# Non-Melanoma Skin Cancer and Keratinocytic Neoplasms

## Overview

Non-melanoma skin cancers (NMSCs) are the most common malignancies worldwide. Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) account for the vast majority of cases. Accurate subtype classification, grading, and margin assessment directly impact clinical management and recurrence risk.

## Basal Cell Carcinoma (BCC)

### General Features

BCC is the most common human malignancy, with ultraviolet radiation serving as the primary risk factor. Despite being locally destructive, metastasis is exceedingly rare (less than 0.1 percent). The molecular basis involves activation of the Hedgehog signaling pathway through either PTCH1 loss-of-function or SMO gain-of-function mutations. Gorlin syndrome (nevoid BCC syndrome) results from a germline PTCH1 mutation and manifests as multiple BCCs at a young age, odontogenic keratocysts, and skeletal anomalies.

### Histologic Features Common to All Subtypes

All BCC subtypes share several characteristic features: basaloid cells with large oval nuclei, scant cytoplasm, and high nuclear-to-cytoplasmic ratio; peripheral palisading of nuclei at the tumor border; retraction artifact (clefting) between tumor nests and the surrounding stroma; a myxoid or mucinous stroma; and frequent mitoses and apoptotic bodies.

### Subtypes and Their Significance

#### Nodular BCC

Nodular BCC is the most common subtype, accounting for 60 to 70 percent of cases. It consists of well-circumscribed nodules and nests of basaloid cells in the dermis, sometimes with central necrosis producing cystic spaces. It carries a low recurrence risk.

#### Superficial BCC

Superficial BCC shows buds of basaloid cells extending from the epidermis into the papillary dermis in a multifocal pattern. It must be distinguished from tangentially sectioned nodular BCC. It has a predilection for the trunk and may be treated with topical therapy such as imiquimod or 5-fluorouracil.

#### Infiltrative/Morpheaform BCC

This aggressive subtype consists of thin cords and strands of basaloid cells embedded in a dense sclerotic or desmoplastic stroma. The margins are poorly defined, and the characteristic peripheral palisading and retraction are reduced. It carries a higher recurrence risk and often requires Mohs surgery. This "aggressive growth" pattern should always be reported separately.

#### Micronodular BCC

Micronodular BCC shows multiple small, round nests scattered through the dermis, typically extending beyond the clinically apparent margins. It carries a higher recurrence risk than nodular BCC.

#### Basosquamous Carcinoma (Metatypical BCC)

This variant shows features of both BCC and SCC with intermediate keratinization. It has higher metastatic potential than conventional BCC. It remains a controversial entity, with some experts considering it a distinct tumor rather than a BCC variant.

### BCC Reporting Elements

Essential reporting elements include the subtype (growth pattern), with all patterns reported when mixed; margin status (peripheral and deep); perineural invasion (rare but important); and tumor depth and dimension.

### Treatment Considerations

Low-risk tumors are managed with standard excision using 3 to 4 mm margins or curettage and electrodesiccation. High-risk tumors (infiltrative/morpheaform, micronodular, recurrent, those with perineural invasion, or those at critical anatomic sites) warrant Mohs micrographic surgery. Hedgehog pathway inhibitors (vismodegib, sonidegib) are reserved for advanced, metastatic, or inoperable BCC.

## Squamous Cell Carcinoma (SCC)

### Precursor Lesions

#### Actinic Keratosis (AK)

Actinic keratosis is the most common precursor to SCC, arising on sun-damaged skin. Histologically, it shows atypical keratinocytes in the lower epidermis with parakeratosis, often producing the "flag sign" (alternating orthokeratosis and parakeratosis). The basal layer atypia does not extend to full thickness. The risk of progression to SCC is approximately 1 to 5 percent per individual lesion over 10 years. Budding (bulbous extensions into the dermis) represents early or incipient SCC.

#### Squamous Cell Carcinoma In Situ (Bowen Disease)

SCC in situ shows full-thickness epidermal atypia with a preserved basement membrane. The cells have a "windblown" appearance with disorganized atypical keratinocytes at all levels. Atypical mitoses and individual cell keratinization (dyskeratosis) are present. Bowenoid papulosis is SCC in situ of genital skin, which is HPV-related and occurs in younger patients.

