heralds higher incidence
of pulmonary and bony disease
Sarcoidosis
 Must do systemic evaluation after confirmatory
biopsy
 Alterations in cell-mediated immune responses
 Rare overlap syndrome with lymphoma
 Corticosteroids/chloroquine mainstay; biologics
increasing in favor but may be controversial
This patient is experiencing progressive thickening of the
skin with a loss of flexion/extension. What is a key part of
her history?
 A. Experienced a tick
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bite
B. Has renal failure
C. Has had MRIs with
exposure to Gadolinium
D. Is ANCA positive
E. B and C
E. B and C above
Nephrogenic Systemic Fibrosis
 Fibrosis or hardening of the skin and internal organs
suggestive of, but distinct from, scleroderma or
scleromyxedema
 Seen exclusively in patients with renal
failure/insufficiency with or without hemodialysis
 Length or cause of kidney disease not relevant
Nephrogenic Systemic Fibrosis
 Diagnosis made by histopatholgy in conjunction with
clinical setting
 Pathophysiology not understood
 Improvement in renal function can lead to some
improvement in clinical disease, but not consistent
 No single effective treatment modality
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All anecdotal/case report
Nephrogenic Systemic Fibrosis
 Incidence equal between males , females
 Affects all ages, though middle-aged more common
 No ethnic predilection
 Can be widespread and fulminant in 5% of cases
 Extensive skin hardening can lead to contractures and
rapid progression to wheelchair status
Nephrogenic Systemic Fibrosis
 Higher incidence in patients that have undergone
surgical procedures—i.e. fistula placement, or have a
history of clotting—question relation to imaging
needs
 Recent association with use of Gadolinium-
containing contrast agents in MRI/MRA studies has
led to an FDA cautionary announcement
This is not ringworm . . .!
Granuloma Annulare
 Serpiginous, annular plaques with peripheral
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expansion
Lightly erythematous to flesh-colored; no epidermal
change
Pediatric age group favored
Frequently at sites of trauma
Singular or eruptive forms
May spontaneously involute
Granuloma Annulare
 Association with diabetes mellitus
 New association with dyslipidemia Arch Dermatol
2012;148 1131-7
 Differential diagnosis
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Sarcoidosis
Lichen planus
Tinea corporis
Amyloidosis
 Treatment success highly variable; steroids mainstay