Figure 98.1. Biopsy proven SCC presenting as a tender hyperkeratotic nodule.

NONMELANOMA SKIN CANCERS

The most common cancer of the skin and overall is the basal cell carcinoma (BCC; see Figure 98.3). This tumor is a result of long-term sun exposure and is seen on sun-exposed surfaces most often. Although the prognosis is excellent for this tumor with exceedingly rare instances of metastasis, it is important that these lesions not be neglected, as large, long-duration tumors both are locally destructive and can infrequently metastasize. A rare genodermatosis is the basal cell nevus syndrome (Gorlin syndrome). This is an autosomal dominant condition in which BCC develops early in life (<20 years old). These patients may develop medulloblastoma at an early age in addition to having odontogenic keratocysts, palmar/plantar pits, calcification of the falx cerebri, and bifid ribs. Some patients display characteristic macrocephaly/frontal bossing.

    SCC is less common than BCC, other than in chronically immunosuppressed patients or patients who received psoralen/UVA therapy for psoriasis. This cancer also develops due to chronic sun exposure. SCC metastasis rate for SCC arising in normal sun-exposed skin is 0.5–3%, whereas SCC arising in mucocutaneous locations, burn scars, x-ray scars, or foci of chronic osteomyelitis have a rate of metastasis of 10–30%. Rate of SCC is increased significantly for chronically immunosuppressed patients. In kidney and heart transplant patients, the risk of SCC was increased 65-fold. The risk of SCC in this population increases from 7% at 1 year to 45% after 11 years and 70% after 20 years of immunosuppression.

    Treatments for nonmelanoma skin cancers (NMSC) are numerous. Treatment can be as simple as using the same topical therapy as is used for treating AKs (imiquimod or 5-fluorouracil) for early and thin lesions, to electrodesiccation and curettage, cryotherapy with LN₂ or other destructive agents, simple excision, or Mohs surgery. The most definitive method for ensuring complete removal of a NMSC is the technique attributed to Dr. Frederic Mohs. This procedure involves histopathologically examining the entire lateral and inferior margins of the fresh frozen surgical specimen to ensure complete removal of a tumor. For extensive tumors in older individuals, consultation with a radiation oncologist may also be helpful for consideration of local x-ray therapy.

MELANOMA

There are four common types of melanoma: superficial spreading (Figure 98.4) (~70% of melanomas), nodular (~15%), lentigo maligna melanoma (~10%), and acral lentiginous melanoma (~5%). Amelanotic melanoma and desmoplastic neurotrophic variants of melanoma are much rarer. Superficial spreading melanomas are the most common in individuals with lighter skin types. Nodular melanoma tends to develop in those >60 years old and arises, especially in men, from normal-appearing skin (not from a preexisting nevus) and is more aggressive and fast-growing compared to other types of cutaneous melanoma (MM). Lentigo maligna melanoma develops most often on the sun-exposed surfaces of the face of older individuals. Initially, it can be mistaken for a benign “age spot” (lentigo). Lesions that are changing/growing should be considered for biopsy. Sometimes multiple samples are necessary. Acral lentiginous melanomas account for 5% of melanomas overall, but in Asian races and people of darker skin types it accounts for about 50%.

    Melanoma grading is done by pathology. The depth of a lesion is graded both in millimeters (Breslow thickness) and by level of invasion (Clark level). The most important feature for staging is the Breslow thickness. Lesions not invading into the dermis are considered in situ. Invasive melanomas are classified by their depth of invasion, ulceration, and rate of mitoses pathologically. Pathologic staging includes pathologic information about the primary melanoma as well as that of the regional lymph nodes after partial or complete lymphadenectomy. Stages are determined by the American Joint Committee on Cancer guidelines. Clinical features of melanoma can be summarized by the ABCDE criterion (see table 98.3).

