Malignant tumors of the epidermis

• Crowding, disorder, and atypia of epidermal keratinocytes

• Arises from the basal layer

• Solar elastosis typically present

Atypical cells commonly surround the follicular infundibulum. In two-dimensional sections, they appear to form a shoulder zone peripheral to the benign follicular epithelium. The overlying stratum corneum may be normal or may have features of a “malignant horn.” A malignant horn is a compact eosinophilic stratum corneum with hyperchromatic brick-like parakeratosis. The brightly eosinophilic zones alternate from left to right with pale basophilic lamellar keratin originating from adnexal structures (flag sign). Broad-based buds of atypical keratinocytes are commonly seen extending downward from the epidermis. The budding can become complex, and separation from superficially invasive squamous cell carcinoma may sometimes be difficult.

Fig 3-1 Actinic keratosis

Bowen’s disease

• Full-thickness atypia with loss of normal maturation (wind-blown pattern)

• Malignant horn typically present

• Atypical cells may occur in an intraepidermal buckshot or nested pattern

• Full-thickness atypia commonly involves follicles

Bowen’s disease is a form of squamous cell carcinoma in situ. The malignant cells probably originate in the follicular epithelium. As the malignant cells migrate into the epidermis, they create a buckshot or nested pattern. With time, they involve the full-thickness of the epidermis. This is the stage most commonly represented in biopsy specimens. It resembles bowenoid actinic keratosis, except that the cells tend to be more anaplastic with a higher nuclear-to-cytoplasm ratio. Areas with a nested or buckshot pattern may persist. Clear cell change or cells with ample glassy eosinophilic cytoplasm may sometimes be present instead of anaplastic cells. Bowen’s disease tends to involve the full-thickness of at least some follicles. Some examples show full-thickness involvement of multiple follicles with relative sparing of the overlying epidermis.

3. Intraepidermal porocarcinoma

1. Paget’s disease

2. Melanoma

4. Sebaceous carcinoma

The malignant keratinocytes of Bowen’s disease can keratinize and become part of the stratum corneum. In contrast, the malignant cells of Paget’s disease or melanoma often “spit out” into the stratum corneum intact. Bowen’s disease contains glycogen and is periodic acid-Schiff (PAS) positive and diastase sensitive. In contrast, Paget’s disease contains sialomucin and is PAS positive, diastase resistant. Bowen’s disease is negative for carcinoembryonic antigen (CEA) whereas Paget’s stains for CEA. Ducts and sebaceous differentiation distinguish porocarcinoma and sebaceous carcinoma.

Fig 3-6 Bowen’s disease

Fig 3-7 Bowen’s disease: buckshot scatter of atypical cells

Fig 3-8 Bowen’s disease: clonal nesting of atypical cells

Fig 3-9 Clear cell change in Bowen’s disease

Squamous cell carcinoma

• Atypical keratinocytes invading the dermis

• Acantholysis may be present

• Desmoplasia may be present

Well-differentiated invasive squamous cell carcinoma closely resembles the surface epidermis in staining characteristics, and keratinization is present. Pseudoepitheliomatous hyperplasia is often noted at the periphery of the tumor, and overlying changes of prurigo nodularis may be present in lesions that have been picked. An adequate biopsy is essential to avoid misdiagnosis.

Nodular lymphoid aggregates are an important clue to the presence of desmoplastic squamous carcinoma. Immunostaining can be used to confirm the presence of atypical squamous cells within the stroma.

Moderately differentiated tumors have a higher nuclear/cytoplastic ratio, but still keratinize. Poorly differentiated tumors are spindled or anaplastic. Keratin immunostaining is typically necessary to confirm the diagnosis of a poorly differentiated tumor.

Fig 3-10 (a,b) Well-differentiated invasive squamous cell carcinoma. (c) Acantholytic squamous cell carcinoma. (d,e) Desmoplastic squamous cell carcinoma (H&E and keratin 907 immunostain)

Verrucous carcinoma

• Well-differentiated glassy squamous epithelium

• Rounded border

Whereas most invasive squamous cell carcinomas have a jagged outline, verrucous carcinomas are composed of well-differentiated glassy eosinophilic keratinocytes and have a blunt, rounded outline. They slowly push into the underlying tissue in a bulldozing fashion.

