Neoplasms and Cysts
Hovik J. Ashchyan, MD
Daniel M. Klufas, MD
Epidermal Neoplasms
Basic Concepts
Epidermal neoplasms encompass a group of benign and malignant tumors of the cornified stratified squamous epithelium. The majority are derived from keratinocytes, which are the most abundant cell type.
 SEBORRHEIC KERATOSIS → Diagnosis Group 1 Reprinted with permission from Goodheart HP. Goodheart’s Same-Site Differential Diagnosis: A Rapid Method of Diagnosing and Treating Common Skin Disorders. Wolters Kluwer Health/Lippincott Williams & Wilkins; 2011. |
Epidemiology
SK is a common benign epidermal neoplasm that can arise de novo or from a preexisting solar lentigo. While the exact pathogenesis is unknown, sun exposure and friction may play a role. Additionally, ˜1/3 of cases harbor a gain-offunction mutation in FGFR3 or PIK3CA.
Though controversial, the abrupt onset of numerous SKs may be a cutaneous marker of an internal malignancy known as the sign of Leser-Trélat. It is most commonly associated with colon or gastric adenocarcinoma, breast adenocarcinoma, and lymphoma.
Drug associations include BRAF inhibitors. Additionally, SKs may become inflamed with systemic antineoplastics (eg, 5-FU, cytarabine, ingenol mebutate).
Clinicopathological Features
SKs classically present as oval-to-round, waxy or warty, papules or plaques that range in color from tan to black. They can occur anywhere on the body but have a predilection for the chest and back.
SK has a “stuck-on” appearance.
On the back, the sign of Leser-Trélat creates a “Christmas tree” pattern.
Dermatosis papulosa nigra (DPN) refers to pigmented SKs favoring the central face, primarily in African American and Asian populations.
Cutaneous melanoacanthoma is a type of heavily pigmented SK. Oral melanoacanthoma is an unrelated reactive proliferation.
Stucco keratosis is a type of white or gray SK favoring the ankles and feet. HPV (eg, HPV23b) has been implicated in the pathogenesis.
SKs may become inflamed. LK represents an inflamed SK, solar lentigo, or AK that appears as a pink-to-red brown scaly papule on a sun-exposed site.
The histopathological features of SK variants are summarized in Table 5.1. Keratinocytes within pigmented SK contain melanin except in cutaneous melanoacanthoma, which is composed of both keratinocytes and pigmented dendritic melanocytes. Signs of irritation include areas of compact eosinophilic parakeratotic keratin, spindled keratinocytes, and squamous eddies (keratin pearls). Signs of inflammation include areas of compact eosinophilic parakeratotic keratin, crust, spongiosis, and lymphocytes ± lichenoid interface dermatitis. LK can NOT be distinguished from LP on histopathology.
Evaluation
The differential diagnosis of SK includes solar lentigo, nevocellular nevus, and melanoma. LK may clinically mimic psoriasis, eczematous dermatitis, superficial BCC, or SCCis.
Dermoscopy features include multiple (3+) milia-like cysts, comedo-like openings, and gyri and sulci (fissures and ridges). Early SKs may demonstrate the fingerprint-like structures and moth-eaten borders characteristic of solar lentigines.
Management
SKs do not require treatment. If inflamed or irritated, they are commonly treated with cryotherapy.
Table 5.1. HISTOPATHOLOGICAL FEATURES OF SEBORRHEIC KERATOSIS VARIANTS AND RELATED DISORDERS | ||||||||||||||||||
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 Figure 5.1. MATCHING EXERCISE: SEBORRHEIC KERATOSIS VARIANTS. A, Acanthotic SK. Note the loose lamellar keratin, broad sheets of small keratinocytes of uniform depth (the “string sign”), horn cysts (closed to the surface), and pseudohorn cysts (open to the surface). B, Reticulated SK. Note the thin interlacing strands of keratinocytes and horn cysts. C, Clonal SK. Note the islands of small keratinocytes within the epidermis. D, Hyperkeratotic SK. Note the hyperkeratosis and papillomatosis. SK, seborrheic keratosis. (Histology images reprinted with permission from Elder DE, Elenitsas R, Rubin AI, et al. Atlas of Dermatopathology: Synopsis and Atlas of Lever’s Histopathology of the Skin. 4th ed. Wolters Kluwer; 2020.) Without context, SK can NOT be distinguished from common epidermal nevus on histopathology. |
“Real World” Advice
Care should be taken when using cryotherapy for SKs on hair-bearing areas (eg, the scalp) as this may result in alopecia. Consider performing gentle curettage instead.
EPIDERMAL NEVUS
Synonyms: keratinocytic nevus, verrucous nevus
Reprinted with permission from Edward S, Yung A. Essential Dermatopathology. Wolters Kluwer Health/Lippincott Williams & Wilkins; 2011.
Keratinocytic epidermal nevi are benign hamartomas caused by postzygotic mutations in HRAS > NRAS > KRAS and PIK3CA in the MAPK and PI3K signaling pathways, respectively. Occasionally, FGFR3 mutations lead to epidermal nevi that can cause hypophosphatemic rickets. While most lesions are present at birth, some lesions may become more prominent or appear with age.
Figure 5.2. SIDE-BY-SIDE COMPARISON: COMMON EPIDERMAL NEVUS AND INFLAMMATORY LINEAR VERRUCOUS EPIDERMAL NEVUS. Both common epidermal nevus and ILVEN are characterized by a well-demarcated zone of hyperkeratosis, acanthosis, and papillomatosis. Common epidermal nevus demonstrates orthokeratosis. ILVEN demonstrates alternating orthokeratosis (granular layer present) and parakeratosis (granular layer absent). A, Common epidermal nevus. B, ILVEN. Solid arrows: orthokeratosis (granular layer present). Dashed arrow: parakeratosis (granular layer absent). ILVEN, inflammatory linear verrucous epidermal nevus; SK, seborrheic keratosis.
(Histology images reprinted with permission from Gru AA, Wick MR, Mir A, et al. Pediatric Dermatopathology and Dermatology. Wolters Kluwer; 2018.)
Without context, common epidermal nevus can NOT be distinguished from SK on histopathology.
• Epidermolytic epidermal nevus: demonstrates EHK (see Figure 2.8).
Common epidermal nevus classically presents as a linear or whorled, verrucous or hyperkeratotic, pink or brown plaque following lines of Blaschko. Epidermal nevus variants include the following:
Epidermolytic epidermal nevus is caused by postzygotic mutation in K1 or K10 during embryogenesis. If the mutation involves gonadal cells, it can be transmitted to the patient’s offspring, resulting in generalized EI.
Epidermal nevus syndrome is a sporadic association of epidermal nevus with systemic involvement, most commonly the skeletal, nervous, and ocular systems. CLOVES syndrome and Proteus syndrome are classified under the umbrella of epidermal nevus syndrome.
ILVEN classically presents as chronic, pruritic, erythematous, scaly papules coalescing into a linear plaque.
Palisaded epidermal nevus with “skyline” basal cell layer (PENS) is a newly described epidermal nevus with prominent basal cells.
Skin biopsy is appropriate to exclude the epidermolytic epidermal nevus. White sponge nevus is a closely related disorder to epidermal nevus caused by AD mutations in K4 and K13. It is characterized by a soft white plaque on the buccal mucosa.
Rarely, neoplasms such as BCC, SCC, and KA may arise within an epidermal nevus. Epidermal nevi are difficult to treat with a high rate of recurrence following cryotherapy, dermabrasion, electrodesiccation, or laser ablation. Surgical excision is advised only for smaller, localized lesions.
CLEAR CELL ACANTHOMA
Synonym: Degos acanthoma
Reprinted with permission from Elder DE, Elenitsas R, Rubin AI, et al. Atlas of Dermatopathology: Synopsis and Atlas of Lever’s Histopathology of the Skin. 4th ed. Wolters Kluwer; 2020
Clear cell acanthoma is a rare benign epidermal neoplasm comprised of clear glycogen-containing epithelial cells. The most common demographic is middle-aged adults.
Multiple or eruptive clear cell acanthomas are associated with hereditary ichthyosis vulgaris.
Clear cell acanthoma classically presents as a wellcircumscribed, pink-to-red brown, moist, shiny papule or nodule. The lesion may be pigmented and have a collarette of scale. Typical locations include the thigh, shin, and calf. There is a small risk of malignant degeneration to SCC.
Other benign epidermal neoplasms not discussed elsewhere are summarized in Table 5.2.
Figure 5.3. CLINICOPATHOLOGICAL CORRELATION: CLEAR CELL ACANTHOMA. Clear cell acanthoma is characterized by a well-demarcated zone of neutrophils and parakeratosis in the stratum corneum and acanthosis. Clear cells contain glycogen (PAS positive, diastase sensitive). PAS, periodic acid-Schiff.
(Histology image courtesy of Noel Turner, MD, MHS and Christine J. Ko, MD.)
On high power, clear cell acanthoma can NOT be distinguished from psoriasis on histopathology.
Dermoscopy features include white superficial scales and dotted vessels in a uniform distribution against a light red background ± red globular rings.
While treatment is not necessary, options include cryotherapy, surgical excision, and CO2 laser.
 BASAL CELL CARCINOMA → Diagnosis Group 1 Nodulo-ulcerative basal cell carcinoma reprinted with permission from Elder DE, Elenitsas R, Rubin AI, et al. Atlas of Dermatopathology: Synopsis and Atlas of Lever’s Histopathology of the Skin. 4th ed. Wolters Kluwer; 2020 |
Epidemiology
BCC is the most common nonmelanoma skin cancer (NMSC). Technically, it is classified as a malignant adnexal neoplasm with follicular matrical differentiation.
Table 5.2. HISTOPATHOLOGICAL FEATURES OF OTHER BENIGN EPIDERMAL NEOPLASMS
Diagnosisa
Histopathological Features
Acantholytic acanthoma
Discrete acanthoma demonstrating acantholysis (resembles Hailey-Hailey disease).
Epidermolytic acanthoma
Discrete acanthoma demonstrating EHK (see Figure 2.8).
Large cell acanthoma
Discrete acanthoma demonstrating cells with large nuclei.
Warty dyskeratoma
Discrete endophytic growth of keratinocytes demonstrating acantholytic dyskeratosis (resembles Darier disease).
EHK, epidermolytic hyperkeratosis.
a Illustrative examples provided.
Table 5.3. HEREDITARY DISORDERS ASSOCIATED WITH BASAL CELL CARINOMA
Diagnosisa
Inheritance Pattern
Gene(s)
Classic Description
BCNS
See below.
Bazex-Christol-Dupré syndrome
XLD
Gene mapped to Xq24-q27
Follicular atrophoderma, local hypohidrosis (above the neck), hypotrichosis, multiple BCCs, and milia. The characteristic hair shaft abnormality with increased fragility is pili torti.
Brooke-Spiegler syndrome
AD
CYLD (increased NFκB signaling)
Multiple BCCs, cylindromas, spiradenomas, and trichoepitheliomas.
MTS (BCCs with sebaceous differentiation)
See Chapter 5: Neoplasms of Sebaceous, Apocrine, and Eccrine Glands.
OCA
See Chapter 2: Pigmentary Disorders.
Rombo syndrome
AD
Atrophoderma vermiculatum, acrocyanosis, hypotrichosis (with loss of eyelashes), multiple BCCs, trichoepitheliomas, and milia.
Schöpf-Schulz-Passarge syndrome
See Chapter 2: Disorders of Sebaceous, Apocrine, and Eccrine Glands.
XP and XP variant
See Chapter 4: Photodermatoses.
AD, autosomal dominant; BCCs, basal cell carcinoma; BCNS, basal cell nevus syndrome; NFκB, nuclear factor κ-light-chain-enhancer of activated B cells; OCA, oculocutaneous albinism; XLD, X-linked dominant; XP, xeroderma pigmentosum.
a Illustrative examples provided.
While sun exposure, tanning bed use, and radiation therapy are strongly associated with BCC, ˜30% of sporadic BCCs are due to somatic mutations in PTCH1 encoding patched, a member of the SHH signaling pathway.
Hereditary disorders associated with BCC are summarized in Table 5.3.