BENIGN SKIN GROWTHS

NEVI

The nevus is a hamartoma of melanocytes within the dermis and/or epidermis. Various types exist, and they, in and of themselves, are not precancerous. Histopathologically, common types are junctional nevi (flat, with melanocytes only in the epidermis), intradermal nevus (nests of melanocytes only in the dermis, usually a papule, with varying pigmentation but usually flesh colored or pink), and compound nevus (combines both types of epidermal and dermal nevus). Atypical or dysplastic nevi are lesions that when examined clinically have atypical features. The atypia in these nevi are may be graded after biopsy by the dermatopathologist as mild, moderate, or severe. Mildly atypical lesions are often not treated further. At this institution, moderate and severely atypical nevi are surgically reexcised to prevent potential further progression to a melanoma or the confusion of pseudomelanoma from a regrowing nevus.

SEBORRHEIC KERATOSIS

Seborrheic keratosis (SK) is an exceedingly common papule potentially found on almost every skin surface on the skin of older adults (Figure 98.5). It is inherited in an autosomal fashion. There are multiple subtypes, and they can vary greatly in morphology, but the clearest identifying feature is their somewhat warty, greasy, and stuck-on appearance. A variant seen in persons of color is termed dermatosis papulosis nigra. These are dark brown to black smooth papules most often appearing in persons of color on the head or neck at a younger age than seborrheic keratoses. Inflammatory or malignancy-related SKs can occur. The sign of Leser-Trelat refers to explosive, new appearance of hundreds of SK lesions in the distribution of skin lines (“Christmas tree” distribution also seen in pityriasis rosea, see below) associated with GI malignancy. SKs do not need to be treated but can be removed with LN₂ or curettage.

SKIN TAG (ACROCHORDON)

The acrochordon is a benign fleshy growth seen most commonly on the neck, axilla, groin, and inframammary areas, usually in middle-aged to older adults. There is no malignant potential. Tags frequently occur in obese or prediabetic individuals, often with acanthosis nigricans (a velvety epidermal growth with brown color often in the axilla and/or groin and back/sides of the neck). In some, multiple tags are a marker of impaired carbohydrate metabolism. Skin tags also can occur more frequently in pregnancy and Birt-Hogg-Dube syndrome (a genodermatosis characterized by renal cell carcinoma and characteristic skin lesions including increased numbers of skin tags).

KERATIN-FILLED CYSTS

Hair-follicle-derived cysts are common in the skin and on the scalp. Epidermal inclusion cysts (EIC; also referred to as sebaceous cysts, although not sebaceous in origin) are commonly seen on the trunk and upper extremities, although they can occur on any skin surface. EIC are by far the most commonly seen lesions. Pilar cysts (also known as wens or trichilemmal cysts) are almost exclusively seen on the scalp. An EIC is a nodule, characteristically with a central or offset pore. Often patients are able to “pop” these lesions, expressing white, smelly keratinaceous cheesy debris. The pilar cyst is slightly deeper in the skin and is without epidermal connection. The EIC is derived from the infundibular portion of the hair follicle, and the pilar cyst is likely derived from the epithelium of the hair follicle distal to or at the insertion of the sebaceous duct. In patients with multiple EICs on atypical locations (lower extremities/scalp/face), occurring at an early age (around puberty), the diagnosis of familial adenomatous polyposis (Gardner syndrome) should be considered. Treatment of both types of cysts is elective surgical excision. Noninflamed lesions do not need to be treated.

