Approach Considerations
Given that basal cell carcinoma rarely metastasizes, laboratory and imaging studies are not commonly clinically indicated in patients presenting with localized lesions. Imaging studies may be necessary when involvement of deeper structures, such as bone, is clinically suspected. In such cases, CT scans or radiography can be used.
Skin Biopsy
A skin biopsy is often required to confirm the diagnosis and determine the histologic subtype of basal cell carcinoma (BCC). Most often, a shave biopsy is all that is required. Nevertheless, in the case of a pigmented lesion where there may be difficulty distinguishing between pigmented BCC and melanoma, an excisional or punch biopsy may be indicated; this is to ensure that the depth of the lesion can be determined if it proves to be a malignant melanoma.
In most cases, a superficial biopsy specimen that contains dermis is all that is required to confirm the diagnosis of BCC, although it is possible to miss the tumor. For example, an ulcerated BCC may reepithelialize with normal epidermis while tumor is still present at a deeper level. Part or all of the BCC may be sampled, but avoid going beyond the clinical margins if the biopsy is only for diagnostic purposes.
Punch biopsy is an easy method to obtain a thick specimen, but is rarely required. The most suspicious area of a lesion may be sampled, or multiple biopsy samples may be taken if the tumor is large or has a varied appearance in different areas. Avoid punch biopsy if curettage is planned for final treatment.
Occasionally, suspected tumors may require more than a single biopsy to make the diagnosis; therefore, with a high clinical index of suspicion, a second biopsy may be needed to obtain a pathological diagnosis of BCC.
Cytology
To accurately and definitively diagnose BCC of the eyelid, histological confirmation is required and is most commonly obtained through excisional (shave or punch) biopsy, which provides more information regarding the histological subtype of BCC. Cytology does provide a rapid alternative that may yield and even help confirm a diagnosis during the initial visit, however.
The accuracy of this technique has been reported to be good, but its sensitivity in diagnosing BCC of the eyelid is unknown. It is not considered to be sufficiently sensitive in planning surgical management.
A study by Barton et al showed that for patients who underwent cytology followed by excisional biopsy, cytology had a sensitivity of 92% in diagnosing BCC with a predictive accuracy of 75%. [62] These values were compared to a second group of patients who had incisional biopsy and histological examination followed by excision with histological confirmation. The second group showed a sensitivity of 100% in diagnosing BCC with a predictive accuracy of 96%.
Histologic Findings
Several histologic types of BCC exist. Distinctions are important because clinical detection of tumor margins is more difficult with certain histologic types. [63] Usually, BCCs are well differentiated and cells appear histologically similar to basal cells of the epidermis.
Tumor cells of nodular BCC, sometimes called basalioma cells, typically have large, hyperchromatic, oval nuclei and little cytoplasm. Cells appear uniform, and if present, mitotic figures are usually few. The nuclei resemble that of the basal cells of the epidermis, although they have a larger nuclear-to-cytoplasmic ratio and lack intercellular bridges. A mitotic figure is very rarely observed. Nodular tumor aggregates may be of varying sizes, but tumor cells tend to align more densely in a palisade pattern at the periphery of these nests (see the image below).
Nodular basal cell carcinoma. Nodular aggregates of basalioma cells are present in the dermis and exhibit peripheral palisading and retraction artifact. Melanin is also present within the tumor and in the surrounding stroma, as seen in pigmented basal cell carcinoma.
Cleft formation, known as retraction artifact, commonly occurs between BCC nests and stroma because of shrinkage of mucin during tissue fixation and staining. Some lobules may have areas of pseudoglandular change, and this is the predominant change in adenoid BCC. In other instances, large tumor lobules may degenerate centrally, forming pseudocystic spaces filled with mucinous debris. These changes are seen in the nodulocystic variant of BCC.
Early lesions usually have some connection to the overlying epidermis, but such contiguity may be difficult to appreciate in more advanced lesions. Increased mucin is often present in the surrounding dermal stroma.
A histopathologic examination of paraffin-embedded sections of BCC usually reveals solid cellular strands, collections of cells with dark-staining nuclei and scant cytoplasm.
The peripheral cell mass is in a palisade arrangement that resembles the basal layer of the epidermis, sometimes with pseudocystic aspects, and with a variable number of mitoses.