Clinicopathological Features
The most common location for BCC is the head and neck, particularly the lower eyelid and the base of the nose. However, BCC may occur anywhere on the body. Clinical presentation varies based on subtype:
Nodular BCC (most common): pearly papule with arborizing blood vessels ± central ulceration.
Pigmented BCC: similar to nodular BCC with brown or black pigment.
Superficial (multifocal) BCC: scaly erythematous papule or plaque.
Morpheaform (sclerosing) BCC: white sclerotic plaque.
Other BCC subtypes (eg, micronodular, infiltrative, adenoid, infundibulocystic) are distinguished histologically, not clinically.
Fibroepithelioma of Pinkus is a skin-colored, sessile lesion favoring the lumbosacral area. While some classify this entity as a rare BCC subtype, others classify it as a premalignant fibroepithelial tumor.
BCC metastasis is extremely rare. Tumors usually require >15 years to develop metastases, which typically spread to the head and neck lymph node basin.
Figure 5.4. For the histopathological differential diagnosis of morpheaform BCC, see Table 5.34.
Evaluation
The differential diagnosis of nodular BCC includes SK, SCC, and sebaceous gland hyperplasia (SGH). Pigmented BCC may clinically mimic melanoma. Superficial BCC may clinically mimic psoriasis, eczematous dermatitis, LK, or SCCis. Morpheaform BCC may clinically mimic a scar.
Dermoscopy features include arborizing blood vessels, spoke wheel-like structures, leaf-like areas, large bluegray ovoid nests, multiple nonaggregated blue-gray globules, ulceration, and shiny white blotches and strands.
If there is suspicion for extensive disease (deep structural involvement such as deep soft tissue, bone, or perineural disease), imaging studies are recommended. For suspected perineural disease, MRI is the preferred imaging modality.
Management
High-risk BCCs have an increased risk for recurrence and metastasis. Factors include size (any size in a high-risk location [eg, the H area], ≥10 mm in moderate-risk locations, ≥20 mm in low-risk locations), ill-defined clinical borders, immunosuppression, sites of prior radiation, perineural disease, and aggressive growth patterns histologically (infiltrative, micronodular, morpheaform, sclerosing).
Surgical treatment is first line for localized BCC. For lowrisk tumors, surgical excision with 4 mm clinical margins
is recommended. While standard surgical excision may be considered for high-risk tumors, National Comprehensive Cancer Network (NCCN) guidelines recommend Mohs micrographic surgery (MMS). In 2012, a combined task force developed the MMS appropriate use criteria (AUC), which is a tool to determine whether MMS is the appropriate treatment for BCC. Toluidine blue may be used to stain serial frozen sections, thereby revealing the stromal change associated with BCC to visualize the margins.
Figure 5.4. CLINICOPATHOLOGICAL CORRELATION: BASAL CELL CARCINOMA. Positive IHC stains include androgen receptor, BCL2 (diffuse), BerEP4, and toluidine blue (stroma). A and B, Nodular BCC. C and D, Pigmented BCC. Solid arrow: basophilic cells containing melanin. E and F, Superficial BCC. Dashed arrow: buds of basophilic cells. G and H, Morpheaform BCC. Dashed arrow: thin strands and small nests of basophilic cells “tadpole-shaped” with a “paisley-tie pattern.” I, Fibroepithelioma of Pinkus. BCC, basal cell carcinoma; BCL2, B-cell lymphoma 2; IHC, immunohistochemistry.
(A, Reprinted with permission from Lugo-Somolinos A, McKinley-Grant L, Goldsmith LA, et al. VisualDx: Essential Dermatology in Pigmented Skin. Wolters Kluwer Health/Lippincott Williams & Wilkins; 2011. B, Histology image courtesy of Noel Turner, MD, MHS and Christine J. Ko, MD. C, Reprinted with permission from Lugo-Somolinos A, McKinley-Grant L, Goldsmith LA, et al. VisualDx: Essential Dermatology in Pigmented Skin. Wolters Kluwer Health/Lippincott Williams & Wilkins; 2011. D, Histology image reprinted with permission from Elder DE, Elenitsas R, Rosenbach M, et al. Lever’s Histopathology of the Skin. 11th ed. Wolters Kluwer; 2015. E, Reprinted with permission from Goodheart HP. Goodheart’s Same-Site Differential Diagnosis: A Rapid Method of Diagnosing and Treating Common Skin Disorders. Wolters Kluwer Health/Lippincott Williams & Wilkins; 2011. F, Histology image reprinted with permission from Elder DE, Elenitsas R, Rosenbach M, et al. Lever’s Histopathology of the Skin. 11th ed. Wolters Kluwer; 2015. G, Reprinted with permission from Khan FM, Gerbi BJ. Treatment Planning in Radiation Oncology. 3rd ed. Wolters Kluwer Health/Lippincott Williams & Wilkins; 2011. H, Histology image reprinted with permission from Crowson N, Magro CM, Mihm MC Jr. Biopsy Interpretation of the Skin: Primary Non-Lymphoid Cutaneous Neoplasia. Wolters Kluwer Health/Lippincott Williams & Wilkins; 2010. I, Histology image courtesy of Noel Turner, MD, MHS and Christine J. Ko, MD.)
• Nodular BCC: nests of basophilic cells with peripheral palisading and clefting between basophilic cells and stroma. The stroma is fibromyxoid.
• Micronodular BCC: similar to nodular BCC with smaller nests of basophilic cells separated by thick dermal collagen bundles and an aggressive growth pattern.
• Pigmented BCC: similar to nodular BCC but basophilic cells contain melanin.
• Superficial BCC: multifocal buds of basophilic cells.
• Morpheaform BCC: thin strands and small nests of basophilic cells with limited peripheral palisading and minimal retractions around epithelial cells. The stroma is sclerotic. Perineural invasion is common.
• Infiltrative BCC: angulated nests of basophilic cells, often with focal squamous differentiation. The stroma is rich in fibroblasts with minimal mucin. Perineural invasion is common.
• Adenoid BCC: nest of basophilic cells with clear spaces.
• Infundibulocystic BCC: pink epithelial strands with buds of basophilic cells and horn cysts.
• Fibroepithelioma of Pinkus: anastomosing pink epithelial strands, often containing eccrine ducts, with buds of basophilic cells. Ample stroma is fibromyxoid. Presence of clefting between basophilic cells and stroma helps distinguish BCC from trichoepithelioma.
Thin strands and small nests of basophilic cells in morpheaform BCC have been described as “tadpole-shaped” with a “paisley-tie pattern.”
(Figure 5.4. Continued)
Electrodesiccation and curettage (ED&C) may be considered for low-risk BCCs in nonterminal hair-bearing locations.
When a surgical approach is contraindicated or impractical, alternative therapies include topical 5-FU or imiquimod, PDT, radiation therapy, or cryotherapy, though the cure rate is lower.
SMO inhibitors (eg, vismodegib) can be used in locally advanced or metastatic BCC.
“Real World” Advice
Given the low risk of metastasis, goals of care discussion should be considered during the shared decision-making management plan of BCC in elderly patients with significant comorbidities. For example, observation or radiation therapy may be appropriate for an elderly patient with Alzheimer dementia and a massive infiltrative BCC.
If a patient has a “scar” without history of trauma, consider biopsy to rule out morpheaform BCC.
SPOTLIGHT ON BASAL CELL NEVUS SYNDROME
Synonyms: Gorlin syndrome, nevoid basal cell carcinoma syndrome Reprinted with permission from Schaaf CP, et al. Human Genetics.
Table 5.4. DIAGNOSTIC CRITERIA FOR BASAL CELL NEVUS SYNDROME
Diagnostic criteria for BCNSa
Major criteria
Minor criteria
Calcification of the falx cerebri
Odontogenic keratocysts of jaw
≥3 palmar or plantar pits
Multiple BCCs or a BCC before age 20, particularly nevoid BCCs.
First-degree relative with BCNS
Macrocephaly and frontal bossing (also agenesis of the corpus callosum)
Various ocular anomalies (eg, colobomas, hypertelorism)
Vertebral/rib anomalies (eg, bifid ribs)
Cleft palate/lip
Polydactyly
Lymphomesenteric or pleural cysts
Ovarian or cardiac fibromas
Medulloblastoma
BCC, basal cell carcinoma; BCNS, basal cell nevus syndrome.
a 2 major criteria OR 1 major criterion before 20 years of age OR 1 major and 2 minor criteria are required for diagnosis.
Basal cell nevus syndrome (BCNS) is an AD syndrome due to mutations in PTCH encoding patched (lossof-function) or SMO encoding smoothened (gain-offunction), which lead to constitutive activation of the SHH signaling pathway.
The classic findings of BCNS are summarized in the diagnostic criteria (Table 5.4). BCCs in BCNS resemble acrochordons (skin tags); however, children rarely get acrochordons prior to puberty.
The histopathology of BCNS demonstrates BCCs, particularly nevoid BCCs.
Genetic testing to confirm the diagnosis should be considered in specific situations: prenatal testing when there is a known family mutation, first-degree relatives of patients with the known mutation, and confirmation in a patient with an unclear diagnosis.
After birth, patients with a known diagnosis of BCNS should have a yearly brain MRIs until age 8 to detect medulloblastoma. Other management options include echocardiogram to assess for cardiac fibromas, dental screening, head circumference and developmental monitoring, ophthalmological examinations, and vision and hearing screenings. In addition to ageappropriate malignancy screening, adult patients require yearly total body skin examinations (TBSEs). A more frequent interval can be considered after diagnosis of the first BCC. Treatment may require a multidisciplinary team. Genetic counseling is recommended for first-degree relatives. SMO inhibitors (eg, vismodegib) can be used in patients with numerous BCCs, locally invasive BCCs, or metastatic disease.
 POROKERATOSIS → Diagnosis Group 2 Disseminated superficial actinic porokeratosis reprinted with permission from Elder DE, Elenitsas R, Rubin AI, et al. Atlas of Dermatopathology: Synopsis and Atlas of Lever’s Histopathology of the Skin. 4th ed. Wolters Kluwer; 2020. |
Epidemiology
Porokeratosis is thought to be a premalignant disorder of cornification caused by an abnormal clonal expansion of keratinocytes. Though the exact pathogenesis is unclear, heterozygous germline and sporadic mutations involving the mevalonate pathway (responsible for cholesterol synthesis) have been implicated.
Eruptive disseminated porokeratosis is associated with gastrointestinal cancer (eg, hepatocellular carcinoma).
Table 5.5. POROKERATOSIS VARIANTS | ||||||||||||||||||||||||||||
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Clinicopathological Features
Porokeratosis classically presents as an annular papule or plaque with a furrowed keratotic rim (correlates with the cornoid lamellae on histopathology).
Porokeratosis variants are summarized in Table 5.5. Risk of malignant degeneration into SCC varies based on the variant.
All forms of porokeratosis may be seen in pediatric patients though disseminated superficial actinic porokeratosis (DSAP) is rare.
Evaluation
The differential diagnosis of porokeratosis includes other annular lesions (eg, ring wart, tinea corporis) and AK. When linear, the differential diagnosis includes linear inflammatory disorders (eg, lichen striatus) and epidermal neoplasms (eg, epidermal nevus).
Management
Photoprotection is recommended for patients with DSAP or linear porokeratosis.
For symptomatic lesions, cryotherapy, topical 5-FU, topical retinoids, imiquimod, or PDT can be considered. Given the role of mutation in the mevalonate pathway in the pathogenesis of porokeratosis, 2% cholesterol/2% lovastatin ointment or lotion has emerged as a novel therapy.
“Real World” Advice
Porokeratosis tends to follow a chronic course and is often treatment refractory.
 Figure 5.5. CLINICOPATHOLOGICAL CORRELATION: POROKERATOSIS. Porokeratosis is characterized by cornoid lamellae (columns of parakeratosis oriented at 45° angles toward the lesion center with underlying dyskeratosis). Intervening skin may appear psoriasiform or lichenoid. Disseminated superficial actinic porokeratosis. Solid arrows: cornoid lamellae. |
 ACTINIC KERATOSIS → Diagnosis Group 1 Reprinted with permission from Goodheart HP, Gonzalez ME. Goodheart’s Same-Site Differential Diagnosis: Dermatology for the Primary Health Care Provider. 2nd ed. Wolters Kluwer; 2022. |
Epidemiology
AK is a premalignant, in situ dysplasia comprised of atypical keratinocytes.