### Invasive SCC

#### Histologic Features

Invasive SCC consists of nests and sheets of atypical squamous cells invading the dermis through a disrupted basement membrane. Features include keratinization (keratin pearl formation, intercellular bridges from desmosomes, and eosinophilic cytoplasm) and a desmoplastic stromal reaction.

#### Grading

Well-differentiated SCC shows abundant keratinization, keratin pearls, intercellular bridges, and mild atypia. Moderately differentiated SCC has less keratinization with more nuclear atypia and increased mitoses. Poorly differentiated SCC shows minimal keratinization and marked atypia, making it difficult to recognize as squamous without immunohistochemistry (p40-positive, CK5/6-positive).

#### High-Risk Features (AJCC/BWH Criteria)

Features that place an SCC at high risk for recurrence or metastasis include tumor diameter of 2 cm or greater, depth of invasion of 6 mm or greater or extension beyond subcutaneous fat, perineural invasion (especially of named nerves 0.1 mm or larger in caliber), poor differentiation, high-risk locations (ear, lip, temple, or non-sun-exposed sites such as vulva and perineum), immunosuppression (organ transplant recipients face 65 to 250 times increased SCC risk), and a desmoplastic growth pattern.

#### SCC Variants

Spindle cell (sarcomatoid) SCC consists of spindled cells mimicking sarcoma and may lose conventional cytokeratin expression, making p40 and p63 the most reliable markers. Adenosquamous carcinoma shows mixed squamous and glandular differentiation and behaves aggressively. Verrucous carcinoma is an exophytic, well-differentiated tumor with pushing margins that is locally destructive but does not metastasize. Its subtypes vary by location: oral florid papillomatosis, giant condyloma (Buschke-Lowenstein tumor), and epithelioma cuniculatum (foot).

### Keratoacanthoma (KA) vs. Well-Differentiated SCC

#### Keratoacanthoma Features

Keratoacanthomas grow rapidly over weeks, forming a crateriform architecture with a central keratin plug. They are symmetric and well-circumscribed with sharp demarcation at the base. The keratinocytes have a glassy eosinophilic quality, and lip-like epidermal buttresses overhang the crater. Neutrophilic microabscesses within tumor lobules are characteristic. Spontaneous regression occurs over months.

#### The Controversy

Whether keratoacanthoma represents a distinct self-regressing entity or a variant of well-differentiated SCC remains controversial. Current practice often leads to a diagnosis of "well-differentiated SCC, keratoacanthoma-type" or "squamous proliferation with keratoacanthoma-like features." Management typically involves excision regardless of the terminology used.

## Merkel Cell Carcinoma (MCC)

### General Features

Merkel cell carcinoma is a rare, aggressive neuroendocrine carcinoma of the skin. Two etiologic pathways exist: Merkel cell polyomavirus (MCPyV)-positive (approximately 80 percent) and UV-induced (MCPyV-negative). It typically affects elderly patients on sun-exposed skin (head and neck) and immunosuppressed individuals.

### Histology

MCC consists of sheets, trabeculae, or nests of uniform small blue cells in the dermis. The nuclei are round with "salt and pepper" chromatin, the cytoplasm is scant, and mitoses and apoptosis are frequent. The "small cell" morphology closely resembles small cell carcinoma of the lung.

### Immunophenotype

CK20 positivity in a paranuclear dot-like pattern (perinuclear cap) is the characteristic and near-defining marker. Neuroendocrine markers (synaptophysin, chromogranin) are positive. CK7 is negative, which helps distinguish MCC from metastatic small cell lung carcinoma (which is CK7-positive, CK20-negative). TTF-1 is negative in MCC but positive in pulmonary small cell carcinoma. CM2B4, which detects MCPyV large T antigen, is positive in virus-positive cases.

### Differential Diagnosis: MCC vs. Metastatic Small Cell Carcinoma

| Feature | MCC | Small Cell Lung CA |
|---------|-----|----|
| CK20 | + (dot) | - |
| CK7 | - | + |
| TTF-1 | - | + |
| MCPyV | + (80%) | - |
| Clinical | Skin primary | Lung mass |

## Margin Assessment

### Standard Excision

Standard excision uses sections cut perpendicular to the margin (the "bread-loaf" technique). This samples only a fraction of the total margin, resulting in a potential false-negative rate. It is appropriate for low-risk tumors.

