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Dermatology Update

I. Tumors of The Skin

A. Melanoma

1. Superficial Spreading Melanoma

a. Clinically characterized by ABCDs

b. Palpability, nodularity or ulceration imply dermal invasion

c. Lesions change shape, color, size) and progress to vertical growth phase

2. Nodular Melanoma

a. arises de novo and is not associated with a superficial spreading component

b. do not obey the ABCDs and can be jet black, amelanotic (pink) or gray

c. rapid enlargement over weeks to months

3. Acral Lentiginous Melanoma

a. located on palms, soles and nail beds

b. most common type of melanoma found in dark skinned people

c. presents as dark brown patch with irregular borders

4. Lentigo maligna (LM)

a. melanoma in situ of the head/neck in an older person

b. tumor progression is slow c. will eventually progress to invasive disease if not excised

5. Prognosis of Melanoma

a. Breslow Level: measurement of depth in mm microscopically

b. ulceration worsens prognosis independently

6. Therapy of Melanoma

a. melanoma in situ:. 5cm margins to subcutaneous tissue

b. 1 mm or less:. 1 cm margins to fascia

c. >l.5mm-4mm: 2cm margins to fascia with sentinel lymph-node procedure 

d. >4mm: 2 cm margins and elective Lymph node dissection if clinically neg

7. Genetics of Melanoma

a. Familial Atypical Mole and Melanoma (FAMM) 

b. CDKN2 mutations

B. Squamous Cell Carcinoma

1 .second most common skin cancer found in Caucasians

2.lesions of lower lip, rim of ear, dorsal hands have metastatic potential

3.nodular plaques are more aggressive and can metastasize

4.scaly patches are superficial and are not aggressive

5.excision of tumor is preferred treatment

C. Basal Cell Carcinoma

1.80% of new skin cancers

2. seen on sun-exposed skin, most often face:

3.pearly papule with telangiectasia, or scaly eroded plaque

4. almost never metastasizes, can cause extensive local damage if untreated

5. treatment is determined by tumor type, location and size; usually destruction or surgical excision.

D. Cutaneous T-Cell Lymphoma

1. Malignant T4(CD-4) cells than home to the skin; clonality suggested by PCR 

2. Begins as erythematous, atrophic scaly patches and plaques

3. Slow progression to plaques, nodules and tumors

4. When extra-cutaneous involvement occurs disease becomes very aggressive 

5. Sezary syndrome: Exfoliative erythroderma, lymphadenopathy and leukemia with >10% circulating atypical lymphocytes

6. Treatment

a. Cutaneous

i) topical nitrogen mustard

ii) UVB

iii) PUVA (Psoralen and UVA)

iv) Total body electron beam

b. Systemic

i) methotrexate

ii) combined systemic chemotherapy 

iii) extracorporeal photopheresis 

iv) retinoids 

v) interferon 

iv) DAB386IL2 infusion toxin

II. Disorders of Connective Tissue 

A. Lupus Erythematosus

1. Chronic Cutaneous Lupus Erythematosus (CCLE)

a. Localized chronic inflammatory plaques with scarring, atrophy, ANA neg 

b. Widespread disease associated with systemic disease(5%) 

c. Rx: sunscreens, topical steroids, antimalarials (hydroxychloroquine)

2. Subacute Cutaneous LE

a. Widespread, non-scarring annular or psoriasis like plaques in photodistribution 

b. ANA pos or Ro/La positive 

c. Associated with mild systemic disease; severe renal, CNS rare 

d. Rx: same as for CCLE

3. Acute Systemic Lupus Erythematosus (SLE)

a. Specific eruption: malar induration ie, butterfly rash or widespread indurated erythema of upper torso  

b. non-specific cutaneous LE phenomenon: vasculitis, alopecia, oral ulcerations, palmar erythema, periungual erythema, Raynaud's phenomenon 

c. implies multisystem disease and renal disease is common

B. Dermatomyositis

1. Inflammatory disease of striated muscles and cutaneous findings

2. Panoply of cutaneous findings

a. Heliotrope rash: reddish, purple erythema of eyelids

b. scaling, red plaques over neck, upper trunk and extensor extremities 

c. Periungual erythema and telangiectasia of posterior nail folds 

d. Gottren's papules: violaceous flat-topped papules over knuckles 

3. Association with malignancy: can precede, coincide with or occur after diagnosis is made. Most common tumors are lung and breast.