AKs develop due to UVB-induced inactivating mutations in TP53 encoding p53, an important regulator of the G1 (not S) phase of the cell cycle. P53, when active, enhances the NER of UV-induced damage to cellular DNA (eg, cyclobutene-pyrimidine dimers), delays cell proliferation, and stimulates apoptosis. When inactivated, p53 cannot perform the critical role of inhibition of photocarcinogenesis.
AKs predominate in lighter skin phototypes, particularly those with heavy cumulative sun exposure, tanning bed use, and radiation therapy.
AKs are also associated with arsenic poisoning, which can result from contaminated drinking water, occupational exposures (eg, farming, glass manufacturing, recycling electronic waste), or foul-play.
AKs may become inflamed with systemic antineoplastics (eg, 5-FU, cytarabine, ingenol mebutate).
Clinicopathological Features
AKs classically present as erythematous papules or plaques with adherent scale in chronically sun-exposed areas such as the scalp, face, ears, forearms, and dorsal hands.
AKs have a characteristic “gritty” scale that forms a “jagged” pattern after cryotherapy.
Arsenical keratoses favor the palms and soles, usually with a latency of ˜20 years following exposure.
The presence of chronic actinic damage to the lower vermilion lip is termed actinic cheilitis. Glandular cheilitis refers to inflammatory hyperplasia of the lower labial salivary glands due to chronic irritation or in association with actinic cheilitis.
 Figure 5.6. CLINICOPATHOLOGICAL CORRELATION: ACTINIC KERATOSIS. AK is characterized by loss of normal epidermal maturation with partial-thickness cytologic atypia (arising from the basal layer). Malignant keratinocytes can keratinize and integrate into the stratum corneum, forming malignant horn with parakeratosis. Solar elastosis is common. Solid arrow: “flag sign” indicating loose lamellar “onion skin” keratin arising from an adnexal structure. AK, actinic keratosis. (Histology image courtesy of Noel Turner, MD, MHS and Christine J. Ko, MD.) • Acantholytic AK: acantholysis. • Bowenoid AK: SCCis without pagetoid scatter or full-thickness follicular involvement. • Hypertrophic AK: prominent malignant horn and acanthosis. • Lichenoid AK: lichenoid interface dermatitis. The “flag sign” refers to malignant horn alternating with loose lamellar “onion skin” keratin arising from adnexal structures. Arsenical keratoses can NOT be distinguished from AK on histopathology. |
Evaluation
The differential diagnosis of AK includes PF, SK, SCC, and erosive pustular dermatosis.
On the face, dermoscopy reveals “strawberry” pattern vessels.
If an AK is presenting as a cutaneous horn (hypertrophic AK), biopsy to rule out underlying SCC.
If arsenical keratoses are suspected, analysis of drinking water or blood, urine, hair, and nails is recommended.
Management
For patients with AKs, the first step in management is sun protection.
For isolated lesions, cryotherapy is recommended in conjunction with topical 5-FU or imiquimod over cryotherapy alone. It is not recommended to use cryotherapy in conjunction with diclofenac or adapalene.
For diffuse, broad areas of involvement, field therapy with topical 5-FU or imiquimod is preferred. Diclofenac and PDT carry conditional recommendations based on recommendations from the 2021 AAD Working Group and may also be considered. Tirbanibulin is a new topical therapy. Of note, as of 2021, ingenol mebutate is no longer manufactured or marketed in the United States.
“Real World” Advice
AKs are easier to identify with palpation than visual inspection.
 SQUAMOUS CELL CARCINOMA → Diagnosis Group 1 Squamous cell carcinoma in situ synonym: Bowen disease Reprinted with permission from Elder DE, Elenitsas R, Rosenbach M, et al. Lever’s Histopathology of the Skin. 11th ed. Wolters Kluwer; 2015. |
Epidemiology
SCC is the second most common NMSC. It is classified as a malignant epidermal neoplasm derived from keratinocytes. The term “SCC in situ” is reserved for SCC without dermal invasion. The pathogenesis of SCC is similar to AK.
SCC is the most common NMSC in Asian Indian and Black populations. Higher rates of SCC are also seen in the Lesbian, gay, bisexual, and transgender (LGBT) population, highlighting an important healthcare disparity. In transplant patients, the risk of SCC is 65-fold higher than the general population. By comparison, the risk of merkel cell carcinoma MCC, BCC, and melanoma is 23.8-, 10-, and 3- to 4-fold higher, respectively, than the general population.
In addition to cumulative UVR exposure and arsenic poisoning, associations with SCC include increasing age, immunosuppression (CD4, not CD8, lymphopenia), scar or chronic ulcer (eg, Marjolin ulcer in a burn site), hypertrophic LP, hypertrophic LE, LS, HS, EAI, and HIV or HPV infection. Occupational exposures that increase SCC risk include outdoor workers and those exposed to arsenic, polycyclic hydrocarbons, and radioactive materials.
Drug associations include azathioprine, cyclosporine, pimecrolimus/tacrolimus (controversial), rituximab, voriconazole, topical mechlorethamine, and BRAF inhibitors. Other risk factors include PUVA and radiation therapy (often with a latency period > 20 years).
Oral SCC is associated with alcohol, tobacco, and betel nut exposure.
Clinicopathological Features
Invasive SCC classically presents as an erythematous papule or nodule arising from an indurated, elevated base often on sun-exposed sites, particularly favoring the lower extremities in women, and sites of preexisting AKs.
SCC may occur on the oral mucosa.
Periungual SCC may resemble a wart with erythema and scaling.
Evaluation
The differential diagnosis of SCC includes hypertrophic AK, KA, and pseudoepitheliomatous hyperplasia (PEH), a reactive phenomenon. SCCis may clinically mimic
psoriasis, eczematous dermatitis, LK, or superficial BCC. The differential diagnosis of oral SCC includes salivary gland tumor, most commonly benign pleomorphic adenoma or malignant mucoepidermoid carcinoma. Location can be a helpful clue as salivary gland tumors favor the posterior hard palate/anterior soft palate.
Table 5.6. PREMALIGNANT SQUAMOUS CELL CARCINOMA AND VERRUCOUS CARCINOMA.
Varianta
HPV Typesa
Classic Description
Notes
Premalignant SCC
SIL/CIN/VIN/VaIN/PIN/AIN
16, 18 Digital/nail: 16 EDV: 5, 8
Bowenoid papulosis: multiple red-brown smooth and warty papules on the external genitalia. Erythroplasia of Queyrat: red smooth plaque on glabrous vulvar, penile, or perianal skin.
Risk of malignant degeneration into SCC/cervical cancer/vulvar cancer/vaginal cancer/penile cancer/anal cancer.
Leukoplakia
16, 18
White plaque favoring the floor of the mouth, lateral and ventral tongue, and soft palate.
Male predominant. Risk of malignant degeneration into SCC.
Erythroplakia
16, 18
Red patch or thin plaque favoring the floor of the mouth, lateral and ventral tongue, and soft palate.
Male predominant. Risk of malignant degeneration into SCC (less common but higher risk than leukoplakia).
Verrucous Carcinoma
Papillomatosis cutis carcinoides (Gottron tumor)
6, 11
Vegetative, verrucous-like lesion on the trunk or extremities.
Florid oral papillomatosis (Ackerman tumor)
6, 11
Verrucous lesions in the oral cavity.
Giant condylomata acuminata (Buschke-Löwenstein tumor)
6, 11
Large exophytic condyloma-like plaques and tumors of the anogenital area.
Slow-growing mass that can invade the bone beneath the tumor.
Epithelioma cuniculatum
6, 11
Vegetative plaques on the plantar surface of the foot.
Miscellaneous
PVL
N/A
Multiple red and white patches on the oral mucosa with variable verrucous change.
Female predominant. Risk of malignant degeneration into SCC or verrucous carcinoma.
Pseudoepitheliomatous keratotic micaceous balanitis
N/A
Thick keratotic plaques on the glans penis.
Elderly circumscribed men. Risk of malignant degeneration into SCC or verrucous carcinoma.
a Illustrative examples provided.
AIN, anal intraepithelial neoplasia; CIN, cervical intraepithelial neoplasia; EDV, epidermodysplasia verruciformis; HPV, human papillomavirus; N/A, not applicable; PIN, penile intraepithelial neoplasia; PVL, proliferative verrucous leukoplakia; SCC, squamous cell carcinoma; SIL, squamous intraepithelial lesion; VaIN, vaginal intraepithelial neoplasia; VIN, vulvar intraepithelial neoplasia.
Dermoscopy features include focal glomerular vessels, rosettes, keratin pearls (white circles), yellow scale, and brown dots aligned radially at the periphery.
A universally accepted staging system for risk stratification for cutaneous SCC does not exist. Stratification of localized SCC using the NCCN guidelines is recommended for clinical practice; however, the Brigham and Women’s Hospital tumor staging system for cutaneous SCC is generally regarded as the best prognostication tool (Table 5.7). While there is an overall low risk of nodal and distant metastasis, imaging (CT, PET/CT, US) may be warranted for high-risk tumors (eg, Brigham and Women’s Hospital ≥ T2b) and when there is concern for deep structural involvement.
Management
Though SCC most commonly carries the risk of local, destructive infiltration, the risk of metastasis is approximately 4%. The two highest risk factors for metastasis are depth of invasion > 4 mm and size ≥ 2 cm. Additional poor prognostic factors include comorbidities (eg, chronic
lymphocytic leukemia [CLL]); location on the lip or ear; SCC arising within a scar or chronic ulcer, hypertrophic LP, hypertrophic LE, or LS; arsenical SCC; and poor histological differentiation or perineural invasion.
Figure 5.7. CLINICOPATHOLOGICAL CORRELATION: SQUAMOUS CELL CARCINOMA. A and B, SCCis. Solid arrow: loss of normal epidermal maturation (“wind-blown” appearance). C and D, SCC. E and F, Verrucous carcinoma. Dashed arrow: round “pushing” border “bulldozing” the underlying dermis. G, Spindle cell SCC. Dotted arrow: atypical spindle cells. H, Metastatic SCC. AK, actinic keratosis; CK, cytokeratin; EMA, epithelial membrane antigen; IHC, immunohistochemistry; PAS, periodic acid-Schiff; PEH, pseudoepitheliomatous hyperplasia; SCC, squamous cell carcinoma; SCCis, squamous cell carcinoma in situ.
(A, Reprinted with permission from Craft N, Fox LP, Goldsmith LA, et al. VisualDx: Essential Adult Dermatology. Wolters Kluwer Health/Lippincott
Williams & Wilkins; 2010. B, Histology image courtesy of Noel Turner, MD, MHS and Christine J. Ko, MD. C, Reprinted with permission from Elder DE, Elenitsas R, Rosenbach M, et al. Lever’s Histopathology of the Skin. 11th ed. Wolters Kluwer; 2015. D, Histology image courtesy of Noel Turner, MD, MHS and Christine J. Ko, MD. F, Histology image reprinted with permission from Crowson N, Magro CM, Mihm MC Jr. Biopsy Interpretation of the Skin: Primary Non-Lymphoid Cutaneous Neoplasia. Wolters Kluwer Health/Lippincott Williams & Wilkins; 2010. G, Histology image reprinted with permission from Crowson N, Magro CM, Mihm MC Jr. Biopsy Interpretation of the Skin: Primary Non-Lymphoid Cutaneous Neoplasia. Wolters Kluwer Health/Lippincott Williams & Wilkins; 2010. H, Histology image reprinted with permission from Elder DE, Elenitsas R, Rosenbach M, et al. Lever’s Histopathology of the Skin. 11th ed. Wolters Kluwer; 2015.)
• SCCis: loss of normal epidermal maturation with full-thickness cytologic atypia (the basement membrane remains intact). Malignant keratinocytes can keratinize and integrate into the stratum corneum forming malignant horn. Pagetoid spread is variably present. Follicular involvement is common.
