IV.2 Acral Melanoma

IV.2

IV.2.1 Definition

Acral melanoma is a melanoma that affects ac- ral areas of the skin, which is the most prevalent site of melanoma in non-Caucasians [5, 10].

Strictly speaking, acral lentiginous melanoma is not a synonym for acral melanoma. Acral len- tiginous melanoma, originally described by Reed in 1976 [21], is one of the four histogenetic types defined by Clark et al. [6]. Almost all acral lentiginous melanomas occur on glabrous (non- hair-bearing) acral skin. Superficial spreading melanomas also occur on acral skin, but they are mostly seen on non-glabrous portions such as dorsal aspects of the hands and feet; however, superficial spreading melanomas can occur also on glabrous skin [12]. Furthermore, nodular melanomas are seen on both glabrous and non- glabrous acral skin. If stratified by the tumor

Chapter IV.2

Acral Melanoma

Toshiaki Saida, Hiroshi Koga, Yoriko Yamazaki, Masaru Tanaka IV.2

Contents

IV.2.1 Definition . . . .196

IV.2.2 Clinical Features . . . .197

IV2.3 Dermoscopic Criteria . . . .198

IV.2.4 Relevant Clinical Differential Diagnosis . . . .198

IV.2.5 Histopathology . . . .199

IV.2.6 Management . . . .200

IV.2.7 Case Study . . . .200

References . . . .202

thickness, biological behavior is not different among the four histogenetic types [16]. More- over, cutaneous melanomas not infrequently show overlapping histopathological features of the four types [36]. Ackerman repeatedly criti- cized the validity of the Clark’s classification and proposed the unifying concept of melano- ma [1].

Recently, Bastian and co-workers defined ac- ral melanoma as melanoma occurring on the non-hair-bearing skin of the palms or soles or under the nails and found that this type of mel- anoma was unique in frequent amplifications of chromosomes 5p15, 5p13, 11q13, and 12q14 [4, 7]. Particularly, amplification of 11q13 was de- tected in ~50% of this type of melanoma. Cyclin D1 is the most important candidate gene located in this chromosome region. It is noteworthy that 5 of 36 acral melanomas defined by Bastian and co-workers were superficial spreading mel- anoma according to Clark’s classification [7].

Another characteristic of acral melanoma is very low rate of mutation of the BRAF onco- gene, which is commonly found in superficial spreading melanoma [8, 18]. These findings suggest that molecular pathogenesis of melano- ma is different depending on anatomical loca- tions and/or degrees of sun exposure, irrespec- tive of Clark’s types. In this chapter we use the term acral melanoma according to the defini- tion by Bastian and co-workers [7].

Proportions of acral melanoma in all mela-

nomas are quite different among races [5, 10,

17]: more than 80% in black persons, ~40% in

Asians, and ~5% in Caucasian; however, there

seems to be no significant difference in absolute

incidence of acral melanoma among races [35].

Acral Melanoma

Toshiaki Saida, Hiroshi Koga, Yoriko Yamazaki, Masaru Tanaka IV.2

IV.2.2 Clinical Features

Acral melanomas occur in older patients. In a recent study of acral melanoma in Japan, a peak of age distribution was in the seventh decade, and slight male preponderance was recognized [10]. Acral melanomas are most commonly seen on the soles, followed by finger nails and then by toe nails. Palms are least frequently affected.

Clinically, most acral melanomas first appear as a brownish macule on glabrous skin. The ini- tial stage may be difficult to recognize clinically because the lesion is small in size and is not so irregular in shape and color [11]. In time, the le-

sion increases in size, and becomes irregular in shape and variegated in color (Fig. IV.2.1a, in- set), permitting differentiation from benign me- lanocytic nevus of the junctional type [23, 25].

Duration of this horizontal growth phase is variable: very long in some cases and transient in others. This macular stage is followed by the vertical growth phase, which is characterized by appearance of indurated portions or elevated nodules. In more advanced lesions, the indu- rated or nodular portions are partly ulcerated [13]. Even in these advanced stages, macular components are usually detected within or sur- rounding the lesions. Occasionally, small pale

Fig. IV.2.1. Clinical, dermo- scopic (a), and histopatho- logical (b) features of acral melanoma. This lesion was from the right heel of an 83- year-old Japanese man. Seven years previously, he noticed a small brown macule on his left heel. At his first visit to us, this lesion was 58¥46 mm in size, and irregular and random in shape and color (a, inset), accompanied by ulcerated crusted areas (arrow). Dermoscopically, the parallel ridge pattern was well recognized along with diffuse irregular pigmentation and the fibrillar pattern (circle).

