Squamous-cell carcinoma of the skin

Authors: Mikael Häggström; Authors of integrated Creative Commons article
Squamous-cell carcinoma (SCC) of the skin may present as suspected malignant skin excisions.

Fixation

Generally 10% neutral buffered formalin.

See also: General notes on fixation

Gross processing

Squamous cell carcinoma in situ.

SCC with scaling and ulceration.

If re-excision, see separate section at bottom.

Gross examination

Note:

• Color
• Well-defined or diffuse border
• Size
• Any elevation

Squamous cell carcinoma in situ (Bowen’s disease) often presents as an asymptomatic, erythematous, well-demarcated, scaly patch or plaque. It usually has a fairly irregular border. Lesions may become hyperkeratotic, crusted, fissured or ulcerated, and can occasionally be pigmented, especially when found in the genital region and the nails.

Invasive SCC typically has ill-marginated, erythematous, scaling, and rough papules or patches.

Tissue selection

Tissue selection from suspected malignant skin lesions, by lesion size:

<4 mm	4 - 8 mm	9 - 15 mm

In table above, each top image shows recommended lines for cutting out slices to be submitted for further processing. Bottom image shows which side of the slice that should be put to microtomy. Dashed lines here mean that either side could be used.

Further information: Gross processing of skin excisions

Microscopic evaluation

Evaluation consists of:

• Determining whether it is a SCC rather than a differential diagnosis.
• Distinguishing a SCC in situ from an invasive SCC
• Radicality, and if radical, determine the least distance to a margin.

Characteristics

Squamous cell carcinoma in situ, showing prominent dyskeratosis and aberrant mitoses at all levels of the epidermis, along with marked parakeratosis.

• Malignant keratinocytes demonstrating intense mitotic activity, pleomorphism, and greatly enlarged nuclei. They will also show a loss of maturity and polarity, giving the epidermis a disordered or “windblown” appearance.

In situ

In SCC in situ (Bowen’s disease) the epidermis will show:

• Atypia spanning the full thickness of the epidermis, being the main finding.
• Hyperkeratosis and parakeratosis
• Marked acanthosis with elongation and thickening of the rete ridges. These changes will overly keratinocytic cells which are often highly atypical and may in fact have a more unusual appearance than invasive SCC.
• Two types of multinucleated cells may be seen:

• Multinucleated giant cell
• Dyskeratotic cell engulfed in the cytoplasm of a keratinocyte.

• Occasionally, cells of the upper epidermis will undergo vacuolization, demonstrating an abundant and strongly eosinophilic cytoplasm.

There may be a mild to moderate lymphohistiocytic infiltrate detected in the upper dermis.

Atypia spanning the full thickness of the epidermis is enough in this case for the diagnosis of SCC in situ. There is also a lymphohistiocytic infiltrate.

Squamous cell-like skin proliferations: Differential diagnosis

Main differential diagnoses and their characteristics:

• 

  Invasive squamous-cell carcinoma of the skin: Atypical and pleomorphic keratinocytes, involving the dermis and the sub-cutis with a potential metastatic spread.

• 

  Squamous-cell carcinoma in situ (Bowen’s disease): Atypical keratinocytes at every layer of epidermis.

• 

  Actinic keratosis: Atypical keratinocytes that do not span the full thickness of the epidermis (or, in Bowenoid variant, are less disordered with less nuclear atypia and crowding).

• 

  Basal-cell carcinoma with squamous cell metaplasia: Basal-cell carcinoma is generally distinguishable by for example relatively less cytoplasm, palisading, cleft formations and absence of horn cyst formation. Yet, a high prevalence means a relatively high incidence of borderline cases, such as those with squamous cell metaplasia (H&e stain in left image). BerEP4 staining helps in such cases, staining only basal-cell carcinoma cells (right image).

• 

  Keratoacanthoma: Symmetrical and circumscribed proliferation of keratinocytes, with central horn plug, with epidermis that extends over the tumor. It can be regarded as a highly differentiated SCC.

• 

  Crush artifacts: Needles used to orient the skin sample may create crush artifacts (black arrow) mimicking cellular atypia with mainly hypereosinophilia and nuclear pleomorphism. Image also shows folding artifacts (white arrows).

• 

  Adnexal carcinomas: Squamous differentiation, but does not show connection with the epidermis and highlights adnexal features.

• 

  Adenosquamous carcinoma: Mixed glandular and squamous differentiation.

• 

  Verrucous squamous cell carcinoma: Exophytic squamous proliferation with marked papillomatosis and low atypia and the presence of koilocyte-like changes. Found in head and neck locations, as well as in the genitalia and sole of the foot.

• 

  Inverted follicular keratosis:: Sharply circumscribed endophytic verrucous proliferation with prominent squamous features.

• 

  Seborrheic keratosis: Acanthosis, absence of atypia, pseudo-horn cysts, in inflamed lesions, mitoses may be present.

• 

  Bowenoid papulosis: Atypical keratinocytes and mitoses. Histology similar to Bowen’s disease.

• 

  Metastasis: Personal medical history of the patient, nodular proliferation without connection to epidermis, immunohistochemical evaluation. Squamous-cell carcinoma metastasis from lungs to the skin is pictured.

In contrast to actinic keratosis, the basal epidermal layer in SCC in situ is frequently spared, and will show little to no visible atypia. Additionally, SCC in situ will almost always involve both the interfollicular and adjacent follicular epithelium and adnexal structures.

