Clinical Detection of Skin Cancer

Michael Schowalter, Allison Vidimos, and Philip L. Bailin

Skin cancer is a broad term that encompasses all malignant entities of the skin from common carcinomas of the surface epithelium to rare tumors involving skin adnexal structures or appendages such as sweat ducts, sebaceous glands, or hair follicles. This chapter will focus on the clinical detection of commonly encountered skin cancers.

2.1 Basal Cell Carcinoma

2.1.1 Introduction

In practice, cutaneous malignancy is commonly broken down into the melanoma and nonmelanoma skin cancers (NMSC). NMSC represents the largest category of malignancies in the United States, occurring on the order of 3.5 million times per year in approximately 2.2 million patients.1 NMSC can be further subdivided into basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). BCCs make up the majority of NMSC and are the most common skin cancer in the United States as well as globally. BCC is a malignancy of the basal keratinocyte. Most tumors are sporadic, but patients with certain hereditary disorders are at an increased risk of developing numerous BCCs. BCC represents a large group with numerous subtypes, and as such the presentation and clinical detection of individual tumors varies and will be discussed separately.

2.1.2 History and Physical Exam

Sporadic BCCs are tumors primarily produced by ultraviolet (UV) radiation. As such, tumors concentrate to areas of high sunlight exposure. Careful examination of the head, face, neck, arms, and dorsal hands should be conducted. Specifically on the head, areas of higher UV exposure include nose, scalp, eyelids, ears, and lips. Clinicians should ask historically about new growths or persistent ones that may bleed or scab unprovoked. BCCs are variably painful or itchy. Thorough history includes questioning the nature of past UV radiation exposure such as tanning bed use, intense sun exposure leading to blistering sun burns, or therapeutic UV radiation such as psoralen and ultraviolet A radiation (PUVA). In patients with personal and family history of numerous BCCs, appropriate evaluation for genetic syndromes should be conducted. Patients with Gorlin’s syndrome or BCC nevus syndrome (BCCNS) carry germline mutations in the PTCH1 gene, vastly increasing their susceptibility to the tumors. A review of medical history and medications for evidence of iatrogenic immunosuppression is essential.

2.1.3 Nodular Basal Cell Carcinoma

Nodular or “classic” BCC is the most commonly encountered type, comprising 60 to 80% of all BCC. Nodular BCC appears as pink or red papules concentrated mainly to the head and neck. These papules may have a pearly, waxy, or translucent appearance. Many have grossly apparent telangiectasias coursing through the lesion. Tumor borders may be rolled forming a central area of depression ( Fig. 2.1). Nodular BCCs are an indolent subtype that slowly enlarge and may ultimately ulcerate and bleed unprovoked, which leads to the formation of an adherent crust overlying the lesion. Typically, nodular BCCs are not painful lesions unless neglected, large, and ulcerated.

2.1.4 Superficial Basal Cell Carcinoma

Superficial BCC is the next most common subtype, making up approximately 15 to 20% of diagnosed BCCs. This subtype classically involves trunk and extremities, and tumor characteristics are distinct from other BCC subtypes. Lesions are characterized as slow growing, flat, or minimally elevated pink to red scaly plaques, and may be quite subtle ( Fig. 2.2). The tumor may focally have superficial erosions or ulcerations with formation of crust. Borders are well defined and may be raised from the adjoining normal skin. These tumors may mimic inflammatory skin conditions such as atopic dermatitis, tinea infections, or psoriasis. Clinicians should be wary of dismissing superficial BCC as a nonmalignant entity in those patients with no prior history of inflammatory skin conditions or when lesions appear in atypical locations such as upper back or extremities distant from joints. These tumors are similarly not painful or pruritic, which may help differentiate these tumors from inflammatory skin conditions. Superficial BCCs are more common in men than in women.

Fig. 2.1 Nodular basal cell carcinoma. Characteristic pearly or translucent appearance, rolled borders, focal ulceration, and overlying crust on the left ear of an elderly, fair-skinned man.

Fig. 2.2 Superficial basal cell carcinoma. Slowly expanding pink scaly plaque with subtle roll to peripheral borders.

