V.1 Pigmented Basal Cell Carcinoma

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V.1.1 Definition

While the majority of basal cell carcinomas are morphologically and histologically devoid of melanin pigmentation, a proportion are pig- mented. The best estimate of the incidence of pigmented basal cell carcinomas as a percentage of all basal cell carcinomas in a predominately white skin population is 6.7% [1]; however, it is clear that there is a strong racial predilection, with the majority of basal cell carcinomas in Asian skin being pigmented (with series show- ing 55% in Koreans [2] and 75% in Japan [3]), and Hispanics having twice the frequency of non-Hispanics [4].

V.1.2 Clinical Features

Clinically, pigmented basal cell carcinoma shares the features of the corresponding histo- logical subtype of its non-pigmented variant. In a series in the United States, pigmented basal

Pigmented Basal Cell Carcinoma

Scott W. Menzies V.1

Contents

V.1.1 Definition . . . .279

V.1.2 Clinical Features . . . .279

V.1.3 Dermoscopic Criteria . . . .280

V.1.4 Relevant Clinical Differential Diagnosis . . . .284

V.1.5 Histopathology . . . .284

IV.1.6 Management . . . .284

References . . . .285

cell carcinomas were more commonly found in lesions with a nodular component compared with superficial lesions [1]. The pigment tends to be seen as well-defined islands of blue, gray, or black, on a background of amelanotic “pearly”

tumor (Figs. V.1.1, V.1.2). In white-skin races the entire lesion is rarely entirely pigmented.

Telangiectasia and ulceration are commonly found, with a history of bleeding a frequent pre- sentation. Probably because of better clinical demarcation, pigmented basal cell carcinoma tends to be completely excised more frequently than its non-pigmented variant [1].

Fig. V.1.1. Pigmented basal cell carcinoma (clinical view). This lesion shows the characteristic features of islands of discrete blue-gray pigment on a background of amelanotic “pearly” tumor. There is also a small area of ulceration present

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V.1 V.1.3 Dermoscopic Criteria

The dermoscopic features of pigmented basal cell carcinoma have been studied in a very large series in a predominantly white skin population (n=142) [5]. In that study, the dermoscopic fea- tures were compared with an equal sample size of invasive melanoma and benign pigmented le- sions (Table V.1.1). Two-thirds of lesions had melanin pigmentation occupying less than half of the lesion, with only 7% of lesions having pig- mentation greater than 75% of the tumor sur- face. This pattern of large areas of amelanotic tumor was significantly different compared with the more homogeneous pigmentation pat- tern seen in melanoma and benign pigmented skin lesions. Dark-brown pigmentation was also significantly less commonly found in pigmented basal cell carcinoma. This is consistent with the lack of suprabasal epidermal melanin found in these lesions. As expected, a pigment network is

Fig. V.1.2. Pigmented basal cell carcinomas (clinical view). Note the extensive areas of ulceration. In contrast to melanoma, basal cell carcinomas tends to ulcerate early in its natural history

Table V.1.1. Dermoscopy features for the diagnosis of pigmented basal cell carcinomas. (From [5])

Feature Sensitivity

(%)

^a

Specificity (%) with

melanoma

^b

(p-value)

^d

Specificity (%) with benign PSLs

^c

(p-value)

^d

Ulceration^e 27 87 (0.035) 97 (<0.0005)

Colors present

Blue 72 25 (n.s.) 69 (<0.0005)

Black 14 68 (0.01) 93 (n.s.)

Gray 49 52 (n.s.) 55 (n.s.)

Tan 76 5.6 (0.002) 15 (n.s.)

Dark brown 58 11 (<0.0005) 15 (<0.0005)

Red 83 20 (n.s.) 59 (<0.0005)

Solitary color 1.4 100 (n.s.) 97 (n.s.)

Multiple (five to six) colors 11 65 (0.001) 94 (n.s.)

Pigmented area (%)

0−25 41 94 (<0.0005) 97 (<0.0005)

25−50 25 99 (<0.0005) 96 (<0.0005)

50−75 23 80 (n.s.) 80 (n.s.)

75−100 7.0 38 (<0.0005) 27 (<0.0005)

Milia-like cysts 10 96 (n.s.) 92 (n.s.)

Asymmetry of pattern 100 0 (n.s.) 13 (0.003)

Large gray/blue ovoid nests^e 55 97 (<0.0005) 99 (<0.0005) Multiple gray/blue globules^e 27 97 (<0.0005) 97 (<0.0005)

Target-like areas 7.0 99 (n.s.) 99 (n.s.)