ACNE AND ROSACEA

ACNE PATHOGENESIS AND THERAPY

Acne vulgaris is almost ubiquitous in teens and young adults manifesting as inflammatory papules and pustules as well as noninflammatory follicular papules and comedones. Distribution is in the areas with the greatest density of sebaceous glands: the face, upper chest, and back. Acne tends to begin around the time of adrenarche. Individuals with nonfunctioning androgen receptors do not have acne. The pathogenesis of acne incorporates four different mechanisms: hyperproliferation of the follicle epithelium with subsequent plugging, excess sebum production, presence of Propionibacterium acnes, and inflammation. Androgens are hypothesized to play a role in the follicular plugging and excess sebum production. P. acnes in the follicle produce proinflammatory mediators that stimulate toll-like receptor 2 on neutrophils and monocytes with subsequent IL-12, IL-18, and tumor necrosis factor-alpha (TNF-α) production. Acne is graded mild, moderate, or severe. Pure comedonal acne has no inflammatory component, only follicular plugging. Nodulocystic acne has severe inflammatory deep-seated papules, pustules, nodules, and comedones with residual scarring. Acne conglobata is a rare severe type of nodulocystic acne with multiple nodules interconnected by burrowing between and severe scarring/disfigurement. Pyogenic athritis, pyoderma gangrenosum and acne syndrome is the combination of pyoderma gangrenosum, acne conglobata, and aseptic arthritis that was reported in one kindred. Causes of acne other than androgen excess include polycystic ovarian syndrome, congenital adrenal hyperplasia, and oral medications such as lithium, antiepileptics, steroids, and iodides.

    Treatment of acne attempts to address one or more of the four causes of acne. The first-line therapies for acne are the over-the-counter benzoyl peroxide and salicylic acid. There are a multitude of prescription treatments for acne, both oral and topical. For milder cases of acne, topical formulations such as retinoids (i.e., tretinoin, adapalene, tazarotene), clindamycin and clindamycin/benzoyl peroxide combinations, sodium sulfacetamide or azelaic acid are useful. For moderate to severe cases of acne, an oral antibiotic from the tetracycline (TCN) family (tetracycline, doxycycline, or minocycline) or second-line agents such as a penicillin derivative or sulfa is added. Topical retinoids are comedolytic and anti-inflammatory. Topical antibiotics are used for their anti–P. acnes properties, and salicylic acid/benzoyl peroxide are active against P. acnes but without reports of resistance. Oral antibiotic therapy is used against P. acnes as well as for its anti-inflammatory properties, especially the TCN derivatives. For severe nodulocystic acne an oral retinoid, isotretinoin, is very helpful for halting or decreasing the inflammatory lesions and scarring. Isotretinoin is severely teratogenic and should be used with caution in females of childbearing potential. Females of childbearing potential need to be enrolled in a federally mandated pregnancy prevention program to receive this medication and can only be treated by providers enrolled in the program.

ROSACEA/PERIORIFICIAL DERMATITIS

Rosacea is a common disease of facial flushing, papules, pustules, and telangiectasias most commonly observed on the central face of middle-aged women. There are four subtypes that are summarized in table 98.4. Therapy for erythematotelangiectatic and papulopustular types of rosacea includes avoidance of food and environmental triggers, a broad-spectrum sunscreen (UVA and UVB) daily, topicals such as metronidazole cream, azelaic acid, tretinoin, or sodium sulfacetamide, and oral antibiotics with doxycycline or minocycline being effective. Severe cases of rosacea respond well to low-dose isotretinoin, although this is not an FDA-approved indication. Phymatous rosacea therapy includes surgical or laser removal of excessive connective tissue. Ocular rosacea is treated with oral antibiotics and ocular topical preparations.

    Perioral dermatitis (PD) is a variant of rosacea characterized by inflammatory papules and pustules around the mouth. A better term for PD may be periorificial dermatitis, as this occurs not only around the mouth, but also eyes and rarely ears. Treatment with oral TCN derivatives or topical metronidazole is usually successful. Recurrences do occur, requiring further therapy.

DERMATITIS

ATOPIC DERMATITIS

Atopic dermatitis (AD) is a common eczematous, pruritic skin condition that starts in early infancy and may continue for a lifetime. In some developed countries the rate is as high as approximately18%. Pathogenesis is unknown, but a link to filaggrin mutations has been shown. Those with filaggrin defects have a relative risk of 3 to develop AD. Heterozygotes for a known mutation have a 60% chance, and homozygotes have a 90% chance of having AD. Filaggrin mutations predispose to asthma, but only in people who have AD as well as high IgE levels Another factor that potentially causes or worsens AD is the chronic colonization of patients’ skin with Staphylococcus aureus. A spectrum of findings are present in many patients with AD and their families including asthma, allergic rhinitis/seasonal allergies, urticaria, increased production of immunoglobulin E (IgE), and acute allergic reactions to foods. The triad of asthma, AD, and seasonal allergies is called atopy. It is hypothesized that superantigen stimulation drives AD as well as causes flares of dermatitis.