2.1.5 Pigmented Variants

Pigmented BCCs are a variant of nodular and superficial BCC in which there is variably retained melanin in the malignant basal cell population ( Fig. 2.3). These variants are common in patients with skin of color. Tumors otherwise retain their primary characteristics. These entities may represent a pitfall in clinical diagnosis of skin cancer and as such should be considered when evaluating pigmented lesions.

2.1.6 Morpheaform and Infiltrative Basal Cell Carcinoma

Morpheaform and infiltrative BCCs are rare, clinically similar entities with aggressive pathological patterns that will be discussed together. These entities make up approximately 5 to 10% of all BCCs. Morpheaform BCCs occur most commonly in areas of intense UV exposure, such as head and neck. They present as skin-colored, white, or, less commonly, pink atrophic plaques. Lesions rarely ulcerate unlike most BCC. These tumors may clinically appear as smooth and shiny plaques and feel indurated when palpated. As such, they are commonly confused for scars ( Fig. 2.4). Pain and itching may accompany this subtype of BCC, given there is a greater tendency for deep invasion into subcutaneous fat and muscle as well as perineural invasion.

2.2 Squamous Cell Carcinoma

2.2.1 Introduction

SCC is the second most common skin malignancy worldwide. SCC is a malignancy of the squamous keratinocyte epithelium. Tumors are sporadic or may be part of genetic conditions such as xeroderma pigmentosum (XP), oculocutaneous albinism (OCA), and epidermodysplasia verruciformis (EV). SCCs are linked to UV exposure, whether natural or occupational. Other risk factors include human papillomavirus (HPV) infection, chronic immune suppression, ionizing radiation, scarring, chronic sinus tract formation, chronic ulcerations, and chemical carcinogenic exposures. In general, patients who have sporadic or UV-induced SCCs do much better than their counterparts who develop the malignancy in chronic wounds, scars, or as a result of immunosuppression. Invasive SCC, defined as tumor that has invaded below the skin basement membrane, can arise within an existing SCC in situ (SCCis) or arise de novo. Various clinical presentations of SCC, including SCCis, will be discussed.

Fig. 2.3 (a) Pigmented variant of superficial basal cell carcinoma in a patient of middle-eastern descent. (b) Pigmented variant of nodular basal cell carcinoma on the inferior orbital rim in a middle-aged Chinese male.

Fig. 2.4 Infiltrative basal cell carcinoma clinically resembling a scar.

2.2.2 History and Physical Exam

SCCs are induced by both chronic UV exposure and chronic inflammation in the setting of scars and nonhealing wounds. Physicians should be vigilant with the patient with general signs of chronic UV exposure, including numerous solar lentigines, fine facial wrinkling, skin atrophy, telangiectasias, and Favre–Racouchot changes. A subtype, the Marjolin’s ulcer, is an ulcerating SCC in sites of past trauma such as burns. As with BCC, a careful examination of areas exposed to UV radiation including head and neck, dorsal hands, and arms should be conducted. Again, a history should concentrate on possible sources for immune suppression, as well as a history of personal or family history of past SCC.

2.2.3 Squamous Cell Carcinoma In Situ

Actinic Keratoses

While some controversy exists over the exact characterization of actinic keratoses (AKs) with regard to malignant potential, AKs, also known as solar keratoses, are generally felt to be a form of low-grade squamous dysplasia. Studies have shown that AKs transform into invasive SCC on the order of 0.025 to 20% per year.2 It is estimated that a quarter of the population in the northern hemisphere has at least one of these lesions. Clinically, AKs present in a number of different forms. Generally, they are ill-defined, pink to erythematous papules with overlying scale. They are small, with the majority being less than 1 cm in size ( Fig. 2.5a). Variants of AKs are named based on clinical appearance: pigmented, hyperkeratotic (or hyperplastic), and verrucous. When exuberantly hyperkeratotic, an AK may be referred to as a cutaneous horn ( Fig. 2.5b). AKs have a rough, scaly, or sandpaperlike texture when palpated. AKs are generally diagnosed in the broader clinical context of more widespread UV or actinic damage. Differential diagnosis for AKs includes inflammatory dermatoses of the head and neck, such as seborrheic dermatitis and contact dermatitis. Neoplasms such as Bowen’s disease, superficial BCC, and melanoma in situ may mimic AK.