• SCC: invasive. Malignant keratinocytes can keratinize and integrate into the stratum corneum forming malignant horn (well- or moderately differentiated). Hypergranulosis / PEH may occur at the periphery. Acantholysis and desmoplasia are variably present. Perineural invasion and plasma cells are common.
• Verrucous carcinoma: well-differentiated glassy eosinophilic keratinocytes with a round border.
• Spindle cell SCC: poorly differentiated SCC with atypical spindle cells abutting the epidermis.
• Metastatic SCC: lacks overlying in situ component, often deeper with a high degree of cytologic atypia.
Clear cells containing glycogen (PAS positive, diastase sensitive) are variably present. IHC is often required to diagnose poorly differentiated SCCs (eg., spindle cell). Positive stains include pan-CK and EMA.
Loss of normal epidermal maturation gives SCCis a “wind-blown” appearance. The round “pushing” border of verrucous carcinoma “bulldozes” the dermis.
Table 5.7. BRIGHAM AND WOMEN’S HOSPITAL TUMOR STAGING SYSTEM FOR CUTANEOUS SQUAMOUS CELL CARCINOMA
TUMOR Classification System
Category
Definition
Risk Factors
T0
SCCis
Tumor diameter ≥ 2 cm Poorly differentiated histology Perineural invasion Tumor invasion beyond subcutaneous fat (excluding bone which upgrades to T3)
T1
0 risk factors.
T2a
1 risk factor.
T2b
2-3 risk factors.
T3
4 risk factors or bone invasion.
SCCis, squamous cell carcinoma in situ.
Per AAD guidelines, surgical excision with 4 to 6 mm margins to the depth of adipose tissue is recommended for lowrisk SCC. ED&C may be considered for low-risk SCCs on nonterminal hair-bearing sites. Standard surgical excision can be considered for some high-risk SCC, though generally MMS is preferred. The MMS AUC is an excellent a tool to determine whether MMS is the appropriate treatment for SCC.
When a surgical approach is contraindicated or impractical, radiation therapy may be considered, though the cure rate is lower.
PDT, cryotherapy, and ED&C can be considered for the treatment of SCCis.
Per AAD guidelines, there is insufficient evidence to recommend use of oral nicotinamide or celecoxib for chemoprevention in patients with a history of SCC. However, a phase III RCT did show that niacinamide 500 mg twice daily reduced the incidence of keratinocytic skin cancer by ˜25% in a high-risk skin cancer population.
For solid organ transplant recipients, oral retinoids may be beneficial for chemoprevention.
“Real World” Advice
For solid organ transplant recipients, consider switching tacrolimus to sirolimus.
KERATOACANTHOMA
Reprinted with permission from Edward S, Yung A. Essential Dermatopathology. Wolters Kluwer Health/Lippincott Williams & Wilkins; 2011
KA is generally regarded as a low-grade form of SCC capable of regression via terminal differentiation. Some KAs arise in the setting of trauma, suggesting a Koebner phenomenon. Drug associations with KAs include BRAF inhibitors and ICIs.
KAs are associated with Muir-Torre syndrome (MTS).
KA classically presents as a rapidly growing papule, eventually forming a keratotic-filled crater. The Ferguson-Smith variant due to AD mutation in TGFBR1 is characterized by multiple spontaneously regressing KAs typically in younger, adolescent patients, while the Grzybowski variant is characterized by thousands of widespread KA papules resembling milia in older individuals.
Figure 5.8. CLINICOPATHOLOGICAL CORRELATION: KERATOACANTHOMA. KA is characterized by a keratin-filled crater composed of glassy eosinophilic keratinocytes with mild cytologic atypia. Hypergranulosis / PEH may occur at the center; elastic trapping may occur at the periphery. Perineural invasion is common, along with lymphocytes ± lichenoid interface dermatitis with admixed neutrophilic microabscesses and eosinophils. A, Low-power view. B, High-power view. Solid arrow: squamous eddy (keratin pearl). KA, keratoacanthoma; PEH, pseudoepitheliomatous hyperplasia.
The classic teaching is that a KA should not demonstrate acantholysis.
• Regressing KA: keratin-filled crater, now involuted to a thin wall, and peripheral scar.
Rapid growth, especially after a biopsy, is a helpful clinical clue to the diagnosis of KA.
While some KAs will spontaneously regress, for those with persistent clinical disease, surgical excision is recommended. In cases where surgery may lead to poor cosmetic or functional outcome, intralesional 5-FU may be considered.
MAMMARY PAGET DISEASE AND EXTRAMAMMARY PAGET DISEASE
Mammary Paget disease (left) reprinted with permission from Goodheart HP. Goodheart’s Same-Site Differential Diagnosis: A Rapid Method of Diagnosing and Treating Common Skin Disorders. Wolters Kluwer Health/Lippincott Williams & Wilkins; 2011. Extramammary Paget disease (right).
Mammary Paget disease (MPD) is an intraepithelial condition of the nipple and peri-areolar skin associated with underlying breast cancer. In some cases, MPD may arise in the absence of underlying breast cancer from Toker cells. Extramammary Paget disease (EMPD) is an intraepithelial condition of the apocrine gland often located on anogenital skin. While patients most often present with primary EMPD, ˜25% present with secondary EMPD due to pagetoid spread of an adjacent or continuous malignancy (most commonly breast, colon, or bladder adenocarcinoma).
MPD and EMPD are each characterized by a welldemarcated, erythematous expanding plaque in the above distribution. Pruritus is common; erosion, bleeding, and pain are signs of late-stage disease.
The combination of pink erythema and white scale is sometimes called a “strawberries and cream” appearance.
IHC for the differential diagnosis of pagetoid spread is summarized in Table 5.8.
Skin biopsy is required to establish the diagnosis of MPD and EMPD, which are often mistaken for inflammatory eruptions (eg, eczematous dermatoses) or infections (eg, tinea).
Figure 5.9. CLINICOPATHOLOGICAL CORRELATION: MAMMARY PAGET DISEASE AND EXTRAMAMMARY PAGET DISEASE. Both MPD and EMPD are characterized by large cells with abundant cytoplasm that scatter or form nests within the epidermis. Paget cells compress the basal layer and may spit out into the stratum corneum. Differentiation relies on staining pattern. Paget cells contain sialomucin (mucicarmine positive; PAS positive, diastase resistant). Solid arrow: Paget cell. EMPD, extramammary Paget disease; MPD, mammary Paget disease; PAS, periodic acid-Schiff; SCCis, squamous cell carcinoma in situ.
(Histology image courtesy of Kristin Smith, MD.)
Beyond MPD/EMPD, the differential diagnosis for pagetoid spread includes SCCis, Spitz nevus, melanoma, sebaceous carcinoma, and intraepithelial porocarcinoma.
MPD prognosis is largely tied to the stage of the underlying breast adenocarcinoma; some studies suggest that MPD is a negative prognostic factor. Management is usually surgical excision or radiation therapy. EMPD can be invasive leading to metastasis and a poor prognosis; however, EMPD generally has a good prognosis with 5-year overall survival ranging from 75% to 95%. MMS is superior to wide local excision (WLE) with regard to higher recurrence-free survival, which is further enhanced by the use of CK7 IHC. Topical cytotoxic chemotherapies (eg, 5-FU), imiquimod, and radiation therapy (eg, brachytherapy) may be used for patients in whom surgery is not practical or contraindicated, and as adjunctive therapy.
Melanocytic Neoplasms
Basic Concepts
Pigmented lesions can result from an increase in melanin production (for example, ephelis, café-au-lait macule [CALM]), or an increase in melanocytes (eg, lentigo simplex).
Melanocytic lesions span a wide range of diagnoses ranging from benign etiologies (eg, lentigo simplex) to malignant etiologies (eg, melanoma).
On dermoscopy, the four primary global features of melanocytic lesions are reticular pattern, globular pattern, homogenous pattern, and starburst pattern. For local and site-related features, see Appendix 4.
 LENTIGO SIMPLEX → Diagnosis Group 1 Synonyms: simple lentigo, lentiginosis (multiple) Reprinted with permission from McConnell TH. The Nature of Disease: Pathology for the Health Professions. Wolters Kluwer Health/Lippincott Williams & Wilkins; 2007. |
Table 5.8. IMMUNOHISTOCHEMISTRY FOR THE DIFFERENTIAL DIAGNOSIS OF PAGETOID SPREAD | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Epidemiology
Lentigo simplex is a benign pigmented lesion that results from an increase in melanocytes.
Hereditary syndromes associated with lentigines are summarized in Table 5.9.
Clinicopathological Features
Lentigo simplex classically presents as a brown to black, well-circumscribed, oval macule, either singly or in multiplicity.
Lentigo variants include ink-jet lentigo (very dark pigmentation), solar lentigo (sun-exposed sites), mucosal melanotic macule (oral, anogenital), nail unit lentigo (longitudinal melanonychia).
Lentigo simplex overlaps with junctional nevocellular nevus in lentiginous nevus.
Evaluation
The differential diagnosis of lentigo simplex includes ephelis, CALM, junctional melanocytic nevus, and lentigo maligna. In contradistinction to lentigo simplex, ephelides and CALMs are benign pigmented lesions that result from an increase in melanin production.
The diagnosis of lentigo simplex can usually be made by clinical and dermatoscopic examination alone; however, skin biopsy may be helpful to confirm the diagnosis.
Management
Treatment is not needed as lentigo simplex is benign. Cosmetic treatment options include cryotherapy, chemical peels, Q-switched lasers (ie, ruby, alexandrite, Nd:YAG), and IPL.
“Real World” Advice
Lentigo simplex on a mucosal surface can have ill-defined borders and nonhomogenous pigment, which can mimic melanoma.
Table 5.9. HEREDITARY SYNDROMES ASSOCIATED WITH LENTIGINES
Diagnosis
Inheritance Pattern
Genes
Classic Description
Localized
Peutz-Jeghers syndrome
AD
STK11
Lentigines favoring perioral skin, oral mucosa, and hands. Systemic features include hamartomatous gastrointestinal polyps, intussusception, and gastrointestinal hemorrhage. Increased risk for gastrointestinal, pancreatic, breast, and lung cancer.
Cowden syndrome/BRR syndrome
See Chapter 5: Adipose Neoplasms.
Cronkite-Canada syndrome
Sporadic
Unknown
Lentigines on face, oral mucosa (often buccal), and acral skin, hypermelanosis, alopecia, onychoatrophy. Systemic features include weight loss, chronic diarrhea, and intestinal polyposis.
Laugier-Hunziker syndrome
Sporadic
Unknown
Lentigines in similar distribution as Peutz-Jeghers syndrome, genital melanosis, longitudinal melanonychia.
Generalized
Noonan syndrome with lentigines (formerly LEOPARD)
AD
PTPN11
Lentigines present in early infancy, CALMs, low-set ears, KP atrophicans faciei. The characteristic hair shaft abnormality without increased fragility is woolly hair. Systemic features include growth retardation, ECG abnormalities (heart block), ocular hypertelorism, deafness, abnormal genitalia, and pulmonary stenosis. Increased risk for GCT.
Remember that the gene implicated in LEOPARD is PTPN11 with the phrase, “LEOPARD print pants.”
LEOPARD is characterized by lentigines, ECG abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, growth retardation, and deafness.
Carney complex
AD
PRKAR1A
Superficial (angio)myxomas, lentigines, blue nevi, and psammomatous melanotic schwannomas. Systemic features include atria myxomas, pigmented nodular adrenocortical disease, myxoid mammary fibroadenomas, and testicular tumors.
Remember that PRKAR1A is the gene implicated in Carney complex with the phrase, “park your car.”
AD, autosomal dominant; BRR, Bannayan-Riley-Ruvalcaba; CALMs, café-au-lait macules; ECG, electrocardiogram; GCT, granular cell tumor; KP, keratosis pilaris.
Figure 5.10. CLINICOPATHOLOGICAL CORRELATION: LENTIGO SIMPLEX. Lentigo simplex is characterized by epidermal acanthosis and a slight increase in melanocytes in the basal layer of the epidermis with hyperpigmentation. Melanophages may be observed in the upper dermis. Solid arrow: melanophage.
(Histology image reprinted with permission from Elder DE, Elenitsas R, Rosenbach M, et al. Lever’s Histopathology of the Skin. 11th ed. Wolters Kluwer; 2015.)