    Skin findings evolve over the course of the disease, although xerosis and pruritus are present in all stages. Infants have eczematous, vesicular, erythematous plaques that initially start in the antecubital/popliteal fossae and/or cheeks but can progress to involve the entire body. The diaper area is usually spared. Children have lesions of similar morphology, but as the ability to scratch increases, lichenification and prurigo nodules develop. Infants rarely have lichenification, although this is a prominent feature in children and adults with AD. For some, AD resolves by the teen years, but a predisposition for hand and eyelid dermatitis may remain.

    Therapy for AD is dependent on the severity of disease. Topical emollient application should be a daily occurrence regardless of activity level, especially those containing ceramides. Xerosis marks the beginning of active dermatitis in many cases. In patients with suspected bacterial colonization, bleach baths 2–3 times weekly followed by topical steroid application may be helpful. Mild topical corticosteroids such as desonide or hydrocortisone acetate should be used on the face, and moderate-potency agents such as triamcinolone acetonide or hydrocortisone butyrate should be used on both extremities for active dermatitis. For moderate to severe cases that have failed initial topical therapy, a steroid-sparing topical such as tacrolimus (Protopic) or pimecrolimus (Elidel) should be considered, especially for the face. A stronger topical steroid for active areas could be used, such as fluocinonide 0.05% or clobetasol propionate on particularly tough areas away from face and intertriginous areas. For severe flares, a prednisone taper can be helpful. Short tapers, such as a 5- or 7-day course, are less helpful, as many cases will reflare after the medication is stopped. Appropriate dosing of prednisone based on weight with dose reduction at 4- to 5-day intervals (i.e., 60 mg, 40 mg, 20 mg, 10 mg) sometimes can stop a flare. In severe cases that do not clear with oral steroids, other oral agents such as cyclosporine, mycophenolate mofetil, or methotrexate may be necessary (rare cases). Narrow-band UVB therapy two to three times weekly also can be very helpful for decreasing dermatitis and pruritus in severely affect atopics.

CONTACT DERMATITIS

There are many chemical and natural botanical agents that cause contact dermatitis. CD is broken into two groups: allergic contact dermatitis (ACD) (~20% of cases) and irritant contact dermatitis (ICD) (~80%). ICD is caused either acutely by, strong irritants such as alkalis and acids that damage the epidermis directly or by chronic, longer-term contact with weaker irritants such as water or detergents. Patients with an atopic background are more likely to develop ICD, especially in the form of hand eczema. ACD is a type I immediate or type IV delayed-type reaction. Contact urticaria (type I reaction) can occur from a variety of chemicals (cinnamic aldehyde, benzyl alcohol) and plants (such as nettles). Delayed-type hypersensitivity (type IV) usually occurs due to small chemical compounds (haptens) <500 daltons in size. The haptens bind proteins in the skin and are recognized and phagocytized by epidermal Langerhans cells or dermal dendrocytes that then migrate to a regional lymph node and are presented to T cells, thus sensitizing the individual to the hapten. If the individual contacts the hapten again, it is recognized, and a T-cell-mediated type IV reaction develops with characteristic erythema, pruritus, and vesiculation in 24–72 hours after exposure.

    In some cases, sunlight (often UVB 290–320 nm) acts on drugs or topically applied chemicals, altering the molecules and creating haptens. Drugs such as 6-methylcoumarin, salicylanilide, hydrochlorothiazide, chlorpromazine, nonsteroidal antiinflammatory agents, sulfonamides, and 5-methoxypsoralen all can induce photoACD. Common topically applied chemicals causing photoACD are sunscreens such as those derived from para-aminobenzoic acid (PABA) or benzophenones, although this is exceedingly rarely seen. Other topicals such as fragrances (musk ambrette or oil of Bergamot) or other topical agents such as benzocaine or neomycin may rarely cause photoACD.