Actinic Cheilitis

Actinic cheilitis (AC) is a clinical variant of AK involving the lips. The characteristic pink or red scaly plaques may simulate chapped or dry lips ( Fig. 2.6). The normally well-demarcated vermilion border of the lip may be obscured or blurred. The lower lips are more extensively involved due to increased UV exposure. There is also increased risk for AC in patients who smoke or chew tobacco products.

Bowen’s Disease

A distinct form of SCCis, Bowen’s disease has distinct clinical and histopathologic presentation. Similar to AK, Bowen’s disease may present on sun-exposed skin and mucosa of the head and neck. Bowen’s disease may also present in oral or anal mucosa, as well as on the genitals. Clinical appearance is that of a red, well-defined scaly papule or plaque with distinct borders. Bowen’s disease lesions may slowly grow both in height and in diameter over time. They may also take on a verrucous or fissured appearance. Differential diagnosis again includes inflammatory conditions, as well as neoplasms mentioned for AK. Mucosal Bowen’s may mimic oral candidiasis or oral blistering conditions such as pemphigus or pemphigoid. Bowen’s disease on the vaginal mucosa may mimic uncomplicated vaginitis.

Fig. 2.5 (a) Multiple actinic keratoses in a middle-aged female with remote history of arsenic exposure. (b) Cutaneous horn.

Fig. 2.6 Actinic cheilitis involving the lower lip in a patient with remote history of tobacco use, ultraviolet exposure, and use of a photosensitizing azole antifungal medication.

Erythroplasia of Queyrat

Similar to Bowen’s disease, erythroplasia of queyrat represents a raised red plaque of the penis, most commonly the glans penis in uncircumcised men.

Oral Leukoplakia

A form of oral SCCis, oral leukoplakia clinically manifests as a white patch or plaque in the mouth that cannot be scrubbed or rubbed off. The most common area of occurrence is the buccal mucosa along the lateral surfaces of the oral cavity, but can involve any mucosal surface including the tongue ( Fig. 2.7). Oral leukoplakia may take on a verrucous appearance, a harbinger for greater propensity for progression to SCC. This entity must be distinguished from benign mucosal conditions such as oral candidiasis, syphilis, or morsicatio buccarum—maceration and irritation of the buccal mucosa due to repeated chewing or biting.

2.2.4 Squamous Cell Carcinoma

Squamous Cell Carcinoma Arising from Squamous Cell Carcinoma In Situ

Most commonly, SCC is associated and contiguous with SCCis that has progressed and invaded over time with lack of treatment. Again, the most common areas affected are those exposed chronically to UV radiation over years, including head and neck, dorsal forearms, and hands. In sunbathers and females, anterior legs including shins are also commonly affected. Middle-aged to elderly men are the highest represented demographic group. Cutaneous SCC may take on a variety of clinical appearances; clinically distinct subtypes will be discussed separately. In general, SCC manifests as a well-defined plaque, larger in size than typical AK or SCCis. Plaques are thicker and may have prominent erosions or ulcerations ( Fig. 2.8). There may be focal areas of increased scale or hyperkeratosis, resulting in an exophytic appearance. The lesions may have exudate or be superficially impetiginized, resulting in an adherent scale crust. SCC may take on unusual or distinct clinical appearances due to the past treatments or partial treatments, duration since onset, location of tumor, or host immune system.

Keratoacanthoma

Keratoacanthoma (KA) is a clinically distinct entity, representing a histopathologically well-differentiated form of SCC. KA occurs most commonly in middle-aged to elderly fair-skinned individuals on sites of heavy UV damage. These tumors have a natural history characterized by approximately 1 month of rapid growth from onset, a period of stability without growth that can last 3 to 6 months, and lastly a period of spontaneous involution that takes place over 1 to 2 subsequent months. KAs clinically appear as dome-shaped red or pink papules, or nodules with a central keratinaceous plug ( Fig. 2.9). Patients often report that the lesion suddenly appeared.