• Ink-spot lentigo: marked hyperpigmentation.
• Solar lentigo: bulb-like elongation of rete ridges in a reticular pattern and solar elastosis in the dermis.
• Mucosal melanotic macule: mucosal location with less prominent epidermal acanthosis.
• Nail unit lentigo: nail matrix location.
DERMAL MELANOCYTOSIS
Synonyms: congenital dermal melanocytosis, Mongolian spot
Reprinted with permission from Jensen S. Nursing Health Assessment: A Best Practice Approach. 3rd ed. Wolters Kluwer; 2018.
Table 5.10. DERMAL MELANOCYTOSIS VARIANTS
Diagnosisa
Classic Description
Notes
Nevus of Ota
Blue-gray patch in the V1 and V2 distribution on the face (often including the sclera of the eye). Can enlarge during puberty under the influence of hormones.
Patients with nevus of Ota are at risk for glaucoma (10%). They also have a slightly increased risk of uveal melanoma.
Nevus of Ito
Unilateral blue-gray patch on the scapular, supraclavicular, or shoulder region.
Hori nevus (acquired nevus of Ota-like macules)
Bilateral blue-gray macules favoring the zygomatic skin.
a Illustrative examples provided.
Figure 5.11. CLINICOPATHOLOGICAL CORRELATION: DERMAL MELANOCYTOSIS. Dermal melanocytosis is characterized by slender dendritic melanocytes in the dermis primarily oriented parallel to the epidermis ± melanophages. The stroma is nonsclerotic. A, Nevus of Ito low-power view. B, Nevus of Ito high-power view.
(Histology images reprinted with permission from Crowson AN, Magro CM, Mihm MC Jr. Biopsy Interpretation of the Skin: Primary Non-Lymphoid Cutaneous Neoplasia. 2nd ed. Wolters Kluwer; 2018.)
Dermal melanocytosis is a benign melanocytic proliferation that is usually present at birth. It most commonly affects Asian, Black, and Latino patients. It is rarely associated with GM1 gangliosidosis type 1, Hurler syndrome, and phakomatosis pigmentovascularis (GNAQ > GNA11 mutations).
Dermal melanocytosis classically presents as blue-gray macules or patches favoring the lumbosacral skin and buttocks that fade over time. Dermal melanocytosis variants are summarized in Table 5.10.
Dermal melanocytosis does not require treatment as it fades over time; however, nevus of Ota and Ito often persist. Q-switched lasers (ruby, alexandrite, Nd:YAG) can help minimize the pigmentation.
 BLUE NEVUS → Diagnosis Group 2 Synonym: dermal melanocytoma Reprinted with permission from Elder DE, Elenitsas R, Rubin AI, et al. Atlas of Dermatopathology: Synopsis and Atlas of Lever’s Histopathology of the Skin. 4th ed. Wolters Kluwer; 2020. |
Epidemiology
Blue nevi are benign tumors of dermal melanocytes.
Most blue nevi present in childhood/adolescence, but up to 25% develop in adulthood.
The genetics of blue nevus most commonly include GNAQ mutations (also seen in nevus of Ota and uveal melanoma) in >50% of cases and GNA11 mutations in ˜10% of cases.
Blue nevi, especially epithelioid blue nevi, are associated with the Carney complex.
 Figure 5.12. CLINICOPATHOLOGICAL CORRELATION: BLUE NEVUS. Common blue nevus is characterized by slender dendritic melanocytes in the dermis primarily oriented parallel to the epidermis ± melanophages. The stroma is sclerotic. A, Blue nevus low-power view. B, Blue nevus high-power view. (Histology images reprinted with permission from Elder DE, Elenitsas R, Rosenbach M, et al. Lever’s Histopathology of the Skin. 11th ed. Wolters Kluwer; 2015.) • Cellular blue nevus: admixed large spindle-shaped or epithelioid cells. • Malignant cellular blue nevus: cytologic atypia, mitotic activity, and necrosis. • Epithelioid blue nevus: large epithelioid cells; nonsclerotic stroma. In cellular blue nevus, a nodule may extend into the subcutis in a “dumbbell” pattern. |
Clinicopathological Features
Blue nevi classically present as solitary blue to blue-black papulonodules.
Common blue nevi favor the distal extensor extremities (˜50%) followed by the scalp.
Blue nevus variants include:
Cellular blue nevus: commonly occurs on the buttocks. There is a small risk of malignant degeneration to malignant cellular blue nevus with BAP-1 loss.
Epithelioid blue nevus: favors the trunk and extremities. It is associated with Carney complex.
Evaluation
The differential diagnosis of blue nevus includes blue tattoo, dermal melanocytic nevus, vascular neoplasms (eg, angiokeratoma, venous lake), pigmented BCC, and melanoma.
The diagnosis of blue nevus is often made by the clinical exam. If the diagnosis is uncertain, a blue nevus is changing, or there is concern for melanoma, a biopsy is indicated.
Management
Common blue nevi do not require excision. However, complete surgical excision of cellular blue nevi is recommended because of the small risk of malignant transformation.
“Real World” Advice
The Tyndall effect refers to optical scatter of different wavelengths of light encountering a clear substance. This effect, responsible for the blue color of both dermal melanocytosis and blue nevus, may also result in bluish discoloration when an HA filler is injected too superficially into the dermis.
 NEVOCELLULAR NEVUS AND ATYPICAL NEVUS → Diagnosis Group 1 Nevocellular nevus synonyms: common acquired melanocytic nevus, mole Atypical nevus synonym: Clark nevus, dysplastic nevus Nevocellular nevus (top) reprinted with permission from Gru AA, Wick MR, Mir A, et al. Pediatric Dermatopathology and Dermatology. Wolters Kluwer; 2018. Atypical nevus (bottom) reprinted with permission from Elder DE, Elenitsas R, Rosenbach M, et al. Lever’s Histopathology of the Skin. 11th ed. Wolters Kluwer; 2015. |
Epidemiology
Nevocellular nevi are benign melanocytic neoplasms that come in three main varieties: junctional, compound, and intradermal.
The genetics of common acquired nevocellular nevus most commonly include BRAF mutations in ˜80% of cases and NRAS mutations in a minority of cases. Gene mutations associated with melanocytic nevi are summarized in Table 5.11.
Cardiofaciocutaneous syndrome (AD mutation in BRAF, most commonly) is associated with multiple dark melanocytic nevi. Cardiofaciocutaneous syndrome is also associated with distinctive facial features (high forehead, short nose, hypertelorism, ptosis, and small chin), cardiac defects, and other cutaneous findings (ichthyosis, KP, and absent eyebrows/eyelashes).
Table 5.11. GENE MUTATIONS ASSOCIATED WITH MELANOCYTIC NEVI
Diagnosisa
Gene Associationsa
Dermal melanocytosis
GNAQ > GNA11
Blue nevus
GNAQ > GNA11
Epithelioid blue nevus
PRKAR1A
Common acquired nevocellular nevus
BRAF > NRAS
Deep penetrating nevus
CTNNB1 (β-catenin)
Atypical nevus
CDKN2A (p16)
Congenital melanocytic nevus
NRAS
Nevus spilus
HRAS
Spitz nevus
HRAS
Atypical epithelioid Spitz nevus
BAP1, BRAF
a Illustrative examples provided.
Nevi are more common in white patients. However, nevi on acral surfaces, nails, and conjunctiva are more prevalent in black and Asian patients.
Sun exposure (both intermittent intense and chronic moderate) and tanning bed use may trigger eruptive atypical melanocytic nevi. Other triggers of eruptive melanocytic nevi include blistering conditions (ie, SJS/TEN), scarring conditions (ie, genital LS), and systemic immunosuppression (eg, HIV infection). Melanocytic nevi may darken under the influence of hormones (eg, pregnancy).
Drug triggers include systemic immunosuppressants (eg, azathioprine, cyclosporine) and BRAF inhibitors (hypothesized role for paradoxical MAPK activation).
Clinicopathological Features
Junctional nevi are usually small (<5 mm), wellcircumscribed, brown macules. Compound nevi show variable elevation but are usually thin papules that are lighter brown compared to junctional nevi. Finally, intradermal nevi are usually skin-colored to light brown papules.
Atypical nevi are often larger (>6 mm) and can have irregular brown pigment and irregular borders.
There are several variants of nevocellular nevi which are summarized in Table 5.11 including recurrent nevus (often mistaken for melanoma given the atypia seen on histopathology), longitudinal melanonychia, balloon cell nevus, and halo nevus.
 Figure 5.13. CLINICOPATHOLOGICAL CORRELATION: NEVOCELLULAR NEVUS AND ATYPICAL NEVUS. Nevocellular nevus is well-nested at the DEJ and demonstrates sharp lateral circumscription, left-right symmetry, maturation, and dispersion. Deep mitoses and deep pigment in nests are absent. Atypical nevus is well-nested at the DEJ and demonstrates maturation and dispersion. Deep mitoses and deep pigment in nests are absent. However, the junctional component extends ≥ 3 rete beyond the intradermal component (shoulder region), and there is left-right asymmetry. Irregular nests of junctional melanocytes ± cytologic atypia bridge adjacent rete. There is concentric papillary dermal fibrosis. Some dermatopathologists grade atypia as mild, moderate, or severe. A, Junctional nevus. B, Compound nevus. C, Dermal nevus. D, Compound nevus. Solid arrow: junctional component. Dashed arrow: intradermal component. E, Atypical compound nevus. Dotted arrow: bridging of adjacent retia. (A, Reprinted with permission from Goodheart HP. Goodheart’s Same-Site Differential Diagnosis: A Rapid Method of Diagnosing and Treating Common Skin Disorders. Wolters Kluwer Health/Lippincott Williams & Wilkins; 2011. B, Reprinted with permission from Gru AA, Wick MR, Mir A, et al. Pediatric Dermatopathology and Dermatology. Wolters Kluwer; 2018. C, Reprinted with permission from Edwards L, Lynch P. Genital Dermatology Atlas and Manual. 3rd ed. Wolters Kluwer; 2017. D, Histology image reprinted with permission from Crowson AN, Magro CM, Mihm MC Jr. Biopsy Interpretation of the Skin: Primary Non-Lymphoid Cutaneous Neoplasia. 2nd ed. Wolters Kluwer; 2018. E, Histology image reprinted with permission from Gru AA, Wick MR, Mir A, et al. Pediatric Dermatopathology and Dermatology. Wolters Kluwer; 2018.) • Junctional nevus: melanocytic nests within the epidermis. • Compound nevus: melanocytic nests within the epidermis and dermis. • Intradermal nevus: melanocytic nests within the dermis. • Acral nevus: elongated nests following dermatoglyphs. • Ancient nevus: melanocytes with large hyperchromatic nuclei. • Balloon cell nevus: melanocytes with swelling of cellular organelles (balloon cells). • Combined nevus: contains ≥2 cell populations, most often nevocellular nevus and blue nevus. • Deep penetrating nevus: heavily pigmented melanocytes penetrating toward or into the subcutis. • Neural nevus: spindle melanocytes; nevic corpuscles resemble Meissner corpuscles. • Recurrent nevus: confluent poorly and/or irregularly nested junctional melanocytic proliferation overlying a scar ± underlying residual nevocellular nevus. • Special site nevus (scalp, ear, breast, axilla, umbilicus, anogenital): may appear atypical or demonstrate large junctional nests with poorly cohesive melanocytes. • Congenital melanocytic nevus / nevus spilus / halo nevus: see below. A “discount” is applied when grading the atypia of special site nevi. |
Evaluation
The differential diagnosis of junctional melanocytic nevus and atypical nevus includes lentigo simplex and melanoma. The differential diagnosis of compound nevus and intradermal nevus includes SK, Spitz nevus, dermatofibroma (DF), and neurofibroma.
Biopsy is recommended to rule out melanoma if there are atypical features or if a lesion is changing.
Management
Nevocellular nevi generally do not require treatment unless a biopsy reveals atypical features.
Surgical re-excision with narrow margins is generally recommended for severely atypical nevi.