Brown globules 51 13 (<0.0005) 44 (n.s.)

Gray globules 21 87 (n.s.) 79 (n.s.)

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Feature Sensitivity

(%)

^a

Specificity (%) with

melanoma

^b

(p-value)

^d

Specificity (%) with benign PSLs

^c

(p-value)

^d

Blue globules 49 79 (<0.0005) 83 (<0.0005)

Black globules 4.2 72 (<0.0005) 99 (n.s.)

Maple leaf-like areas^e 17 100 (<0.0005) 100(<0.0005)

Spoke-wheel areas^e 10 100 (0.007) 100 (0.007)

Pigment network^e 2.8 41 (<0.0005) 45 (<0.0005)

Depigmentation 93 13 (n.s.) 48 (<0.0005)

Irregular depigmentation 69 20 (n.s.) 63 (<0.0005)

Scar-like depigmentation 5.6 59 (<0.0005) 93 (n.s.)

Telangiectasia 73 35 (n.s.) 65 (<0.0005)

Central 68 54 (0.011) 72 (<0.0005)

Peripheral 58 63 (0.012) 76 (<0.0005)

Arborizing (tree-like)^e 52 77 (<0.0005) 92 (<0.0005)

Pin-point 30 49 (0.01) 75 (n.s.)

Hairpin 8.5 89 (n.s.) 94 (n.s.)

Large diameter 21 87 (0.022) 94 (0.007)

Kinking 66 65 (<0.0005) 85 (<0.0005)

Red-blue lacunes 4.2 100 (n.s.) 100 (n.s.)

Blue-white veil 15 49 (<0.0005) 94 (n.s.)

Pseudopods 1.4 87 (0.009) 97 (n.s.)

Radial streaming 2.8 76 (<0.0005) 94 (n.s.)

Multiple brown dots 4.2 77 (0.001) 99 (n.s.)

Multiple blue-gray dots 24 61 (0.047) 79 (n.s.)

Broadened pigment network 0 65 (<0.0005) 80 (<0.0005)

Peripheral black dots/globules 1.4 92 (n.s.) 100 (n.s.)

Graduated edge 46 83 (<0.0005) 59 (n.s.)

Lesions in a training set of 71 pigmented basal cell carcinomass, 71 invasive melanomas, and 71 benign pigmented lesions were scored for 45 surface microscopy features

a Sensitivity of the feature for diagnosis of pigmented basal cell carcinomas; equal to the number of scored positive basal cell carcinomas for that feature divided by the total number of basal cell carcinomas s (expressed as a percentage)

b Specificity of the feature for diagnosis of pigmented basal cell carcinomas using the invasive melanoma set;

equal to the number of melanomas lacking that feature divided by the total number of melanomas (expressedas a percentage)

c Specificity of the feature for diagnosis of pigmented basal cell carcinomas using the benign PSL set; equal to the number of benign PSLs lacking that feature divided by the total number of PSLs (expressed as a percent-

d age)Statistical significance of each feature for pigmented basal cell carcinomas vs non-basal cell carcinomas was determined using the χ² test of independence; with P<0.05 defining significance

e Subsequently used to create the diagnostic model in Table V.1.2 Table V.1.1. (Continued)

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V.1 rarely found in pigmented basal cell carcinoma.

Ulceration and telangiectasia with arborization (tree-like) and large-diameter vessels were all significantly found in an increased frequency in pigmented basal cell carcinoma. Finally, certain patterns of pigmentation are specific for these lesions. Most commonly, pigment is seen in large gray-blue ovoid nests (55%), followed by multiple gray-blue globules (27%), leaf-like ar- eas (17%), and spoke-wheel areas (10%).

From this a model has been developed to di- agnose pigmented basal cell carcinoma (Ta- ble V.1.2) [5]. Here, for a pigmented basal cell carcinoma to be diagnosed, it must have the

negative feature pigment network absent and at least one of the six positive features mentioned above present. On an equal-sample-size inde- pendent test set the method gave a sensitivity of

Table V.1.2. Method of diagnosis of pigmented basal cell carcinomas. (From [5])

Negative feature

(cannot be found) Positive features

(at least one feature found) Pigment network Maple leaf-like areas

Spoke-wheel areas Large blue-gray ovoid nests Multiple blue-gray globules Arborizing (“tree-like”) telangiectasia