Clinical clues

• Biopsy from sun exposed area.
• Generally middle-aged or older individuals.

In situ versus invasive

In situ (Bowen's disease)

Intact basement membrane.

• 

  High magnification, demonstrating an intact basement membrane.

Invasive

Dermal infiltration

• 

  Superficially invasive squamous cell carcinoma (SCCSI). These lesions often do not show the marked pleomorphism and atypical nuclei of SCC in situ, but demonstrate early keratinocyte invasion of the dermis.

• 

  High magnification demonstrates the pleomorphism of the invading keratinocytes.

• 

  Invasive nests with characteristic large celled centers. Ulceration (at left) is common in invasive SCC.

This infiltrate can be somewhat difficult to detect in the early stages of invasion: however, additional indicators such as full thickness epidermal atypia and the involvement of hair follicles can be used to facilitate the diagnosis. Later stages of invasion are characterized by the formation of nests of atypical tumor cells in the dermis, often with a corresponding inflammatory infiltrate.

Radicality

Determine whether the distances between atypical cells are more or less than 1 mm from the deep and radial edges. If less than 1 mm, quantify the distance.

Degree of differentiation

Applicable to invasive SCC.

• 

  Well-differentiated (and yet invasive) SCC, showing prominent keratinization and may form “pearllike” structures where dermal nests of keratinocytes attempt to mature in a layered fashion. Well-differentiated SCC has slightly enlarged, hyperchromatic nuclei with abundant amounts of cytoplasm. Intercellular bridges will frequently be visible.

• 

  Moderately differentiated lesions of invasive SCC show much less organization and maturation with significantly less keratin formation.

• 

  Poorly differentiated, where attempts at keratinization are often no longer evident. This is a clear-cell squamous cell carcinoma. The dysplastic cells here infiltrate in cords through the dermis. Poorly differentiated SCC has greatly enlarged, pleomorphic nuclei demonstrating a high degree of atypia and frequent mitoses.

• 

  Poorly differentiated clear-cell squamous cell carcinoma. For this type of SCC, immunostains will likely be required to classify it unless other areas of the tumor show obvious squamous cell features such as seen here (arrow).

Perineural or vascular invasion

In SCC, at least a quick glance for any perineural or vascular invasion is warranted.

• 

  Perineural invasion: the arrow indicates a large peripheral nerve that has been surrounded by tumor cells.

• 

  Vascular invasion: the arrow indicates a small cluster of atypical squamous cells in a small vessel.

Vascular invasion most frequently involves a complete encircling of the nerve or vessel by tumor cells. An incomplete, crescent-like pattern of atypical cells is also commonly seen. Occasionally, tangential contact, permeation, and lamination can be observed. Invasion almost always occurs contiguous to the main body of the tumor; however, it has been known on occasion to affect more distant nerve and vascular sites. Usually, tumor cells arranged in solid or sheet-like patterns are less invasive, and will pass around the nerve or vessel. In contrast, individual tumor cells will generally penetrate and track along associated structures.

Optionally: Grading

Multiple variables can be combined to classify a SCC as low or high grade:

Low-Grade SCC	High-Grade SCC
Well to moderately differentiated: intercellular bridges and keratin pearls Tumor cells arranged in solid or sheet-like patterns Association with solar damage and precursor actinic keratosis Diameter less than 2 cm Depth less than 2 mm	Poorly differentiated: clear-cell, sarcomatoid, or single cell features Presence of infiltrating individual tumor cells Arising de novo or in site of prior injury (ulcer, burn scar, or osteomyleitis) Perineural and/or perivascular invasion Diameter greater than 2 cm Depth greater than 2 mm

Microscopy report

In this page, the following signs and text coloring are used for comprehensiveness:

• Minimal depth
• (Moderate depth)
• ((Comprehensive))

Components of the report:

• Diagnosis of squamous-cell carcinoma
• Whether it is in situ or invasive. If invasive:

• Degree of differentiation.
• (High or low grade.)
• ((Even absence of perineural or vascular invasion.))

• Radicality, mainly into either of the following:

• >1 mm (as per Radicality above): "Clear margins".
• <1 mm but not continuous with edge: "Close margins at __ mm at (location)." Numbers are generally given at an exactness of 0.1 mm.
• Continuous with margin: "Not radically excised at (location)."

Examples

Squamous cell carcinoma in situ:

((Skin excision with squamous epithelium with))(central parakeratosis. The epidermis is thickened and exhibits disturbed stratification. )All cell layers show atypical epithelial cells with polymorphic and partially hyperchromatic nuclei. The basement membrane is intact. Clear margins. ((There is elastosis and inflammatory cells in the dermis.))

Invasive squamous cell carcinoma:

((Skin excision with ))( with squamous epithelium, with central ulceration, surrounded by hyperkeratosis. )In this area in the dermis there are inflitrative nests of epithelioid cells with nuclear pleomorphism and <sparse / moderate / abundant> keratin formation. Atypical cells are seen ___ mm from the deep/radial resection edge. / Clear margins. ((No perineural or vascular invasion is seen. There are inflammatory infiltrates adjacent to atypical cells. General elastosis is noted in the dermis.))

See also: General notes on reporting

Re-excisions

Gross processing

Depending on radicality of previous excision:

• Previously radical (including thin margins): Submit at least one central section across the surgical scar.
• Previously non-radical:

• Visible lesion: Submit the entire scar.
• Lesion not visible: At least one additional radicality slice towards the tips, up to the entire specimen.