C. CREST

1. A variant of localized scleroderma with mild systemic features.

2. Clinical findings

a. Calcinosis cutis

b. Raynaud's phenomenon

c. Esophageal dysmotility

d. Sclerodactyly

e. Telangiectasias

3. Most patients are anti-centromere positive

III. Inflammatory reaction patterns with potential systemic manifestations 

A. Vasculitis: palpable purpura in the skin

1. Septic-embolic: asymmetrical, countable lesions on acral areas 

a. Staph aureus (acute bacterial endocarditis) 

b. Strep viridans (subacute bacterial endocarditis) 

c. Meningiococcemia 

d. Gonnococcemia (arthritis dermatitis complex) 

e. Pseudomonas (echthyma gangrenosum) 

f. Rocky Mountain Spotted Fever

2.Allergic vasculitis

a. Systemic disease, Immune Complex Mediated

i) Drug induced

ii) Hepatitis C, cryoglobulinemia

iii) Collagen Vascular disease: RA, Lupus

iv) Infections: strep, staph

v) Dysproteinemias and gammopathies

vi) Malignancy

vii) Inflammatory bowel disease

b. Cutaneous only: same list as above without systemic manifestations of vasculitis

3.Pauci-immune complex disease (ANCA associated)

a. Wegener's Granulomatosis

b. Churg-Strauss 

c. microscopic polyangiitis

B. Flushing

1.Transient erythema secondary to vasodilatation, usually facial

2.Causes include:

C. Erythema nodosum

1. Definition: A reaction pattern in the subcutaneous fat of the lower extremities characterized by tender nodules with ecchymoses usually on the anterior tibial surface. Lesions never ulcerate.

2. Common causes:

3. Therapy: rest, NSAIDS, directed work-up to elucidate underlying causes.

C. Epidermolysis bullosa:

1. Rare non-hereditary mechanobullous disorder characterized by skin fragility and blisters after mild trauma. Lesions occur on extensor surfaces of extremities and heal with scarfing and milia (tiny cysts).

2. Pathogenesis

IgG antibodies are made and bind to type VII collagen which is present at the basement membrane of the skin (anchoring fibrils that attach the basement membrane to the dermis).

3. Histopathology

Subepidermal bullae with minimal inflammation. Direct inununofluorescence of skin shows linear deposition of IgG and complement at the dermoepidermal junction in both lesional and normal skin. There are also circulating antibodies to the EBA antigen in patients' serum.

4. Associated diseases: 30% of patients with EBA have inflammatory bowel disease; cutaneous reactivity corresponds with flares of GI disease. Other disease associations include amyloidosis, SLE, TB, and cryoglobulinemia.

C. Pyoderma gangrenosum

Starts as a non-infectious pustule which rapidly breaks down to form a painful ulcer. Classic form has a violaceous undermined border with purulent exudate on the surface of the ulceration. There are many causes:

1. Inflammatory bowel disease, most commonly Ulcerative colitis

2. Rheumatoid arthritis

3. Multiple myeloma

4. Myeloproliferative disorders (atypical, bullous pyoderma gangrenosum)

5. Often idiopathic

Diagnosis of exclusion (rule out infectious causes with biopsy and tissue culture for bacterial, fungal and mycobacteria).

Therapy consists of local ulcer care, gentle debridement (risk of pathergy) and intralesional steroids for mild cases. For more severe aggressive cases immunosuppressive therapy is required (Prednisone, Imuran, Cyclosporin A)

D. Pemphigus

1. Flaccid bullae and erosions of skin and mucous membranes. 50% begin in mouth and may be limited to oral mucous membranes for months. May be associated with other autoimmune diseases (SLE, myasthenia gravis) or may be induced by drugs such as penicillamine, captopril, rifampin. Firm pressure causes sloughing of the epidermis, i.e. Nikolsky's sign.

2. histology-acantholysis, separation of epidermal cells is the hallmark.