Ulceration

Fig. V.1.4. Pigmented basal cell carcinoma (dermoscopy). This lesion lacks a pigment network and has large gray-blue ovoid nests, widespread leaf-like areas (arrows), and extensive ulceration

Fig. V.1.3. Pigmented basal cell carcinoma (dermoscopy). This lesion lacks a pigment network and has three of the positive features outlined in Table V.1.2: large gray- blue ovoid nests (thick arrow), arborizing (tree-like) ves- sels (thin arrow), and small areas of early ulceration

Fig. V.1.5. Pigmented basal cell carcinoma (dermoscopy). This lesions lacks a pigment network and has both multiple gray-blue globules (thin arrows) and large gray- blue ovoid nests (thick arrows)

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97% (95% CI: 90–100) for the diagnosis of pig- mented basal cell carcinoma and a specificity of 93% (95% CI: 83–97; invasive melanoma) and 92% (95% CI: 83–97; benign pigmented skin le- sions). The method has been validated as robust by other investigators with a series of 56 pig- mented basal cell carcinomas being all correctly classified [6]. It was noted that the features of leaf-like areas and large blue-gray ovoid nests lacked good agreement, and perhaps were con- fused with themselves or other positive features.

This method is now incorporated into the inter- nationally accepted first step in differentiating melanocytic from non-melanocytic lesions us- ing dermoscopy [7].

The dermoscopy definitions of the six posi- tive features are defined as previously reported [5, 8]:

1. Large gray-blue ovoid nests are well- circumscribed confluent, or near- confluent, pigmented ovoid or elongated areas, larger than globules, and not intimately connected to a pigmented tumor body (Figs. V.3, V.4, V.5).

2. Multiple gray-blue globules (Figs. V.5, V.6,) are smaller than their correspond- ing large ovoid nests but should be differentiated from the finer pepper-like morphology of multiple gray/blue dots (melanophages).

3. Leaf-like areas (formally referred to as mapleleaf-like areas) are brown to gray- blue discrete bulbous extensions forming a leaf-like pattern. They should be distinguished from pseudopods because maple leaf areas are discrete pigment nests (islands) never arising from a pigment network and usually not arising from an adjacent confluent pigmented area (Fig. V.4) [9].

Fig. V.1.7. Pigmented basal cell carcinoma (dermoscopy).

This lesion lacks a pigment network and has the highly specific feature of spoke- wheel areas (arrows)

Fig. V.1.6. Pigmented basal cell carcinoma (dermoscopy). This lesion lacks a pigment network and has multiple gray-blue globules and fine, central tree-like vessels

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V.1 4. Spoke-wheel areas are well-circumscribed radial projections, usually tan in color but sometimes blue or gray, meeting at an often darker (dark brown, black, or blue) central axis (Fig. V.7). Arborizing telangiectasia (telangiectasia with ramification) are telangiectasia with distinct “tree-like” branching (Figs. V.3, V.6). Ulceration, the absence of the epidermis often associated with con- gealed blood, should not be due to a well- described recent history of trauma (Figs. V.3, V.4).

V.1.4 Relevant Clinical Differential Diagnosis

Because of its relative rapid growth with bleed- ing as a common presenting symptom, invasive melanoma is the main differential diagnosis of pigmented basal cell carcinomas; however, basal cell carcinomas tend to ulcerate and bleed ear- lier in their natural history than melanoma.

Less often, hemangioma or cellular/atypical blue nevus might be a clinical differential diag- noses; however, as stated above, more than 90%

of lesions should be easily diagnosed using the standard dermoscopy model described.

V.1.5 Histopathology

Recently, studies have shown that the production of the cytokine endothelin-1 by basal cell carci- noma tumor cells plays an important role in the hyperpigmentation (melanocyte stim- ulation) of the tumor [10]. Most basal cell carci- noma histological patterns can have pigmented varieties; however, fibrosing and infiltrative sub- types are less commonly pigmented. Melanin can be found in the tumor mass and surround- ing dermis. Within the tumor mass, melanocytes are often hyperplastic and melanosomes are of- ten confined to the melanocytes [11, 12]; howev-

er, while they may be taken up by surrounding malignant epithelial cells, fewer melanosomes are found in the tumor cells than in the sur- rounding normal perilesional keratinocytes.

This interrupted melanosome transfer to basal cell carcinoma cells seems related to a decreased expression of the phagocytic receptor PAR-2 in the tumor cells, and results in the accumulation of melanosomes within the perinuclear region of melanocytes as well as in the intercellular sur- rounding spaces or in the stroma outside the ba- saloid cells [13, 14]. Melanin is preferably seen in the superficial component of the tumor. Further- more, hyperplastic melanocytes can be found in the overlying epidermis. In the dermis, melanin is found primarily in melanophages, but small amounts may be lying free (Fig. V.1.8) [1].