Histopathologically, random proliferation of melanocytes is detected in the lower epi- dermis. It is noteworthy that the degree of proliferation is more prominent in the crista profunda intermedia (arrows) underlying the surface ridge of the skin marking (b) a

b

198 T. Saida, H. Koga, Y. Yamazaki, M. Tanaka

IV.2

brownish macules not continuous to the main lesion are detected in the periphery (skip mac- ules), which may be explained by the “field cell”

theory by Bastian [3].

Most melanomas affecting nail apparatus are initially seen as longitudinal pigmented bands of the nail plate (see Chap. IV.11) [24, 27]. In time, the pigmented band of the nail plate in- creases in width and becomes variegated in col- or from tan to black. Later, pigmented macules on the nail folds (Hutchinson’s sign) may devel- op [32]. Still later, deformity of the nail plate is recognized, and finally, the nail plate is de- stroyed, producing nodular lesions often ac- companied by ulceration.

Acral melanomas are not infrequently hy- popigmented; 10~20% of acral melanoma in Japanese was reported to be partly or completely amelanotic [13]. Clinical diagnosis of amelanot- ic melanoma is difficult and often misdiagnosed as other neoplastic or non-neoplastic lesions (see Chap. IV.3) [34].

IV2.3 Dermoscopic Criteria

Dermoscopic features of advanced primary le- sions of acral melanoma are common to those affecting other anatomical sites: diffuse pig- mentation with variegated shades of brown from tan to black; abrupt edge; blue whitish veil;

and regression structures with whitish or gray- ish color. In addition to irregular streaks found at the periphery, dots/globules of variable sizes are randomly distributed within a lesion [30, 31]. Ulceration is also common in advanced le- sions.

In macular portions of acral melanoma, a very unique dermoscopic finding, termed the parallel ridge pattern, is frequently detected (Fig. IV.2.1a). This pattern is characterized by band-like pigmentation on the ridges of the skin markings, which run in a parallel fashion on glabrous skin [20, 31]. More importantly, the parallel ridge pattern is also frequently detected in the lesions of melanoma in situ [28]. The sen- sitivity and specificity of the parallel ridge pat- tern to acral melanoma are 86 and 99%, respec- tively [29]. The sensitivity and specificity are almost same between invasive and in-situ mela-

nomas, and thus this pattern is very much help- ful in detecting early lesions of acral melanoma [11]. Irregular diffuse pigmentation is another dermoscopic finding of acral melanoma (Fig. IV.2.1a), which is detected in more ad- vanced macular portions [15, 29]. Moreover, dermoscopic patterns observed in melanocytic nevus on acral volar skin, such as the parallel furrow pattern, the lattice-like pattern, or the fibrillar pattern, could be also detected in acral melanoma (see Chap. III.2) [28, 31]; however, they are just focally detected within the lesion of acral melanoma, in contrast to overall regular distribution of the patterns in melanocytic ne- vus. Characteristic dermoscopic findings of pig- mented bands of the nail-apparatus melanoma have not yet been fully clarified [22] (see Chap. IV.11). If hyponychial volar skin is in- volved by nail apparatus melanoma, the charac- teristic parallel ridge pattern is detected there, which helps us to determine the diagnosis [14, 28]. In addition, dermoscopy enables us to rec- ognize tiny pigmentation on the cuticle not dis- cernible with the naked eye (micro-Hutchinson sign) [14, 22]. This sign strongly suggests evolv- ing lesions of melanoma of nail apparatus (Fig. IV.2.2); however, even by use of dermosco- py, it is still difficult for us to differentiate pig- mented bands of the nail plate caused by early melanoma from those due to benign condi- tions.

IV.2.4 Relevant Clinical Differential Diagnosis

Differentiation of early acral melanoma from

melanocytic nevus on glabrous skin is impor-

tant. Melanocytic nevus is not uncommon on

the glabrous skin: about 7% of Japanese general

populations have melanocytic nevi on their

soles [25]. In general, melanocytic nevus on gla-

brous skin is regular in shape, usually oval or

spindle-shaped, up to 7 mm in maximum di-

ameter, and homogeneous in color. In contrast,

most acral melanomas are seen as large, irregu-

lar lesions; however, we often encounter diffi-

culties in clinical differentiation of the two bio-

logically distinct entities. Dermoscopy is

immensely helpful in this differentiation; the parallel ridge pattern is unique to acral mela- noma and the parallel furrow and the lattice- like patterns are characteristic of melanocytic nevus (see Chap. III.2) [29]. Regularly distrib- uted fibrillar pattern also strongly suggests me- lanocytic nevus.