There are several distinct subtypes of KA based on clinical appearance, location, or number of lesions. Subungual KAs develop on nail beds and may cause significant pain due to rapid growth. Mucosal KAs arise on any mucosal surface, and may occur in syndromes with multiple KAs. Giant KAs are similar in morphology, but larger in size than typical KA. Ranging from 2 to more than 15 cm, these variants have a predilection for the nose, eyelids, and face.³ While they may spontaneously involute as typical KAs, they may be locally and permanently disfiguring. Keratoacanthoma centrifugum marginatum (KCM) are similarly large, growing sometimes greater than 15 or 20 cm, but have spontaneous central involution. Clinically, this presents as an expanding erythematous rim with central clearing. These variants are less likely to spontaneously resolve than typical or giant KA.⁴

Fig. 2.7 Oral leukoplakia involving the lateral tongue.

Fig. 2.8 Large ulcerated and bleeding squamous cell carcinoma of the scalp.

Fig. 2.9 Pink papule on the scalp with central keratin plug. Consistent pathologically with keratoacanthoma.

Generalized eruptive keratoacathomas of Grzybowski is a rare syndrome characterized by abrupt occurrence of numerous KAs over many body surface areas, including mucosal surfaces. Hundreds to thousands of pruritic, variably sized lesions may develop over a short period of time.5 Multiple KAs may present as part of multiple self-healing squamous epithelioma (MSSE) also known as Ferguson–Smith disease, an autosomal dominant disorder involving the transforming growth factor beta receptor 1(TGFBR1) gene.

Verrucous Squamous Cell Carcinoma

Verrucous SCC is considered a low-grade variant of SCC that commonly affects the oral mucosa, feet, and genitalia. These tumors are very slow growing and have a characteristic papillomatous or warty exterior. Though slow growing, these tumors may be locally destructive and disfiguring ( Fig. 2.10a). HPV and carcinogen exposure are thought to be driving forces behind this malignancy, rather than UV radiation. Depending on the anatomical locale at presentation, different terms can be used to describe these tumors. Verrucous SCC of the oral cavity is also known as oral florid papillomatosis, while that of the anogenital region is known as a Buschke–Lowenstein tumor ( Fig. 2.10b). The later subtype may be associated with verrucous SCC of the urethra or bladder. When presenting on the palms or soles, the term epithelioma cuniculatum is used.

Fig. 2.10 (a) Verrucal squamous cell carcinoma (SCC) of the subungual fingertip. (b) Photograph after complete resection via Mohs micrographic surgery demonstrates the locally destructive nature of the lesion. (c) Verrucal SCC of the penis.

2.3 Melanoma

2.3.1 Melanoma In Situ

Almost all melanomas begin as melanoma in situ, with epidermal proliferation of malignant melanocytes that eventually invade past the epidermal basement membrane into the dermis. Melanoma in situ can clinically present in a number of different ways and be clinically indistinguishable from banal nevi.

Lentigo Maligna

Lentigo maligna (LM) is a specific type of melanoma in situ that commonly occurs on the head and neck of elderly Caucasian individuals. LM clinically presents as a brown, tan, or multi-colored pigmented macule or patch that grows slowly over time ( Fig. 2.11a). Clinical diagnosis is often difficult or impossible to make in elderly individuals with years of sun damage and numerous obscuring lentigines, seborrheic keratoses, and AKs. Clues that a particular lesion may signify an LM include the following: irregular borders, lesion asymmetry, and radial growth over time. LM is notorious for having malignant extension beyond the visible borders of the tumor. In these circumstances, histologic “skip areas” are seen, further complicating the clinical characterization of LM. A lesion may develop other colors as part of its natural progression, and exhibit black, blue, pink, red, or white hues. Lesions may keep their brown or tan color, but exhibit uneven darkening through the lesion. LM is flat without surface change, which helps to distinguish it from an actinic or solar keratosis. However, a pigmented nodule within a larger LM is typically a harbinger for progression to lentigo maligna melanoma (LMM). Of note, LM is sometimes associated with desmoplastic melanoma, which will be discussed later.