The connective tissue stroma surrounding the tumor islands is arranged in parallel bundles and often shows young fibroblasts immediately adjacent to the tumor. The specific histologic pattern of each type of BCC varies in terms of desmoplastic reaction of the morpheaform type and in the stromal islands separated by basal cells strands of the fibroepithelial type. Artificial retraction of the stroma from the tumor islands is frequently observed histologically. Additionally, the stroma is often mucinous. Cells from recurrent BCC often show squamous aspects.
Histologically, BCC is divided into 2 categories: undifferentiated and differentiated. When there is little or no differentiation, it is referred to as solid BCC and includes pigmented BCC, superficial BCC, sclerosing BCC, and infiltrative BCC (a histologic subtype).
Differentiated BCC often has slight differentiation toward cutaneous appendages, including hair (keratotic BCC), sebaceous glands (BCC with sebaceous differentiation), or tubular glands (adenoid BCC). Noduloulcerative (nodular) BCC is usually differentiated. See the images below.
Histologic pattern of a well-differentiated basal cell carcinoma (original magnification X140). Courtesy of Prof Pantaleo Bufo, University of Foggia, Italy.
When the presence of a dense inflammatory infiltrate obscures the histologic margins of BCC, immunohistochemical stains for cytokeratins can help to identify tumor cells. These stains can be used with fixed or frozen tissue. Such staining with frozen tissue can take as little as 19 minutes, making it practical for use with Mohs micrographic surgery or with standard excision with frozen section margin control. [64]
Nodular basal cell carcinoma
Nodular or noduloulcerative basal cell carcinoma, the most common type, generally consists of large, round or oval tumor islands within the dermis, often with an epidermal attachment. The solid (nodular) type accounts for approximately 70% of all cases. Artificial retraction of the tumor islands from the surrounding stroma is commonly seen. Ulcerations may be seen in large tumors.
Micronodular basal cell carcinoma
Another aggressive variant, micronodular BCC, appears as small, nodular aggregates of basaloid cells. See the image below.
Micronodular basal cell carcinoma often has an absence of retraction artifact. The characteristic histology is small size and uniformity of the tumor nodules. Courtesy of Shang I Brian Jiang, MD.
Retraction artifact tends to be less pronounced than in the nodular form of BCC, and subclinical involvement is often significant. Micronodular basal cell carcinoma is similar to the noduloulcerative type, although the tumor islands are small (often < 15 cells in diameter).
Pigmented basal cell carcinoma
In pigmented basal cell carcinoma (BCC), benign melanocytes in and around the tumor produce large amounts of melanin. These melanocytes contain many melanin granules in their cytoplasm and dendrites.
Adenoid basal cell carcinoma
The adenoid type consists of strands of basaloid cells in a reticulate pattern, frequently with prominent stromal mucin. It may occur with the solid type.
Morpheaform (sclerosing) basal cell carcinoma
The more aggressive morpheaform BCCs have growth patterns resulting in strands of cells rather than round nests, within a fibrous stroma. They constitute approximately 5% of BCCs. Morpheaform BCC arises as thin strands of tumor cells (often only 1 cell in thickness) that are embedded in a dense fibrous stroma. The morpheaform basal cell carcinomas exhibit islands of tumor extending into the tissue and may exhibit perineural invasion in 3% of patients. This finding helps classify these 2 histotypes as the most aggressive, with the highest rates of recurrence and positive margins after excision.
Infiltrative basal cell carcinoma
This type of BCC accounts for 10% of BCCs. Tumor cells have growth patterns resulting in strands of cells infiltrating between collagen bundles rather than round nests.
The strands of infiltrating BCC tend to be somewhat thicker than those seen in morpheaform BCC, and they have a spiky, irregular appearance (see the image below).
Infiltrative basal cell carcinoma. Tumor cells are arranged in narrow strands, and mucin-rich stroma is often present. Courtesy of Shang I Brian Jiang, MD.
Infiltrating BCC usually does not exhibit the scarlike stroma seen in morpheaform BCC. Peripheral palisading and retraction are less pronounced in morpheaform and infiltrating BCC than in less aggressive forms of the tumor, and subclinical involvement is often extensive.
Cystic basal cell carcinoma
Cystic basal cell carcinoma consists of large, round or oval tumor islands within the dermis with mucin present in the center of the island. This space is caused by central tumor cell degeneration.