    Phototoxic reactions to UV light (most commonly UVA 320–400) can occur to anyone coming in contact or ingesting these substances. No sensitizing period is required. Presentation usually looks like intense sunburn. Causes are the drugs amiodarone, chlorpromazine, fluoroquinolones (nalidixic acid, ciprofloxacin), nonsteroidal anti-inflammatory drugs (NSAIDs) (piroxicam, benoxaprofen), and tetracyclines (demeclocycline > doxycycline/tetracycline) and plants containing furocoumarins including the families Rutaceae (lime, lemon, bergamot, bitter orange, gas plant, burning bush), Apiaceae (Umbelliferae) (carrots, cow parsley, celery, wild chervil, parsnip, fennel, dill, hogweed), and Moracea (figs).

DRUGS

A multitude of oral medications can cause morbilliform or exanthematous dermatitis. Although almost any type of morphology can be seen (bullous, urticarial, etc.), morbilliform reactions are most common. A drug reaction should be suspected in cases where a symmetric dermatitis develops soon after starting a new medication. Common causes include antibiotics and sulfa-based diuretics, NSAIDs, allopurinol, chemotherapeutic agents, anticonvulsants (phenytoin, carbamazepine, phenobarbital), and psychotropic agents, although almost any medication can cause dermatitis.

    Most drug reactions are self-limited and not life threatening, but important findings to watch for include blistering and mucous membrane involvement. The Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) spectrum causes significant morbidity and potential mortality. SJS initially presents as three-zone target lesions (dusky, purple center, surrounding white, lighter skin, and an outer ring of erythema) and erythematous, morbilliform dermatitis as well as mucosal erosions/bullae. This can progress to full-thickness skin sloughing. TEN does not have the typical target lesions but will begin with painful erythematous skin (similar to a sunburn) followed by full-thickness epidermal sloughing. Both of these conditions should be managed as inpatients, preferentially in a burn unit. Treatment is supportive; some believe that intravenous immunoglobulin (IVIg) is useful, although this is controversial. Systemic corticosteroids should be avoided.

    Anticonvulsant hypersensitivity syndrome is a potentially life-threatening complex of symptoms caused by aromatic anticonvulsants such as phenytoin, phenobarbital, and carbamazepine. Symptoms include fever, pharyngitis, SJS-like dermatitis, and lymphadenopathy on physical examination and laboratory abnormalities including hepatitis, nephritis, and leukocytosis with eosinophilia. Presentation is often within 3 weeks after starting the medication, though it can occur 3 months or more into therapy. It may occur as frequently as 1:1000–1:10,000 exposures. It is a dose-independent, idiosyncratic reaction requiring complete avoidance of all aromatic anticonvulsants. An alternative to the aromatic anticonvulsants is valproic acid.

AUTOIMMUNE CONNECTIVE TISSUE DISEASES

There are multiple diseases that are within the spectrum of “connective tissue diseases.” Most of these syndromes have specific criteria for diagnosis, but the presentation initially may show overlaps between the syndromes. The most frequently seen autoimmune connective tissue diseases are lupus erythematosus, dermatomyositis, and scleroderma/morphea.

SYSTEMIC LUPUS ERYTHEMATOSUS

The most common autoimmune disease seen is the lupus erythematosus spectrum (acute cutaneous, subacute cutaneous, chronic cutaneous). Skin findings can be present in systemic lupus erythematosus (SLE) that are consistent with all three types of cutaneous lupus in any patient. Findings necessary for diagnosis of SLE according the American Rheumatologic Association are summarized in table 98.5. SLE presents with malar rash (55–90%) and polyarthralgias in many joints. Other presenting systemic symptoms include weight loss, anorexia, fever, fatigue, and malaise. It is more commonly seen in females (90%) and in blacks (1:250) versus Caucasians (1:1000). The 10-year survival rate is 75–85%, and the 20-year rate is 70%.

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