3. Immunofluorescence direct (tissue): IgG in intercellular spaces. Indirect (serum): IgG levels correlate with disease activity

4. Treatment:

high-dose steroids

Immunosuppressives: azathioprine, methotrexate, cyclophosphamide

Gold

5. Paraneoplastic Pemphigus

severe mucocutaneous eruption with features of Erythema multiform/Stevens Johnson syndrome. Associations: Non-Hodgkin's lymphoma, lymphocyte leukemia and other malignancies.

E. Bullous Pemphigoid

1. Clinical

a. tense blisters and bullae; commonly involve inner arms, inner thighs, palms, soles

b. more common in older individuals >65 yr. old

c. spontaneously clears in months to years

2. Pathology

subepidermal bullae with eosinophils and neutrophils along basement membrane 3. Immunopathology

a. antibodies bound in upper lamina Lucida of basement membrane zone (BMZ) 

b. complement is activated and neutrophils/eons release proteins 

c. BMZ disruption leads to blisters

4. Immunofluorescence

Direct: IgG, C3 deposited in lamina lucida

Indirect: 70% have circulating IgG to BMZ; not related to disease activity

5. Treatment

Mild:

Topical steroids 

 Tetracycline/Niacinamide 

Dapsone

Severe:

Systemic steroids

Immunosuppressives

Imuran

Methotrexate

Cyclophosphamide

IV. Paraneoplastic Cutaneous Phenomena

A. Pemphigus (paraneoplastic, see pemphigus)

B. Erythroderma

Chronic erythema and scale involving >50% of body surface area. Common etiologies include drugs, primary skin disease (atopic derm, psoriasis) and malignancy especially lymphoreticular malignancy and Cutaneous T-Cell Lymphoma (CTCL)

C. Hypertrichosis Lanuginosa

Acquired presentation of soft downy lanugo hair increase; can be associated with malignancy (malignant down). Common associated malignancies include lung, bladder, gallbladder, rectum, colon, uterus and breast.' A painful glossitis or taste disturbance can also be present. In most patients the cancer was present at the time of presentation; in others it presaged diagnosis by 1-2 years.

D. Acquired ichthyosis

acquired presentation of dry fish scale like skin. Associated with sarcoidosis, lymphoma, HIV, Leprosy and cholesterol lowering agents.

E. Acanthosis nigricans

Skin in flexural areas is velvety smooth, pigmented. When this finding is seen in an adult, and is extensive (eg, involves mucosal surfaces) it may presage abdominal cancers (particularly gastric) or Hodgkin's lymphoma. Acanthosis nigricans can also be obesity related and familial. It can be endocrinopathy associated: acromegaly, Cushing's, diabetes mellitus, thyroid, PCO.

F. Amyloidosis

1. Pathogenesis:

a. AL amyloidosis is a plasma cell dyscrasia related to multiple myeloma. Clonal plasma cells in the bone marrow produce immunoglobulins that are amyloidogenic. 

b. The familial amyloidoses (ATTR) are a group of autosomal dominant disorders which involves transthyretin a transport protein. In ATTR transthyretin becomes unstable precipitation/fibrillogenesis occur.

c. Secondary amyloidosis is formed by serum amyloid A an acute phase protein produced in response to inflammation. AA amyloidosis is rare especially with the abolition of chronic infectious diseases like osteomyelitis, tuberculosis and bronchiectasis in western societies. Patients with RA, inflammatory bowel disease and familial Mediterranean fever can develop AA.

2. Clinical features of the Amyloidoses

a. AL

skin: pinch purpura, periorbital purpura (raccoon eyes), macroglossia

systemic: low voltage EKG, nephrotic syndrome, carpal tunnel syndrome, neuropathy 

b. ATTR: autonomic neuropathy, less renal disease than AL, no macroglossia 

c. Diagnosis: abdominal fat biopsy aspirate stained with congo red will be positive in 85% of pts with AL amyloidosis. In the absence of a family history of amyloidosis the next step in the work-up is a bone marrow biopsy. If bone marrow is normal isoelectric focusing of the serum can identify variant transthyretin. 

d). Prognosis:

Patients with AL amyloid have a poor prognosis; median survival 1-2 years.