Fig 3-11 Verrucous carcinoma

Spindled squamous cell carcinoma

• Atypical spindle cells abutting the epidermis

• Squamous cell carcinoma (keratin positive)

Spindled squamous cell carcinoma can closely resemble other spindle cell neoplasms. The microscopic differential diagnosis for an atypical spindle cell tumor SLAMmed up against the epidermis includes:

• Leiomyosarcoma (smooth muscle actin and desmin positive)

• Atypical fibroxanthoma (diagnosis of exclusion)

• Melanoma (S100 positive)

Fig 3-12 Spindled squamous cell carcinoma

Keratoacanthoma

Keratoacanthomas grow rapidly, then involute. Unfortunately, they can sometimes be difficult to distinguish from well-differentiated invasive squamous cell carcinomas that will never involute. Perineural extension may be seen in both. Explosive growth after a biopsy is consistent with a diagnosis of keratoacanthoma. In contrast, the presence of acantholysis indicates that the lesion will behave like squamous cell carcinoma. Neutrophilic microabscesses, eosinophils, and elastic trapping are common in keratoacanthoma, but rare in squamous cell carcinoma.

Pseudoepitheliomatous hyperplasia and hypergranulosis in follicles occur in the central portion of early keratoacanthomas but only at the periphery of squamous cell carcinomas. The defining feature of a keratoacanthoma is its ability to undergo terminal differentiation, a process whereby the tumor keratinizes itself to death.

Table 3-1

Characteristics of keratoacanthoma versus squamous cell carcinoma

Characteristic	Keratoacanthoma	Squamous cell carcinoma
Pseudoepitheliomatous hyperplasia and hypergranulosis	At center of lesion	At periphery of lesion
Cell type	Large light pink glassy cells	Often large, light pink and glassy
Dermal infiltrate	Eosinophils common	Plasma cells common
Gland involvement	Pushes eccrine glands down	Invades eccrine glands
Traps elastic tissue	Commonly	Rarely
Acantholysis	No	Often
Perineural invasion	Yes	Yes
Neutrophilic microabscesses	Common	Rarely
Growth	Explosive	Slow
Terminal differentiation	Yes	No

Fig 3-13 Keratoacanthoma

Regressing keratoacanthoma

• Crater-like outline, often with scalloped outline

• Crater filled with keratin

• Proliferative epithelium has involuted to a thin wall resembling the lining of an epidermoid cyst

• Scar peripheral to regressed epithelium

The most striking feature of a regressing keratoacanthoma is the massive keratin within the crater, out of proportion to the thin epithelium that lines the scalloped crater.

Basal cell carcinoma (BCC)

• Blue islands

• High nuclear/cytoplasmic ratio

• Retraction artifact

• Fibromyxoid stroma

Superficial multifocal BCC

• Distinctive fibromyxoid stroma displaces solar elastosis downward

• Multifocal blue buds

• Retraction artifact common

Fig 3-14 Regressing keratoacanthoma

Fig 3-15 Superficial multifocal basal cell carcinoma

Superficial multifocal BCC grows in a pattern resembling garlands draped from the epidermis. In two-dimensional sections, this gives the appearance of multifocal blue buds. Because the buds are spaced far apart, margin evaluation is based largely on the surrounding tumor stroma. The tumor stroma displaces the reticular dermis and solar elastosis downward.

Nodular BCC

• Nodular blue islands

• Distinctive fibromyxoid stroma

• Retraction artifact

Fig 3-16 Nodular basal cell carcinoma

Micronodular BCC

• Small blue islands

• Retraction artifact focally

• Distinctive fibromyxoid stroma surrounds individual islands, but normal dermis is present between islands

Fig 3-17 Micronodular basal cell carcinoma

Micronodular BCC is characterized by aggressive worm-like growth into the dermis. In cross-section, the appearance is micronodular. Because of the thick dermal collagen bundles between tumor islands, the tumors are poorly defined clinically, and curettage has a high failure rate.