“Real World” Advice
Surgical re-excision of moderately atypical melanocytic nevi is an area of controversy. Recent data suggest that close observation of such nevi that have been excisionally biopsied with no residual clinical pigmentation but with histologically positive margins may be reasonable.
CONGENITAL MELANOCYTIC NEVUS
Reprinted with permission from Salimpour RR, Salimpour P, Salimpour P. Photographic Atlas of Pediatric Disorders and Diagnosis. Wolters Kluwer Health/Lippincott Williams & Wilkins; 2013.
Congenital melanocytic nevi are melanocytic nevi that are present at birth. They are traditionally divided into four categories based on the adult size: small (<1.5 cm), medium (1.5–20 cm), large (>20 cm), and giant (>40 cm). The majority (˜80%) are caused by NRAS mutations.
Congenital melanocytic nevi classically present as brown thin plaques ± hypertrichosis. There may be perifollicular hypo- or hyperpigmentation. Lesions can become more elevated and pebbly (develop proliferative papules and nodules) with age. Neurocutaneous melanosis (NCM) is characterized by meningeal melanosis in the setting of a large/giant congenital melanocytic nevus or multiple (>3) medium congenital melanocytic nevi. Even in the absence of a large/giant congenital melanocytic nevus, having multiple satellite lesions confers the highest risk. NCM is associated with a high mortality in symptomatic patients. Large and giant congenital melanocytic nevi have an increased risk for developing melanoma (˜3%). The majority of melanomas develop in the first decade of life.
Patients with medium or large congenital melanocytic nevi with ≥20 satellite lesions or giant congenital melanocytic nevi should get MRI of the brain and spine to rule out NCM (though some argue for a lower satellite lesion threshold).
Surgical excision of medium and large congenital nevi can be considered. However, surgery has not been shown to decrease the risk of melanoma. Surgery is usually done after 6 months of age to avoid the highest risk period for general anesthesia. Surgery is often staged and utilizes tissue expanders. An acceptable alternative to surgery is yearly TBSEs with photography. Any changing areas within the lesion should be biopsied to rule out melanoma.
 Figure 5.14. CLINICOPATHOLOGICAL CORRELATION: CONGENITAL MELANOCYTIC NEVUS. Congenital melanocytic nevus differs from acquired nevocellular nevus due to greater breadth and depth. Perivascular, periadnexal, and interstitial melanocytes extend into deeper tissues. Solid arrow: Periadnexal melanocytes. (Histology image reprinted with permission from Husain AN. Biopsy Interpretation of Pediatric Lesions. Wolters Kluwer; 2014.) |
 NEVUS SPILUS → Diagnosis Group 2 Synonym: speckled lentiginous nevus |
Epidemiology
Nevus spilus is increasingly being considered a type of congenital melanocytic nevus. It is associated with HRAS mutations.
Nevus spilus is associated with phakomatosis pigmentovascularis types III and IV (see Chapter 5: Vascular Malformations and Neoplasms) and phakomatosis pigmentokeratotica (rare neurocutaneous disorder due to HRAS mutation characterized by the combination of nevus spilus, nevus sebaceous, and hypophosphatemic vitamin-D-resistant rickets).
Do NOT confuse phakomatosis pigmentovascularis with phakomatosis pigmentokeratotica.
Clinicopathological Features
Nevus spilus classically presents as a CALM-like light tan ovoid patch that is speckled with darker brown macules or papules. There is often an increased degree of speckling over time.
The appearance of nevus spilus resembles a “chocolate chip cookie.”
While there are reports of melanoma arising within a nevus spilus, the overall risk is thought to be very low. Similar to congenital melanocytic nevus, the risk may be associated with lesion size.
Evaluation
The differential diagnosis of nevus spilus includes CALM and agminated nevus.
Figure 5.15. CLINICOPATHOLOGICAL CORRELATION: NEVUS SPILUS. Nevus spilus resembles a lentigo simplex with multifocal lentiginous nevi. Solid arrows: multifocal lentiginous nevi.
(Histology image reprinted with permission from Elder DE, Elenitsas R, Rubin AI, et al. Atlas and Synopsis of Lever’s Histopathology of the Skin. 3rd ed. Wolters Kluwer Health/Lippincott Williams & Wilkins; 2012.)
The diagnosis of nevus spilus is made clinically since it has very distinctive features.
Management
Given the low risk of melanoma, patients should get periodic skin examinations for clinical monitoring. Macules or papules that are changing should be biopsied to rule out melanoma.
“Real World” Advice
Photodocumentation with regular skin examination is helpful for monitoring nevus spilus.
HALO NEVUS
Synonym: Sutton nevus
Reprinted with permission from Lugo-Somolinos A, McKinley-Grant L, Goldsmith LA, et al. VisualDx: Essential Dermatology in Pigmented Skin. Wolters Kluwer Health/Lippincott Williams & Wilkins; 2011.
Halo nevus is a benign variant of melanocytic nevus with surrounding hypopigmentation. The most common
demographic is <20 years of age. Halo nevus is thought to be due to a cell-mediated response to altered melanocytes. Twenty percent of patients with halo nevi may develop vitiligo.
Halo nevus classically presents as a brown macule or papule surrounded by a well-marginated depigmented ring favoring the trunk, especially the upper back. Halo nevi can demonstrate the Koebner phenomenon.
Halo nevi with atypical features should be biopsied to rule out melanoma.
Adults with new onset multiple halo nevi should be evaluated for cutaneous and uveal melanoma.
 SPITZ NEVUS → Diagnosis Group 2 Synonyms: benign juvenile melanoma, Spitz juvenile melanoma Reprinted with permission from Gru AA, Wick MR, Mir A, et al. Pediatric Dermatopathology and Dermatology. Wolters Kluwer; 2018. |
Epidemiology
Spitz nevus is a melanocytic neoplasm that typically occurs in children.
Figure 5.16. CLINICOPATHOLOGICAL CORRELATION: HALO NEVUS. Halo nevus is characterized by a dense lymphocytic infiltrate admixed with junctional and intradermal melanocytes. In the halo region, melanin and melanocytes are reduced or absent. Solid arrow: dense lymphocytic infiltrate.
(Histology image courtesy of Noel Turner, MD, MHS and Christine J. Ko, MD.)
The genetics of Spitz nevus most commonly include HRAS mutations, ALK1 fusions, and gain of chromosome 11p. Unlike common acquired nevocellular nevi, Spitz nevi do not harbor BRAF mutations. The one exception is the more recently described atypical epithelioid Spitz nevus (BAPoma), which often concurrently harbors loss of BAP1 and BRAF mutations. BAP1 mutation predisposes to a variety of malignancies including RCC (clear cell variant), uveal melanoma, and mesothelioma. Finally, Spitz nevi may harbor CDKN2A mutations leading to focal loss of p16. However, widespread loss of p16 should raise suspicion for Spitz melanoma.
Pigmented spindle cell nevus of Reed is a spindle cell variant of Spitz nevus that most commonly occurs in young adult women.
Clinicopathological Features
Common Spitz nevus classically presents as a pink or brown dome-shaped papule favoring the head and neck.
Pigmented spindle cell nevus of Reed classically presents as a dark brown dome-shaped papule favoring the thigh.
Agminated Spitz nevus is characterized by a variable number of grouped Spitz nevi in a localized or segmental distribution.
Atypical Spitz nevus has ≥1 atypical feature that deviates from common Spitz nevus. These features include large size (>5 mm), asymmetry, involvement of deep dermis or
subcutis, ulceration, lack of maturation, pagetoid spread, or high mitotic rate (>2 mitoses/mm2).
Figure 5.17. SIDE-BY-SIDE COMPARISON: SPITZ NEVUS AND PIGMENTED SPINDLE CELL NEVUS OF REED. Both classical Spitz nevus and the pigmented spindle cell nevus of Reed variant are well-nested at the DEJ and demonstrate sharp lateral circumscription, left-right symmetry, maturation, and dispersion. Deep mitoses and deep pigment in nests are absent. There is overlying hyperkeratosis, hypergranulosis, and PEH. Pagetoid spread, clefts around nests, pink Kamino bodies derived from the basement membrane (PAS positive, diastase resistant), and melanophages are variably present. In Spitz nevus, vertically oriented nests are comprised of epithelioid and spindled melanocytes and Kamino bodies are enriched. In pigmented spindle cell nevus of Reed, nests are comprised primarily of spindled melanocytes and melanophages are enriched.
A, Spitz nevus. B, Pigmented spindle cell nevus. Solid arrows: clefts around nests. Dashed arrow: Kamino body. DEJ, dermo-epidermal junction; PAS, periodic acid-Schiff; PEH, pseudoepitheliomatous hyperplasia.
(A, Histology image reprinted with permission from Husain AN. Biopsy Interpretation of Pediatric Lesions. Wolters Kluwer; 2014. B, Histology image reprinted with permission from Elder DE, Elenitsas R, Rosenbach M, et al. Lever’s Histopathology of the Skin. 11th ed. Wolters Kluwer; 2015.)
Vertically oriented nests may be described as a “raining down pattern” or “bananas on the tree.”
Atypical Spitz nevus has a risk of metastasis. Features associated with risk of metastasis include ulceration, Breslow thickness, atypical mitotic figures, and loss of p16 (CDKN2A).
Evaluation
The differential diagnosis of Spitz nevus includes intradermal nevus, melanoma, DF, and mastocytoma.
There can often be a high clinical suspicion for a Spitz nevus from clinical and dermatoscopic examinations. However, given the difficulty in classifying Spitz nevus along with the variability in clinical presentation, a biopsy may be indicated to rule out atypical Spitz nevus or melanoma.
While controversial, some recommend a sentinel lymph node biopsy (SLNB) for atypical Spitz nevus.
Management
Treatment remains controversial. Historically, the recommendation was to excise all Spitz nevi. However, many pediatric dermatologists now favor monitoring lesions that do not display any clinical or histopathological atypia.
There is mounting evidence that metastatic atypical Spitz nevi do not behave like metastatic melanoma and instead have a more benign course. Death is very rare. Patients with metastatic atypical Spitz nevi are often referred to oncology for co-management. Those with a positive SLNB are typically treated as having stage III melanoma with cytotoxic chemotherapy and immunotherapy.
“Real World” Advice
Terminology can be confusing. “Spitz melanomas” have hallmark mutations of Spitz nevi, whereas “Spitzoid melanomas” have histopathologic morphology resembling Spitz nevi.
 MELANOMA → Diagnosis Group 1 Superficial spreading melanoma |
Epidemiology
Melanoma is a malignant neoplasm that arises from melanocytes. Although it is most commonly cutaneous in origin, it can also arise on mucosal surfaces and the uvea.
Initiating oncogenic mutations usually involve the MAPK and PI3K signaling pathways. Genetic mutations associated with melanoma are summarized in Table 5.12. Overall, BRAF (V600E) is the most common mutation.
Table 5.12. GENE MUTATIONS ASSOCIATED WITH MELANOMA
Diagnosisa
Gene Associationsa
Superficial spreading melanoma
Non-CSD: BRAF > NRAS CSD: c-KIT > BRAF, NRAS
Lentigo maligna/lentigo maligna melanoma
c-KIT > BRAF, NRAS
Acral lentiginous melanoma
c-KIT > BRAF > NRAS
Nodular melanoma
NRAS
Uveal melanoma
GNAQ, GNA11, BAP1
Mucosal melanoma
c-KIT > NRAS
CSD, chronic sun-damaged.
a Illustrative examples provided.
Sun exposure (both intermittent intense and chronic moderate) and tanning bed use may trigger the development of melanoma. Other triggers are similar to melanocytic nevi.
Dysfunction of the MC1R can lead to red hair, inability to tan following UVR exposure, and increased risk of melanoma and NMSC. Melanoma is further associated with OCA (see Chapter 2: Pigmentary Disorders); XP, XP variant, and adult progeria (see Chapter 4: Photodermatoses); Li Fraumeni syndrome (AD mutation in TP53 encoding p53); and FAMMM syndrome (see below).
Clinicopathological Features
Melanoma can have a variety of clinical presentations based on subtype:
Superficial spreading melanomas initially present as dark brown to black macules with color variation, asymmetry, and irregular borders. A horizontal growth phase can develop into a more rapid vertical growth phase, which is clinically seen as papules forming within the macule. This subtype is most often seen on the trunk of men and legs of women.