Patients with this disorder can live up to 15 years depending on age at presentation and family history. Prognosis of AA amyloid depends on underlying condition. 

e) treatment of AL; some are advocating chemotherapy (melphelan). Liver transplantation has been advocated for ATTR amyloidosis (transthyretin is mostly synthesized in the liver).

VI. Adverse Drug Eruptions

A. Erythema multiforme/ Stevens Johnson Syndrome spectrum

1. E. multiforme is a mild to moderate presentation of acral erythematous inflammatory papules (classically target lesions) and hemorrhagic stomatitis(25%). The most common etiologies are drug (sulfa, hydantoins, PCN), mycoplasma pneumonia and Herpes simplex virus (HSV). Recurrent EM is nearly always associated with recurrent HSV. Other etiologies of significance include: collagen vascular disease, streptococcal infection, TB and malignancy.

2. Steven's ,Johnson Syndrome is a more dramatic presentation of E. multiforme with a significant percentage of the body surface involved with epidermal necrosis, prominent mucous membrane involvement (ocular, oral, genital), fever and toxicity. Etiologies are similar to E. multiforme although drug is more likely.

3. Toxic Epidermal Necrolysis

Sudden onset of widespread cutaneous necrosis always linked to a medication. Prominent mucous membrane involvement, significant toxicity with a high mortality rate. Patients are most effectively managed in a burn unit, no data to support high dose steroids which may actually be detrimental by adding significant immunosuppression.

B. Vasculitis: Implicated drugs include penicillins, aminopenicillins, sulfonamides, allopurinol, thiazides, pyrazolones, retinoids, quinolones, hydantoins, and propylthiouracil. Propylthiouracil and hydralazine appear to cause vasculitis by inducing ANCA. Foreign proteins such as streptokinase, cytokines and monoclonal antibodies produce vasculitis by an immune complex mechanism. (NEJM vol. 337 no 21 p1518, 11/20/99)

C. Hypersensitivity syndrome

1. This reaction is characterized by a severe idiosyncratic reaction including skin rash and fever, often with hepatitis, arthralgias, lymphadenopathy, or hematologic abnormalities

2. Classically the eruption presents with erythematous follicular papules and pustules. Bullae and purpura can also be seen.

3. The aromatic antiepileptic agents (phenytoin, carbamazepine and phenobarbital) and the sulfonamides are the most frequently implicated.

4. Recovery is usually complete, but the reaction can be severe enough to require oral steroids.

VII. Metabolic/Endocrinologic Cutaneous Disease

A. Diabetes

1. Necrobiosis Lipoidica Diabeticorum

a. Clinical: Raised red border, atrophic center with yellowish center, vessels visible through skin. Ulcerations 25%. 

b. Pathogenesis: Small vessel disease results in abnormal collagen with granuloma formation and lipid deposition. 

c. Associated with diabetes, not related to severity or control. 70% of NLD patients have at least chemical diabetes. 0.3% of diabetics get NLD.

2. Thyroid 

a. myxedema: a generalized increase in mucin deposition leading to soft doughy skin; it is diagnostic of severe hypothyroidism.

Ichthyosis like changes

Hyperkeratosis of palms and soles

Course expressionless facies, dull flat expression

Enlarged tongue

Feet/Hands: edematous/puffy

Lower body temperature yellow secondary to carotenemia 

Chronic periorbital edema 

Brittle nails

Diffuse alopecia, thinning of lateral third of eyebrows brittle nails 

Rheumatic complaints

b. pretibial myxedema: plaques, nodules and diffuse infiltration of the lower extremities. The condition usually arises after therapy of hyperthyroidism (thyrotoxicosis).

c. Graves ophthalmopathy: ranges from mild exophthalmous to proptosis (intraocular) extraocular: ranges from lid lag through periorbtal edema and chemosis (inflammation of the sclerae)

d. Other cutaneous signs of thyroid disease:

Goiter: most commonly related to Hashimoto's thyroiditis subosteal new bone formation (acropachy) and clubbing of the fingers 

Hyperthyroidism: warm moist skin palmar erythema

Hypothyroidism: cool, dry skin, diffuse alopecia with fine friable scalp hair, thinning of the lateral third of the eyebrows, onycholysis