IV.1.6 Management

The management of pigmented basal cell carci- noma corresponds to that of its non-pigmented histological variant.

Fig. V.1.8. Pigmented basal cell carcinoma (histopathology). In pigmented basal cell carcinomas focal collections of melanin are seen within tumor nests. The melanin is produced from captured melanocytes stimulated by tumor cytokines (e.g., endothelin-1), with melanin (melanosomes) mainly confined to these melanocytes or lying in the intercellular tumor space. Melanin in the dermis is found mainly in melanophages. (Magnification ×50, he- matoxylin and eosin stain)

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C

Core Messages

■

In white-skin races approximately 7%

of basal cell carcinomas are pigmented;

however, there is a heavy racial predi- lection, whereby in Asian skin the majority of basal cell carcinomas are pigmented.

■

Clinically, in white-skin races, the pigment tends to be seen as well- defined islands of blue, gray, or black, on a background of amelanotic “pearly”

tumor. Two-thirds of pigmented basal cell carcinomas have less than 50% of their tumor surface pigmented and only 7% have greater than 75% of their surface pigmented.

■

Because of the disrupted transfer of melanosomes into tumor cells, the majority of melanin in pigmented basal cell carcinoma is found in melanocytes or the intercellular space within the tumor nests, and not in the tumor cells themselves.

■

The dermoscopic features of pigmented basal cell carcinoma are an absent pigment network and one or more of the positive features of large gray-blue ovoid nests, multiple gray-blue glob- ules, leaf-like areas, spoke-wheel areas, ulceration, and tree-like vessels.

References

1. Maloney M, Jones D, Sexton F (1992) Pigmented basal cell carcinoma: investigation of 70 cases. J Am Acad Dermatol 27:74–78

2. Cho S, Kim M, Whang K, Hahm J (1999) Clinical and histopathological characteristics of basal cell carcinoma in Korean patients. J Dermatol 26:494–

3. Kikuchi A, Shimizu H, Nishikawa T (1996) Clini-501 cal and histopathological characteristics of basal cell carcinoma in Japanese patients. Arch Dermatol 132:320–324

4. Bigler C, Feldman J, Hall E, Padilla R (1996) Pig- mented basal cell carcinoma in Hispanics. J Am Acad Dermatol 34:751–752

5. Menzies S, Westerhoff K, Rabinovitz H, Kopf A, McCarthy W, Katz B (2000) Surface microscopy of pigmented basal cell carcinoma. Arch Dermatol 136:1012–1016

6. Peris K, Altobelli E, Ferrari A, Fargnoli M, Piccolo D, Esposito M, Chimenti S (2002) Interobserver agreement on dermoscopic features of pigmented basal cell carcinoma. Dermatol Surg 28:643–645 7. Argenziano G, Soyer P, Chimenti S et al. Dermosco-

py of pigmented skin lesions: results of a consensus meeting via the internet (2003) J Am Acad Derma- tol 48:679–693

8. Menzies S, Crotty K, Ingvar C, McCarthy W (2003) An atlas of surface microscopy of pigmented skin lesions, 2nd edn: dermoscopy. McGraw-Hill. Syd- 9. Menzies S, Crotty K, McCarthy W (1995) The mor-ney phologic criteria of the pseudopod in surface microscopy. Arch Dermatol 131:436–440

10. Lan C, Wu C, Cheng C, Yu C, Chen G, Yu H (2005) Pigmentation in basal cell carcinoma involves en- hanced endothelin-1 expression. Exp Dermatol 14:528–534

11. Bleehen S (1975) Pigmented basal cell epithelioma.

Br J Dermatol 93:361–370

12. Tezuka T, Ohkuma M, Hirose I (1977) Melanosomes of pigmented basal cell epithelioma. Dermatologica 154:14–22

13. Sakuraba K, Hayashi N, Kawashima M, Imokawa G (2004) Down-regulated PAR-2 is associated in part with interrupted melanosome transfer in pigmented basal cell epithelioma. Pigment Cell Res 17:371–378 14. Nigel K (1997) Tumors and cysts of the epidermis.

In: Elder D, Elenltsas R, Jaworsky C, Johnson B Jr (eds) Lever’s histopathology of the skin, 8th edn.

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