Lentigo maligna melanomas are invasive melanomas that arise within lentigo maligna, a form of melanoma in situ (MIS). They present as asymmetric brown to black macules with irregular, often ill-defined, borders. This subtype is most often seen on chronic sun-damaged (CSD) skin, especially the nose and cheeks. Of note, lentigo maligna and lentigo maligna melanoma are controversial entities.
Acral lentiginous melanomas present as asymmetric brown to black macules. This subtype is the most common subtype seen in skin of color. A disproportionate number are diagnosed at an advanced stage.
Nodular melanomas present as blue-black nodules. They have minimal-to-no horizontal growth phase, but instead can have a rapid vertical growth phase leading to ulceration. This subtype is most often seen on the head and neck and trunk.
Other melanoma variants include amelanotic melanoma (pink), desmoplastic/neurotropic melanoma (head and neck), mucosal melanoma (oral, anogenital), and nail unit melanoma (longitudinal melanonychia).
The “ABCDE”s of melanoma are asymmetry, irregular borders, color variation, diameter > 6 mm, and evolution.
The “ABCDEF”s of nail unit melanoma are age (50-70 years), band of black-brown color, change in size/growth, digits (thumb > big toe > index finger), extension of color onto cuticle, and family history of melanoma.
Figure 5.18. Do NOT confuse Hutchinson sign of nail unit melanoma with Hutchinson sign of herpes zoster or Hutchinson teeth in Hutchinson triad of late congenital syphilis.
Figure 5.18. HUTCHINSON SIGN. Longitudinal melanonychia results from melanin production by nail unit melanocytes. Multiple bands, common in individuals with skin phototypes IV-VI, are typically due to melanocyte activation. A single band may be a sign of melanocyte hyperplasia (eg., lentigo, nevus, or melanoma). Hutchinson sign, periungual extension of pigmentation from longitudinal melanonychia onto the proximal and lateral nail folds, is an important indicator of nail unit melanoma.
(Hutchinson sign image reprinted with permission from Lugo-Somolinos A, McKinley-Grant L, Goldsmith LA, et al. VisualDx: Essential Dermatology in Pigmented Skin. Wolters Kluwer Health/Lippincott Williams & Wilkins; 2011.)
Clear cell sarcoma (“melanoma of soft parts”) is an aggressive soft tissue malignancy that is thought to be a melanoma variant. It usually presents as a nodule on the distal extremities. Unlike cutaneous melanoma, clear cell sarcoma is characterized by the chromosomal translocation t(12;22).
Regression, which is clinically seen as a hypopigmented focus within a melanoma, is observed in ˜2/3 of superficial spreading melanomas.
Metastatic melanoma to the skin usually presents as a blue-black nodule. The most common location is the lower extremities.
IHC and FISH for melanocytic neoplasms are summarized in Table 5.13.
Evaluation
The differential diagnosis of melanoma includes solar lentigo, nevocellular nevus, atypical nevus, and Spitz nevus. On acral surfaces, hemorrhage within the skin (ie, black heel and palm) can be hard to differentiate from a melanoma without a dermatoscopic examination. The differential diagnosis of amelanotic melanoma includes wart, BCC, and SCC.
Patients with suspected melanoma should get an excisional biopsy (with 1-2 mm margins) to evaluate the entire lesion. Sampling lesions with punch or shave biopsies can miss the diagnosis and is not advised. If an excisional biopsy is not possible, saucerization biopsies are preferable over thin shave biopsies, as thin shave biopsies may transect the melanoma and obscure the depth of invasion.
Nail matrix biopsy is the gold standard to diagnose nail unit melanoma.
Once the diagnosis of melanoma is made, evaluation depends on the clinical stage of the melanoma and symptoms. The American Joint Committee on Cancer (AJCC, 8th edition) TNM classification and staging for malignant melanoma is summarized in Tables 5.14 and 5.15.
Localized cutaneous melanoma (stage I and II) does not require laboratory or imaging evaluation in asymptomatic patients.
Patients with melanoma stage IB or higher should undergo SLNB.
Evaluation of stage III and IV melanomas usually includes imaging such as CT of the chest, abdomen, and pelvis or full body PET scan. Brain MRI is helpful in the assessment for intracranial metastases. Symptom-specific evaluation may also be helpful, such as colonoscopy for patients with gastrointestinal symptoms/bleeding and bone scan for patients with bone pain.
Management
The most important prognostic factor is Breslow thickness, which is measured from the top of the stratum granulosum to the deepest invasive cell. Historically, Clark’s levels (five levels based on depth of invasion) were used for melanoma staging. However, Clark’s level is no longer used in the AJCC TNM classification and staging for malignant melanoma as it is less prognostic and more subjective than Breslow thickness.
Other negative prognostic factors include male gender, increasing age, ulceration, head/neck/trunk location, palpable nodes, and increased tumor mitotic rate.
Melanoma leukoderma is a positive prognostic factor.
Treatment of melanoma is surgical for localized disease (stage I and II). WLE is the most common surgical treatment for melanoma. The recommended surgical margins are:
0.5 to 1 cm for melanoma in situ.
1 cm for Breslow thickness of ≤1 mm.
1 to 2 cm for Breslow thickness of 1.01 to 2 mm.
2 cm for Breslow thickness >2 mm.
Adjuvant chemotherapy (in particular, INFα and ipilimumab) has been shown to improve survival in stage II and III melanoma after surgical resection.
Advanced melanoma (stage III and IV) is typically treated with systemic immunotherapy. Historically, IFNα, IFNβ, and IL-2 were used. However, the discovery and success of ICIs such as CTLA4 inhibitors (eg, ipilimumab) and PD1 inhibitors (eg, nivolumab, pembrolizumab) has transformed the landscape of melanoma, such that ICIs have become the standard of care. PD1 inhibitors are more effective than CTLA4 inhibitors.
In patients with BRAF mutations, targeted antineoplastics include BRAF (V600E) inhibitors (eg, dabrafenib, vemurafenib) and MEK 1/2 inhibitors (eg, trametinib). Concurrent BRAF and MEK inhibition prolongs the development of resistance. In patients with known BRAF V600E mutations and a high tumor burden, BRAF and MEK inhibitors are often used as first-line therapies.
Figure 5.19. CLINICOPATHOLOGICAL CORRELATION: MELANOMA. Melanoma is typically broad and poorly nested at the DEJ. Irregular nests of junctional melanocytes extend from the tips and sides of rete to the tops of dermal papillae and display variable cytologic atypia. Lateral circumscription is variable, and there is left-right asymmetry, failure of maturation, and failure of dispersion. Deep mitoses and deep pigment in nests are variably present, along with pagetoid spread, melanophages, and a dense lymphocytic infiltrate at the base. Melanoma may enter both horizontal and vertical growth phases. A and B, Superficial spreading melanoma. C and D, Lentigo maligna E and F, Acral lentiginous melanoma. G and H, Nodular melanoma. DEJ, dermo-epidermal junction; MIS, melanoma in situ.
(A, Reprinted with permission from Elder DE, Elenitsas R, Rosenbach M, et al. Lever’s Histopathology of the Skin. 11th ed. Wolters Kluwer; 2015. B, Histology image courtesy of Noel Turner, MD, MHS and Christine J. Ko, MD. C, Reprinted with permission from Craft N, Fox LP, Goldsmith LA, et al. VisualDx: Essential Adult Dermatology. Wolters Kluwer Health/Lippincott Williams & Wilkins; 2010. D, Histology image reprinted with permission from Crowson AN, Magro CM, Mihm MC Jr. Biopsy Interpretation of the Skin: Primary Non-Lymphoid Cutaneous Neoplasia. 2nd ed. Wolters Kluwer; 2018. F, Histology image reprinted with permission from Crowson AN, Magro CM, Mihm MC Jr. Biopsy Interpretation of the Skin: Primary Non-Lymphoid Cutaneous Neoplasia. 2nd ed. Wolters Kluwer; 2018. G, Reprinted with permission from Edwards L, Lynch P. Genital Dermatology Atlas and Manual. 3rd ed. Wolters Kluwer; 2017. H, Histology image reprinted with permission from Elder DE, Elenitsas R, Rosenbach M, et al. Lever’s Histopathology of the Skin. 11th ed. Wolters Kluwer; 2015.)
• Superficial spreading melanoma: horizontal growth phase, pagetoid spread.
• Lentigo maligna: junctional MIS with adnexal extension, solar elastosis (controversial).
• Lentigo maligna melanoma: lentigo maligna with vertical growth phase (controversial).
• Acral lentiginous melanoma: junctional, acral location.
• Nodular melanoma: vertical growth phase, necrosis.
• Amelanotic melanoma: absence of melanin.
• Desmoplastic melanoma: spindle cells, desmoplastic stroma, nodular lymphoid aggregates.
• Neurotropic melanoma: desmoplastic melanoma with endoneurial invasion.
• Mucosal melanoma: mucosal location.
• Nail unit melanoma: nail matrix location.
• Regressing melanoma: zones of fibrosis and melanophages.
• Metastatic melanoma: radial symmetry or epidermotropic/nevoid, invasion of lymphatic vessels.
Intralesional therapies include IL-2 and the oncolytic virus talimogene laherparepvec (T-VEC).
Some dermatologists treat lentigo maligna and lentigo maligna melanoma with MMS given that these melanomas are often located on the face and have ill-defined margins (controversial). Melan-A (melanoma antigen recognized by T-cells 1 [MART-1]) is often utilized to stain serial frozen sections during in MMS for melanoma in order to better define the margins.
Table 5.13. IMMUNOHISTOCHEMISTRY AND FLUORESCENCE IN SITU HYBRIDIZATION FOR MELANOCYTIC NEOPLASMS | |||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||
“Real World” Advice
Amelanotic melanomas do not differ in prognosis than other melanomas of the same stage. However, the atypical appearance often results in a significant diagnostic delay.
Terminology can be confusing. Cutaneous melanomas that are very difficult to diagnose are sometimes called “melanocytic tumor of unknown malignant potential (MELTUMP).”
Table 5.14. AMERICAN JOINT COMMITTEE ON CANCER TNM CLASSIFICATION FOR MALIGNANT MELANOMA
T Category
Thickness
Ulceration Status
Tis
N/A
N/A
T1
≤1.0 mm
Unknown or unspecified
T1a
<0.8 mm
Without ulceration
T1b
<0.8 mm
With ulceration
0.8-1.0 mm
With or without ulceration
T2
>1-2 mm
Unknown or unspecified
T2a
>1-2 mm
Without ulceration
T2b
>1-2 mm
With ulceration
T3
>2-4 mm
Unknown or unspecified
T3a
>2-4 mm
Without ulceration
T3b
>2-4 mm
With ulceration
T4
>4 mm
Unknown or unspecified
T4a
>4 mm
Without ulceration
T4b
>4 mm
With ulceration
N Category
Number of Metastatic Nodes
Metastasis Status
N0
N/A
N/A
N1
0-1
a: clinically occult, no MSI
b: clinically detected, no MSI
c: 0 nodes, MSI present
N2
1-3
a: 2-3 clinically occult, no MSI
b: 2-3 clinically detected, no MSI
c: 1 node, clinical or occult, MSI present
N3
>1
a: >3 nodes, all clinically occult, no MSI
b: >3 nodes, ≥1 clinically detected or matted, no MSI
c: >1 node, clinical or occult, MSI present
M Category
Anatomic Site
LDH Level
M0
N/A
N/A
M1
Evidence of distant metastasis
M1a
Distant metastasis to skin, soft tissue including muscles, and/or nonregional lymph node
0 = not elevated
1 = elevated
M1a (0)
M1a (1)
M1b
Distant metastasis to lung with or without M1a sites of disease
0 = not elevated
1 = elevated
M1b (0)
M1b (1)
M1c
Distant metastasis to non-CNS visceral sites with or without M1a or M1b sites of disease
0 = not elevated
1 = elevated
M1c (0)
M1c (1)
M1d
Distant metastasis to CNS with or without M1a, M1b, or M1c sites of disease
0 = not elevated
1 = elevated
M1d (0)
M1d (1)
CNS, central nervous system; LDH, lactate dehydrogenase; M, metastasis; MSI, microsatellite instability; N, node; N/A, not applicable; T, tumor.