Superficial basal cell carcinoma
Superficial BCC appears as buds of basaloid cells attached to the undersurface of the epidermis. Nests of various sizes are often seen in the upper dermis. The tumor cell aggregates typically show peripheral palisading.
The (multifocal) superficial type (see the image below) is characterized by numerous small nests of tumor cells usually attached to the undersurface of the epidermis by a broad base. Approximately 10-15% of all BCCs are of this type. This is the most common pattern seen in BCCs of the shoulder.
Histology of superficial basal cell carcinoma. Nests of basaloid cells are seen budding from the undersurface of the epidermis. Courtesy of Michael L Ramsey, MD.
Keratotic basal cell carcinoma
The keratotic type resembles the solid type and its nests of basaloid cells with peripheral palisading. The island centers display keratinization and squamous differentiation. See the image below.
Keratotic basal cell carcinoma. Rare type characterized by keratocysts. Courtesy of Shang I Brian Jiang, MD.
Infundibulocystic basal cell carcinoma
The infundibulocystic type is rare and is usually found on the face. It resembles the keratotic type. Nests are arranged in an anastomosing pattern and lack stroma. Many small, infundibular cyst-like structures with keratinous material are present. Melanin is sometimes present.
Metatypical basal cell carcinoma
Metatypical BCC is rare. In this type, nests and strands of cells mature into larger and paler cells, and peripheral palisading, if any, is less developed than in other types. Prominent stroma, prominent mitotic activity, and many apoptotic cells may be present. This form may be best diagnosed when one evaluates a BCC with features between those of a nodular BCC and squamous cell carcinoma. These tumors are often aggressive, with an increased tendency for lymphatic and perineural spread.
Basosquamous carcinoma
The basosquamous type is controversial. It has been defined as a basal cell carcinoma (BCC) with differentiation towards squamous cell carcinoma (SCC). It is made up of basaloid cells that are a larger, paler, and rounder than those of a solid BCC. It also consists of squamoid cells and intermediate cells. Some consider the diagnosis of this type most appropriate when one evaluates a tumor with contiguous areas of BCC and SCC. This type is considered to have metastatic potential and is considered an aggressive skin cancer (see the image below).
Basosquamous basal cell carcinoma. Foci of neoplastic cells with squamous differentiation are present. Courtesy of Shang I Brian Jiang, MD.
Fibroepithelioma of Pinkus
The fibroepithelioma type consists of thin, anastomosing strands of basaloid cells in a prominent stroma.
According to some studies, the so-called fibroepithelioma of Pinkus, considered to be a premalignant skin condition, must be considered as a fenestrated variant of basal cell carcinoma. [65, 66, 67]
Ultrasonography
The use of ultrasonography is controversial. High-frequency (20 MHz) and ultra-high-frequency (40-100 MHz) ultrasound systems have been used; their accuracy in delineating malignant lesions from benign lesions remains inadequate, however, with a success rate of approximately 20%. Furthermore, the claims of reliable tumor sizing and depth of invasion are promising but still passionately debated.
Laser Doppler
As an adjunct tool, laser Doppler may assist ophthalmologists in distinguishing between benign and malignant adnexal skin lesions and in establishing the tumor margin.
It is reported that cutaneous perfusion to the eyelids is statistically significantly higher than other regions of the body (eg, forearm). Furthermore, the mean perfusion in pretarsal skin has been shown to be 50% greater than that in preseptal skin. In histologically documented basal cell carcinoma of the eyelid, cutaneous perfusion was significantly greater. [68]
Staging
Basal cell carcinoma rarely metastasizes and is usually not staged, unless the cancer is very large and is suspected of spreading to other parts of the body. BCC staging may be similar to the staging of squamous cell carcinoma, which is according to the following scheme:
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Stage 0: Cancer involves only the epidermis and has not spread to the dermis
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Stage I: Cancer is not large (ie, < 2 cm) and has not spread to the lymph nodes or other organs
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Stage II: Cancer is large (ie, >2 cm) but has not spread to lymph nodes or other organs
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Stage III: Cancer has spread to tissues beneath the skin (eg, muscle, bone, cartilage), and/or to regional lymph nodes but not to other organs.