It should be noted that many ordinary BCCs demonstrate small finger-like projections that appear as small round balls in cross-section. Only tumor stroma separates the islands, with no thick collagen bundles in between. These tumors do not qualify as micronodular BCC.

Morpheaform BCC

• Thin infiltrating strands of basaloid cells, usually only two cells thick

• Sclerotic stroma

• Tadpole-like islands with small horn cysts may be present focally

Morpheaform BCC presents clinically as scar-like lesions that gradually expand. Perineural extension is common. It is usually deeply infiltrative by the time the diagnosis is made. The pink sclerotic stroma contains little to no mucin, and at first glance may resemble a scar. However, the architecture is not that of a scar. In scars, the collagen has an east/west orientation while blood vessels have a north/south orientation. This is unlike the haphazard structure of the tumor stroma. Occasionally, a superficial biopsy will demonstrate tadpole-like islands with small horn cysts, creating a “paisley-tie” appearance.

Fig 3-18 Morpheaform basal cell carcinoma

1. Morpheaform BCC (older patient with a scar-like lesion)

2. Microcystic adnexal carcinoma (firm plaque on the upper lip, medial cheek, or chin)

3. Desmoplastic trichoepithelioma (doughnut-like firm lesion with central dell on the cheek of a young female)

4. Syringoma (small papules on the lower lids or widely eruptive papules)

5. Eruptive syringomas (chest and back or penis, often skin type VI)

Infiltrative BCC

• Fibroblast-rich stroma with little mucin

• Spiky growth pattern

• Areas of squamous differentiation common

• Perineural extension common

Fig 3-19 Infiltrative basal cell carcinoma

Fig 3-20 Infundibulocystic basal cell carcinoma

At first glance, the fibroblast-rich stroma of an infiltrative BCC can resemble the stroma of a trichoepithelioma. Glance again. Trichoepitheliomas never have spiky islands. If you remember that spiky things are likely to hurt you, it may help you to remember that this feature matches with an aggressive form of BCC. Papillary mesenchymal bodies are absent in infiltrative BCC.

Infundibulocystic BCC

• Pink strands, blue buds

• Horn cysts

• Fibromyxoid stroma

Infundibulocystic BCC differentiates towards the follicular infundibulum. It is characterized by pink strands of squamous epithelium, blue basaloid buds at the tips of the strands, and horn cysts. It closely resembles basaloid follicular hamartoma. The two entities are best distinguished clinically.

Fibroepithelioma of Pinkus

• Pink strands, blue buds

• Eccrine ducts often visible within strands

• Ample fibromyxoid stroma

Fibroepithelioma of Pinkus is composed of anastomosing pink epithelial strands embedded in a fibromyxoid stroma. Ducts are often visible within the strands. Blue basaloid buds are present at the tips and periphery of strands.

Adenoid BCC

• Blue islands with adenoid pattern (clear spaces in middle of islands)

Fig 3-21 Fibroepithelioma of Pinkus

• Fibromyxoid stroma

• Retraction artifact

Fig 3-22 Adenoid basal cell carcinoma

Paget’s disease

Paget’s disease of the breast represents intraepidermal extension of underlying intraductal carcinoma. Extramammary Paget’s disease may represent an extension of an underlying adenocarcinoma, but more commonly arises de novo, probably from pluripotent cells or mammary-like glands along milk lines. Sialomucin stains PAS+, diastase resistant, and with Alcian blue and toluidine blue at high (but not low) pH.

1. Melanoma (S100+, HMB-45+, never crushes basal layer, cells can spit into stratum corneum)

2. Bowen’s disease (keratin+, CEA−, cells rarely spit into stratum corneum intact)

3. Intraepidermal porocarcinoma (related to acrosyringeal keratinocytes, demonstrates focal duct differentiation, may have adjacent benign hidroacanthoma simplex)

Fig 3-23 Extramammary Paget’s disease

Lymphoepithelioma-like carcinoma