1. LORIE GOTTWALD, MD PROFESSOR AND CHIEF DIVISION OF DERMATOLOGY UNIVERSITY OF TOLEDO Dermatology for the Internist

3. Objectives Review common dermatological conditions recognizing uncommon variants; why are these important? Distinguish which cases to refer, and to whom List emerging therapies

4. Disclosures Speakers Bureau: Amgen, Centicor, Abbott, Galderma Consultant: Abbott

5. Outline Skin Cancers  Non-Melanoma Skin Cancers (NMSC)--Basal and Squamous Cell  Melanoma Psoriasis Manifestations of Systemic Disease

7. 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

8. 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%  This decreases to 62% for regional disease, and 15% for distant spread  In 2004, the direct cost associated with treating non- melanoma skin cancer was $1.5 billion in the U. S.  The 2010 cost for treating melanoma in the U.S. was $2.36 billion

9. This is a huge burden!

10. Non-Melanoma Skin Cancers

14. 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

16. Squamous Cell Carcinoma  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

18. Management Caveats—When to Refer Histology  BCC: Sclerosing/morpheaform; multifocal, micronodular, recurrent/within scar tissue—BAD signs  SCC: Moderately to poorly differentiated; neurotropic, inflitrating; adenoid/adenosquamous/desmoplastic Size  Anything greater than 20 mm or greater than 6 mm if in a high risk area Location  Mask areas of face; genitalia; hands/feet; cosmetically sensitive Clinical  Concomitant immunosuppression  Chronic inflammation/ulceration/scarring  Genetic disorders

20. 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

21. Emerging Therapies: Squamous Cell Cituximab  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  Multiple studies in organ transplant, immunocompetent and – compromised, and high UV exposure patients Ingenol mebutate  Clinical trials

22. Melanoma

25. Risk Factors Personal history of melanoma Family history of melanoma Atypical (>5) or multiple moles (>50) Fair skin type  Light eyes  Red-blonde hair 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

26. 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  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

27. Definition Cancer of melanocytes, the pigment producing cells of 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:  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

28. 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

29. Assessment Breslow level  Measurement of depth of invasion from granular cell layer down to last malignant cell  Expressed in millimeters Ulceration  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

30. 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 Consideration of SLN biopsy for lesions > 1mm thick or discordant Clark/Breslow  Ulceration  High mitotic rate

31. 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

32. 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

33. 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

34. 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

37. 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 Recommendations

38. 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

39. 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

40. New and Emerging Therapies Vemurafenib  Inhibitor of mutated BRAF genes; 40-60% of melanomas carry this mutation—”mutation-specific” therapy  86% ages 20-30  22% aged 70+  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  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

41. New and Emerging Therapies Ipilimumab  Inhibitor to CTLA4 (inhibits the inhibitor)  3mg/kg every three weeks/ 4 cycles Two studies:  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  Ipilimumab 10 mg/kg +dacarbazine v dacarbazine mono Robert NEJM 2011  Median 11.2 mos for both drugs  9.1 mos dacarbazine alone

42. New and Emerging Therapies Ipilimumab: Significant side effects  Colitis  Cutaneous  Stevens-Johnson/Toxic Epidermal Necrolysis  Generalized eruptions  Autoimmune hepatitis  Endocrine abnormalities  Thyroid  Pituitary  Demyleination  Severe or fatal Sea in 10-15% of patients  Cost $120,000 for a 70 kg person

43. Psoriasis

45. 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  Metabolic, treatment-related, suicide  About 25% of patients have moderate to severe disease  Body surface area measurements  Psoriasis Area and Severity Index (PASI) scores

46. 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  Independent of co-morbidities Increased risk of diabetes mellitus and likelihood of treatment for such Arch Dermatol 2012;148(9):995-1000  Independent of co-morbidities Inherent risk of lymphoma

47. Psoriasis Co-Morbidities

50. 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

52. Types of Psoriasis Plaque  Most common, 80% of all cases  Raised, red scaly lesions Guttate  Small, dot-like lesions Erythrodermic  Intense redness, inflammation, some scaling Pustular  Pus-filled lesions, some scaling; often localized to palms and soles Photos from the National Psoriasis Foundation

53. Types of Psoriasis Nail  Pitting, onycholysis, “oil drop” changes Inverse  Intertriginous areas Annular  Circumferential and sepriginous Psoriatic arthritis

55. Therapies/Emerging Therapies Standard  Topicals: Steroids, vitamin A and D derivatives, tar, anthralin  Systemic: Methotrexate, Acitretin, Cyclosporine, Sulfasalazine’ Mycophenolate mofetil, hydroxyurea  Phototherapy and chemophototherapy Biologic  TNF-alpha blockers: Infliximab, etanercept, adalimumab, golimumab  IL 12/23 blocker: Ustekinumab  T cell blocker: Alefacept Watch for: Infection, heart failure, demyelinization  Non-melanoma skin cancer, lupus, hematologic  No increase in lymphoma to date with psoriasis use

56. Emerging Therapies Biologic  TH 17 blockers  Three finishing phase three trials Systemic  Fumaric acid esterases

57. 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

59. (THERE ARE WELL OVER A HUNDRED) Manifestations of Internal Disease

60. What is your diagnosis? A. Stasis dermatitis B. Cellulitis C. Necrobiosis lipoidica diabeticorum D. Psoriasis

61. 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

62. Management of this lesion should include: A. Wide surgical debridement B. Oral Vitamin C supplementation C. IV antibiotics D. Oral steroids

64. 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

65. Pyoderma Gangrenosum Bullous variant recognized, associated with hematologic disorders Differential diagnosis  Venous ulcers/vascular disease  Infectious processes  Sweet’s syndrome  Erythema nodosum Treatment via immunosuppressives and local care; biologics

67. What should we screen for in this condition? A. ANA B. CCP or RA C. Blood glucose D. Zinc deficiency

68. C. Blood glucose

69. Necrobiosis Lipoidica Diabeticorum Well-circumscribed, yellow-brown plaques with an erythematous border Progress to atrophic or slcerotic patches Lower extremities>>upper extremities; women>>men Strong association with the development of diabetes mellitus Differential diagnosis  Dermatitidies, Erythema nodosum, Infection

71. You see these lesions on a patient’s ankle— where else should you look?

72. 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

73. 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

76. 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

77. A. Perform a biopsy

78. 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

79. 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

80. 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 bite B. Has renal failure C. Has had MRIs with exposure to Gadolinium D. Is ANCA positive E. B and C

81. E. B and C above

82. 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

83. 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  All anecdotal/case report

84. 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

85. 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

86. This is not ringworm...!

87. Granuloma Annulare Serpiginous, annular plaques with peripheral 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

88. Granuloma Annulare Association with diabetes mellitus New association with dyslipidemia Arch Dermatol 2012;148 1131-7 Differential diagnosis  Sarcoidosis  Lichen planus  Tinea corporis  Amyloidosis Treatment success highly variable; steroids mainstay