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Stage IV: Cancer can be any size and has spread to other organs
High-risk tumors
High-risk BCCs include the following:
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Recurrent or incompletely excised BCC
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Primary BCC with clinically indistinct borders
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Lesions in high-risk (the H, or mask) areas, mainly the embryonic fusion planes (eg, eyelids, nose, ear, nasolabial folds, upper lip, vermillion border, columella, periorbital region, temples, preauricular and postauricular areas, and scalp)
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Lesions that develop in cosmetically and functionally important areas (eg, face, genitals, anal and perianal regions, hands and feet, and the nail unit areas)
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Tumors with aggressive clinical behavior (ie, growing rapidly or >2 cm)
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Tumors with aggressive histologic subtype, including sclerosing (morpheaform), basosquamous (metatypical or keratinizing), perineural, periappendageal, or perivascular invasion, infiltrating, adenoidal, or multicentric
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Tumors that develop in sites with previous radiation therapy
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Tumors that develop in immunosuppressed patients
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A pink, scaly lesion on the skin. Superficial basal cell carcinoma (BCC) is often misdiagnosed as eczematous dermatitis or guttate psoriasis and is often difficult to distinguish clinically from Bowen disease (squamous cell carcinoma in situ). Features that suggest the diagnosis of superficial BCC are the absence of significant white, adherent scale and a history of the lesion remaining unchanged for several months or years. Treatment options for this tumor include electrodesiccation and curettage, surgical excision, cryosurgery, 5-fluorouracil, 5% imiquimod cream, and superficial radiotherapy. Electrodesiccation and curettage is the modality most commonly used, with a cure rate of approximately 95%.
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Basal cell carcinoma.
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A 68-year-old patient presenting with an advanced basal cell carcinoma (BCC) of the right periorbital region, frontal view. Courtesy of M Abraham Kuriakose, DDS, MD.
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Lateral view of face showing extent of tumor. Courtesy of M Abraham Kuriakose, DDS, MD.
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Basal cell carcinoma of the right lower lid.
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Biopsy-proven basal cell carcinoma of the upper lid margin. Note the loss of cilia (madarosis) in the area of the tumor.
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Medial canthal/lower lid basal cell. Note the pearly nodular surface with characteristic telangiectatic vessels. Proximity to the lacrimal system will impact its treatment and reconstruction.
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Nodular basal cell carcinoma.
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Nodular basal cell carcinoma appearing as a waxy, translucent papule with central depression and a few small erosions.
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Scale, erythema, and a threadlike raised border are present in this superficial basal cell carcinoma on the trunk.
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Large, superficial basal cell carcinoma.
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Basal cell carcinoma. Courtesy of Hon Pak, MD.
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Pigmented basal cell carcinoma.
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Pigmented basal cell carcinoma.
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Pigmented basal cell carcinoma has features of nodular basal cell carcinoma with the addition of dark pigmentation from melanin deposition. The pigmentation often has the appearance of dark droplets in the lesion, as shown here.
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This infiltrating basal cell cancer has ill-defined borders and telangiectases.
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This translucent pink papule has telangiectases and a crusted erosion, characteristic of nodular basal cell carcinoma.
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Large, scarlike morpheaform basal cell cancer.
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Nodular basal cell carcinoma. Nodular aggregates of basalioma cells are present in the dermis and exhibit peripheral palisading and retraction artifact. Melanin is also present within the tumor and in the surrounding stroma, as seen in pigmented basal cell carcinoma.
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Histologic pattern of a well-differentiated basal cell carcinoma (original magnification X140). Courtesy of Prof Pantaleo Bufo, University of Foggia, Italy.
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Histologic pattern of a well-differentiated basal cell carcinoma (original magnification X250). Courtesy of Prof Pantaleo Bufo, University of Foggia, Italy.
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Micronodular basal cell carcinoma often has an absence of retraction artifact. The characteristic histology is small size and uniformity of the tumor nodules. Courtesy of Shang I Brian Jiang, MD.
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Infiltrative basal cell carcinoma. Tumor cells are arranged in narrow strands, and mucin-rich stroma is often present. Courtesy of Shang I Brian Jiang, MD.
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Keratotic basal cell carcinoma. Rare type characterized by keratocysts. Courtesy of Shang I Brian Jiang, MD.
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Basosquamous basal cell carcinoma. Foci of neoplastic cells with squamous differentiation are present. Courtesy of Shang I Brian Jiang, MD.
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Histology of superficial basal cell carcinoma. Nests of basaloid cells are seen budding from the undersurface of the epidermis. Courtesy of Michael L Ramsey, MD.