Table 5.15. AMERICAN JOINT COMMITTEE ON CANCER STAGING FOR MALIGNANT MELANOMA
Clinical Staging
Pathologic Staging
Stage 0
Tis
N0
M0
0
Tis
N0
M0
Stage IA
T1a
N0
M0
IA
T1a
N0
M0
Stage IB
T1b
T2a
—
—
IB
T1b
T2a
—
—
Stage IIA
T2b
T3a
N0
M0
IIA
T2b
T3a
N0
M0
Stage IIB
T3b
T4a
—
—
IIB
T3b
T4a
—
—
Stage IIC
T4b
—
—
IIC
T4b
—
—
Stage III
Any T
≥ N1
M0
IIIA
T1-2a
T1-2a
N1a
N2a
M0
IIIB
T0
T1-2a
T1-2a
T2b-3a
N1b-c
N1b-c
N2b
N1a-2b
—
IIIC
T0
T0
T1-3a
T3b-4a
T4b
N2b-c
N3b-c
N2c-3c
Any N
N1a-2c
—
IIID
T4b
N3a-c
M0
Stage IV
Any T
Any N
M1
IV
Any T
Any N
M1
SPOTLIGHT ON FAMILIAL ATYPIVAL MULTIPLE MOLE MELANOMA SYNDROME
FAMMM syndrome is an AD disorder due to mutations in CDKN2A, which encodes p16 (tumor suppressor gene that inhibits CDK4). It is estimated that ˜5% to 12% of melanomas are hereditary and about 40% of those are caused by CDKN2A mutations.
FAMMM syndrome is associated with multiple melanocytic nevi, atypical nevi, and a family history of melanoma. The most common internal malignancies are pancreatic cancer and astrocytoma.
The histopathology of FAMMM syndrome demonstrates melanocytic nevi, atypical nevi, and melanoma.
The NIH diagnostic criteria for FAMMM syndrome are (1) ≥50 clinically atypical nevi, (2) malignant melanoma in ≥1st- or 2nd-degree relative, and (3) nevi with histologic features of atypia. Patients with suspected FAMMM syndrome can get referred for genetic testing. However, this remains controversial as some clinicians believe testing positively will not change screening recommendations.
In addition to age-appropriate malignancy screening, patients need TBSEs every 6 to 12 months. Screening for melanoma in FAMMM kindreds should begin at 10 years of age. There are no specific screening recommendations for pancreatic cancer. However, many physicians will offer screening with CT, MRI, or endoscopic US starting at 50 years of age or 10 years younger than the earliest family member with pancreatic cancer.
Fibrous Neoplasms
Basic Concepts
Fibrous neoplasms comprise a diverse group of diagnoses that are generally characterized by an increased production of collagen in the skin.
Fibrous neoplasms range from benign entities (eg, DF) to malignant entities (for example, dermatofibrosarcoma protuberans [DFSP]). The term “undifferentiated pleomorphic sarcoma” refers to a heterogeneous group of soft-tissue sarcomas.
 KELOID → Diagnosis Group 1 |
 Figure 5.20. SIDE-BY-SIDE COMPARISON: HYPERTROPHIC SCAR AND KELOID. Scar is characterized by epidermal atrophy and proliferation of perpendicularly orientated fibroblasts (horizontal) and blood vessels (vertical) in the dermis with loss of elastic fibers and adnexal structures. Both hypertrophic scar and keloid demonstrate nodules and whorls of thick collagen fibers. Hypertrophic scar has thick collagen fibers. Keloid has thick hyalinized collagen fibers. IHC may be helpful. COX-1 expression increases with progression from scar to hypertrophic scar to keloid. CD34 and factor XIIIa are negative. A, Hypertrophic scar. Solid arrow: thick (“ropy”) collagen fibers. B, Keloid. Dashed arrow: thick (“ropey”) and hyalinized (pink “bubble gum”) collagen fibers. CD, cluster of differentiation; COX-1, cyclooxygenase 1; IHC, immunohistochemistry. (Histology images reprinted with permission from Fisher C, Montgomery EA, Thway K. Biopsy Interpretation of Soft Tissue Tumors. 2nd ed. Wolters Kluwer; 2015.) Collagen fibers in hypertrophic scar are “ropy.” Collagen fibers in keloid are “ropy” and pink, Collagen fibers in hypertrophic scar are “ropy.” resembling “bubble gum.” |
Epidemiology
Keloids represent an abnormal wound healing response to skin injury. TGFβ plays a key role, stimulating fibroblasts to produce excessive collagen during the proliferative phase of wound healing. Collagen III is overrepresented in keloids.
Keloids most commonly occur in patients <30 years of age. There is a higher prevalence in Asian, black, and Latino populations.
Multiple keloids are associated with Rubinstein-Taybi syndrome.
Clinicopathological Features
Keloid is characterized by a smooth firm papule or plaque that extends beyond the boundaries of the original wound. The color can range from pink to skin-colored to brown. Keloids favor areas of high tension such as the shoulders, chest, and upper back.
In contrast, hypertrophic scar is characterized by a smooth firm papule or plaque that is confined to the boundaries of the original wound.
Evaluation
Beyond hypertrophic scar, the differential diagnosis of keloid includes xanthoma disseminatum and lobomycosis. Hypertrophies and atrophies are summarized in Table 5.16.
Hypertrophies: for Beare-Stevenson cutis gyrata syndrome, see Chapter 2: Papulosquamous Disorders and
Palmoplantar Keratodermas; for hyaline fibromatosis syndrome, see Chapter 5: Other Malformations and Neoplasms. Atrophies: for atrophoderma vermiculatum and follicular atrophoderma, see Chapter 2: Eczematous Dermatoses and Related Disorders.
Table 5.16. HYPERTROPHIES AND ATROPHIES
Diagnosisa
Classic Description
Notes
Hypertrophies
Cutis gyrata
Cerebriform folding of the skin on the scalp.
Primary or secondary. Associations include acromegaly, myxedema, Graves disease, and paraneoplastic syndrome due to metastatic carcinoma.
Fibromatosis
See below.
Keloid/hypertrophic scar
See above.
Atrophies
Anetoderma
Well-circumscribed areas of flaccid skin that may be papular, macular, or depressed.
Primary or secondary. Associations include inflammation, infection, or skin tumor.
Atrophia maculosa varioliformis cutis
Varioliform or linear depressions resembling scars.
No history of trauma to the skin.
Atrophoderma of Pasini and Pierini
Depressed brown patches.
Most common in women. May be associated with Borrelia burgdorferi infection, but this remains controversial.
The edge of atrophoderma resembles a “cliff drop.”
Diabetic dermopathy
Red to brown slightly depressed patches usually on the shins.
Associated with diabetes mellitus.
Mid-dermal elastolysis
Well-circumscribed symmetric areas of fine wrinkling.
Most common in Caucasian women 30-50 years of age.
Piezogenic pedal papules
Skin-colored papulonodules usually near the heels.
Induced by weight bearing. Disappear when leg is raised.
Striae
Well-circumscribed linear, atrophic plaques that range in color from purple to white.
Most common in women. Associations include puberty and pregnancy.
Elastic Tissue Disordersb
Elastoma
Firm skin-colored to yellow papules favoring the trunk.
Type of connective tissue nevus.
Elastofibroma dorsi
Deep tumor/nodule on the mid-upper back.
Favors older women.
Late-onset focal dermal elastosis
Small skin-colored to yellow coalescing papules that favor the neck and intertriginous surfaces.
Linear focal elastosis
Multiple, palpable linear plaques (striae-like) on the trunk.
A skin biopsy is usually not required for keloid but can be helpful to confirm the diagnosis.
Management
ILK is first line. It both flattens keloids and alleviates symptoms such as pruritus. In needle-averse patients, a potent topical corticosteroid under silicone dressing occlusion may have some benefit.
Surgical excision should be undertaken with caution due to the high rate of recurrence. Postsurgical ILK may help reduce recurrence.
Cryotherapy (needle > spray) done monthly for several months has some efficacy.
Other therapies that have been shown to have some efficacy in treating keloid include topical 5-FU, PDL, silicone sheeting, and pressure therapy.
Radiation therapy is reserved for treatment-resistant keloids.
Newer therapies with promising results include intralesional avotermin (recombinant TGFβ3), intralesional IL- 10 (anti-inflammatory), and intralesional insulin (inhibits myofibroblasts).
“Real World” Advice
The management of keloids remains challenging, and a multimodal approach is often beneficial:
Cryotherapy causes tissue edema and may improve the penetration of ILK.
ILK or radiation therapy decreases the rate of recurrence after surgical excision.
 ANGIOFIBROMA → Diagnosis Group 2 Synonyms: fibrous papule Reprinted with permission from Goodheart HP. Goodheart’s Same-Site Differential Diagnosis: A Rapid Method of Diagnosing and Treating Common Skin Disorders. Wolters Kluwer Health/Lippincott Williams & Wilkins; 2011 |
 Figure 5.21. CLINICOPATHOLOGICAL CORRELATION: ANGIOFIBROMA. Angiofibroma is characterized by a domeshaped dermal proliferation of dilated blood vessels with concentric perivascular fibrosis. Stellate stromal cells are factor XIIIa and stromolysin 3 positive. Solid arrow: dilated blood vessel with concentric perivascular fibrosis. (Histology image courtesy of Noel Turner, MD, MHS and Christine J. Ko, MD.) |
Epidemiology
Angiofibroma is a descriptive term to characterize a variety of fibrous neoplasms with overlapping histopathological features.
Multiple facial angiofibromas are associated with TSC and MEN1.
Clinicopathological Features
Angiofibroma classically presents as a skin-colored to red dome-shaped papule.
Location-specific variants of angiofibroma include facial angiofibromas, pearly penile papules (around the corona of the glans penis), and periungual fibromas.
Evaluation
The differential diagnosis of angiofibroma varies based on the variant. For example, a solitary facial angiofibroma may be mistaken for BCC, intradermal nevus, or an adnexal neoplasm, whereas pearly penile papules may be mistaken for condyloma acuminata.
Patients with ≥3 facial angiofibromas and ≥2 ungual fibromas should be evaluated for TSC.
Management
Treatment options for angiofibroma include PDL, fractional ablative laser, and electrosurgery.
Topical mTOR inhibitors (eg, sirolimus) have also been successfully employed to treat angiofibromas.
“Real World” Advice
Understanding the genetic basis of genodermatoses such as TSC has led to the discovery of targeted therapies. Examples of this include topical mTOR inhibitors (eg, sirolimus) for angiofibromas.
SPOTLIGHT ON TUBEROUS SCLEROSIS COMPLEX
Synonyms: Bourneville disease, Bourneville-Pringle disease
Table 5.17. CLINICAL FEATURES OF TUBEROUS SCLEROSIS COMPLEX
Cutaneous Features
Infancy:
Hypomelanotic macules (“ash-leaf” macules) and “confetti” macules
CALMs
Prepubertal:
Facial angiofibromas
Fibrous cephalic plaque (connective tissue nevus)
Shagreen patch (connective tissue nevus)
Adolescence:
Periungual fibromas (Koenen tumors)
Adulthood:
Gingival/intraoral fibromas
Systemic Features
Cardiac: myocardial rhabdomyomas
Endocrine: precocious puberty
Dental: enamel pits
Nervous: cortical tubers, seizures (leading cause of mortality), subependymal giant cell astrocytomas, subependymal nodules
Ocular: retinal hamartomas
Renal: cysts, bilateral angiomyolipomas
Respiratory lymphangioleiomyomatosis
CALMs, café-au-lait macules.
TSC is an AD hereditary disorder due to mutations in TSC1 (hamartin) and TSC2 (tuberin), which lead to activation of the PI3K signaling pathway.
Clinical features of TSC are summarized in Table 5.17.
The histopathology of TSC demonstrates hypomelanotic macules, angiofibromas, CALMs, and collagenomas.
Diagnostic criteria for TSC are summarized in Table 5.18. MEN syndromes (Table 5.19) have overlapping features with TSC.Related posts:
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