3. Xanthomas and Hypertriglyceridemias

a. Xanthelasma-50% trivial, -50% associated with a lipoprotein disorder (inc. LDL)

b. Tuberous xanthomas (usually elevated triglycerides, but also in severe familial type II and in biliary cirrhosis without hypertriglyceridemia)

c. Tendon (increased cholesterolemia and increased chylomicrons or VLDL)

d. Eruptive (usually hypertriglyceridemia and increased chylomicrons or VLDL)

e. Palmar (Type 3, biliary obstruction, dysglobulinemia)

In summary, any xanthoma calls for a complete work-up of plasma lipids

VIII. Hepatic and Gastrointestinal disease

A. Hepatitis C has solved many heretofore idiopathic dermatologic entities.

1. 85% of patients with vasculitis and mixed essential cryoglobulinemia will have Hepatitis C RNA detectable in their serum. 

2. Pruritus can be the presenting sign of Hep C infection. 

3. Hepatitis C antibodies are now reported to be present in 50% of patients with chronic urticaria previously felt to be idiopathic 

4. Porphyria Cutanea Tarda is frequently associated with Hepatitis C antibodies

5. Hepatitis C antibodies have been found in some cases of Lichen Planu

B. Sprue/Dermatitis Herpetiformis

1. Dermatitis Herpetiformis (DH) is an exquisitely pruritic condition characterized by grouped vesicles on the elbows, knees, buttocks and scalp.

2. IgA deposits in the dermal papillae detected by immunofluorescence.

3.Villous atrophy will be revealed by a single intestinal biopsy in two-thirds of patients and by multiple biopsy 95% of patients.

4.Both the enteropathy and the rash of dermatitis herpetiformis are dependent on the presence of gluten in the diet. Hence a gluten-free diet is the treatment of choice for patients with celiac disease and DH..

C. pancreatic fat necrosis

1 .subcutaneous nodules that break down and ulcerate usually on the lower leg.

2.Most commonly associated with alcoholic pancreatitis, but can be associated with pancreatic carcinoma.

3.Liberation of pancreatic enzymes results in saponification and digestion of cutaneous fat. 4.Elevated serum amylase and lipase are suggestive of the diagnosis, but biopsy of subcutaneous tissue is definitive.

D. Porphyria Cutanea Tarda

1. Increased fragility of sun exposed skin leading to bullae and erosions in traumatized areas-usually backs of hands.

2. Heal with scarring and milia (tiny cysts) 

3. Pathogenesis: 

a. Autosomal dominant with hepatic and erythrocytic deficiency of uroporphrynogen decarboxylase (UD). 

b. sporadic variant with UD deficiency in liver only. 

c. Stress factors with result in enough enzyme deficiency to produce clinical disease include: alcoholism, iron overload, estrogen therapy and liver disease (especially Hep C). 

4.Diagnosis: Spot acidified urine will fluoresce with woods light. 24 hour urine collection will show elevated uroporphyrins.

5. Complications: long standing PCT is associated with an increased risk of hepatoma.

6. Mimickers: 

a. drug-induced (NSAIDS, tetracyclines) and pseudo PCT of dialysis produce a similar cutaneous picture with normal urinary porphyrins.

b. Variegate porphyria and hereditary coproporphyria can produce identical cutaneous findings with neurologic and acute visceral attacks.

IX. Renal disease

A. perforating disease

1. seen in patients on dialysis with diabetes

2.umbilicated pigmented papules occur which are extremely pruritic. 

3.distributed over the trunk and extremities, often in linear arrays.

4.The features of lichen simplex chronicus are often present secondary to intense itch. 5.Notoriously difficult to treat.

B. calciphylaxis

1.Hyperparathyroidism secondary to chronic renal failure is associated with metastatic calcification

2.As the level of serum phosphate increases the associated fall in serum calcium level stimulates the parathyroid glands to become hyperplastic and to hyperfunction.

3.bones: resorption and cyst formation

4.skin: metastatic calcification in the dermis and subcutaneos tissues produces grossly visible nodules.

5.vasculopathy: in some patients calcification of the vessels develops leading to gangrene of the fingers and toes and cutaneous infarction on the lower abdomen and legs(calciphylaxis).