### Mohs Micrographic Surgery

Mohs surgery provides complete circumferential peripheral and deep margin assessment (CCPDMA) through frozen sections examining 100 percent of the surgical margin. It achieves the highest cure rates (99 percent for BCC, 97 percent for SCC) and is indicated for high-risk subtypes, recurrent tumors, and cosmetically sensitive sites (nose, eyelids, ears, lips).

<image>A medical illustration showing the histologic subtypes of basal cell carcinoma. Panel A (Nodular BCC): Well-circumscribed nests of basaloid cells with peripheral nuclear palisading, retraction artifact (clefting) between tumor and stroma, and central necrosis. Panel B (Superficial BCC): Multifocal buds of basaloid cells extending from the epidermis into the papillary dermis with palisading and retraction. Panel C (Infiltrative/Morpheaform BCC): Thin cords and strands of basaloid cells embedded in dense sclerotic stroma, with poorly defined margins and reduced palisading. Panel D (Micronodular BCC): Numerous small rounded nests of basaloid cells scattered diffusely through the dermis, extending beyond the main tumor mass.</image>

<image>A medical illustration comparing keratoacanthoma and invasive squamous cell carcinoma. Left panel (Keratoacanthoma): Symmetric crateriform architecture at low power with central keratin-filled crater, lip-like epidermal buttresses overhanging the crater rim, well-circumscribed base with sharp demarcation, and glassy eosinophilic keratinocytes at high power with neutrophilic microabscesses. Right panel (Invasive SCC): Asymmetric infiltrative architecture with irregular deep margin, keratin pearl formation, desmoplastic stromal response, and cytologic atypia with atypical mitoses at high power. An inset shows perineural invasion with tumor cells surrounding a dermal nerve.</image>

<image>A medical illustration demonstrating Merkel cell carcinoma. Panel A: Low-power view showing sheets of small blue cells filling the dermis with a Grenz zone (sparing of papillary dermis). Panel B: High-power view showing uniform small round cells with finely granular (salt-and-pepper) chromatin, scant cytoplasm, nuclear molding, and numerous mitotic figures. Panel C: CK20 IHC showing characteristic paranuclear dot-like (perinuclear cap) staining pattern. Panel D: Synaptophysin IHC showing diffuse cytoplasmic positivity. Panel E: TTF-1 IHC showing negativity (contrasted with a small inset of metastatic small cell lung carcinoma showing TTF-1 positivity).</image>

## Clinical Pearls

Infiltrative/morpheaform and micronodular BCC subtypes extend beyond clinically visible margins, making Mohs surgery or wide excision with complete margin assessment the recommended approach. In immunosuppressed patients (especially organ transplant recipients), SCC is far more common than BCC (reversing the ratio seen in the general population) and behaves more aggressively with higher metastatic rates.

Perineural invasion in SCC is an independent high-risk feature that should be specifically reported, including nerve caliber when measurable, as it may indicate the need for adjuvant radiation. CK20 paranuclear dot staining is the single most useful immunohistochemical marker for distinguishing Merkel cell carcinoma from metastatic small cell carcinoma of the lung (which is CK20-negative/TTF-1-positive).

Verrucous carcinoma has a pushing (non-infiltrative) deep margin and does not metastasize; it should not be treated with radiation, which may induce anaplastic transformation. When reporting BCC, all growth patterns present should be listed (for example, "basal cell carcinoma, nodular and infiltrative subtypes") because the most aggressive component determines management. Actinic keratosis with "budding" or bulbous extension into the dermis represents early or incipient invasion and should be reported to alert the clinician.

## References
- Elder DE, et al. *WHO Classification of Skin Tumours*. 4th ed. IARC; 2018.
- Schmults CD, et al. Factors predictive of recurrence and death from cutaneous squamous cell carcinoma. *JAMA Dermatol*. 2013;149(5):541-547.
- Bichakjian CK, et al. Guidelines of care for the management of basal cell carcinoma. *J Am Acad Dermatol*. 2018;78(3):540-559.
- Harms PW, et al. The biology and treatment of Merkel cell carcinoma. *Cancer Treat Rev*. 2018;64:15-26.
- Amin MB, et al. *AJCC Cancer Staging Manual*. 8th ed. Springer; 2017.