Pigmented macules seen in Peutz–Jeghers syndrome and Laugier–Hunziker syndrome show the parallel ridge pattern [28, 31], but these conditions are easily diagnosed clinically: mul- tiple tiny macules on the fingers and toes as well as on the lips. In our evaluation, brown macules induced by cytotoxic drugs such as 5-fluoroura- cil also show the parallel ridge pattern on der- moscopy. But this condition also can be clini- cally diagnosable, as multiple lesions on the background of grayish red atrophic skin. Volar melanotic macules commonly seen in black per- sons may show the parallel ridge pattern. So- called black heel, i.e., calcaneal petechiae in-

duced by ill-fitted shoes of athletes, is included in clinical differential diagnosis of acral mela- noma. This condition is definitely diagnosed by the unique dermoscopic findings termed the reddish black “pebbles on the ridges” [31] and homogeneous pigmentation [38].

IV.2.5 Histopathology

Histopathologically, in macular portions of ac- ral melanoma, melanocytes randomly prolifer- ate in the lower epidermis, which shows acan- thosis and is often accompanied by elongated rete ridges [23]. Preferential proliferation of me- lanocytes in the crista profunda intermedia, an epidermal rete ridge underlying the surface ridge, can be recognized (Fig. IV.2.1b). The pro- liferating melanocytes are usually round or oval in shape but occasionally spindle-shaped or dendritic. The nuclei are often large and hyper-

Fig. IV.2.2. Dermoscopic and histopathological features of early melanoma in situ affecting nail apparatus. This le- sion was from the right little finger of a 28-year-old Japa- nese woman. She had noticed the nail pigmentation more than 10 years before. The longitudinal pigmented bands were 4.1 mm in width. Dermoscopically (inset), the pig- mented bands were not so irregular, but the nail plate was partly destroyed at the distal tip (arrowhead). Moreover, proximal to the pigmented bands, pigmentation on the

cuticle and proximal nail fold (withe asterisk) was well recognized (Hutchinson’s sign). These findings prompted us to excise this lesion. Histopathologically, random pro- liferation of solitary arranged atypical melanocytes was detected in the lower epithelium of the nail matrix and nail bed, confirming the diagnosis of melanoma in situ.

In addition, solitary melanocytes were detected in the epidermis corresponding to the cuticle (circle)

200 T. Saida, H. Koga, Y. Yamazaki, M. Tanaka

IV.2

chromatic. Near the invasive portions, the de- grees of melanocytic proliferation become more pronounced: atypical melanocytes are often distributed throughout the entire epidermis [17]. In the invasive areas, growth of atypical melanocytes is seen in the dermis, usually ar- ranged in densely packed nests or in sheets, of- ten accompanied by lymphocytic infiltration.

In more advanced lesions, epidermis is de- stroyed by infiltration of atypical melanocytes, producing necrotic, ulcerated areas.

Histopathological features of melanoma in situ affecting glabrous skin are similar to those of macular portion of acral melanoma. It is noteworthy that, corresponding to the der- moscopic parallel ridge pattern, proliferation is prominent in crista profunda intermedia, an epidermal rete ridge underlying the surface ridge [11, 20, 21, 26, 28]. This is in contrast to histopathological findings of melanocytic ne- vus showing the parallel furrow pattern, in which proliferation of melanocytes (nevus cells) are mostly confined to crista profunda limitans, an epidermal rete ridge underlying the surface sulcus [19]. To recognize these important find- ings, excised tissues must be cut perpendicularly to the skin markings [9, 11]. If the tissue of me- lanocytic nevus is cut parallel to the skin mark- ings, continuous, irregular proliferation of me- lanocytes is seen in the lower epidermis, which mimics the features of melanoma in situ [33].

We occasionally see acral pigmented lesions which exhibit the parallel ridge pattern on der- moscopy, but their histopathological features are too subtle to diagnose as melanoma in situ:

only slight increase of melanocytes in the basal layer of the crista profunda intermedia [11]. In about 40% of these subtle lesions, we have found amplification of cyclin D1 by fluorescent in-situ hybridization analysis, which strongly supports that these subtle lesions are evolving melanoma in situ [37].

IV.2.6 Management

Primary lesions of acral melanoma without metastatic lesions should be surgically excised with the free margin of 1–2 cm. Acral melano- ma in situ is cured by simple excision with only

5 mm free margin. Suspicious lesions whose di- agnosis cannot be definitely determined, even with dermoscopy, should be excised and evalu- ated histopathologically. In this case, the tissue specimen should be cut perpendicularly to the skin markings.

If nail-apparatus melanoma is detected early in the in-situ stage, amputation of the digit is not necessary. Such an early nail-apparatus mel- anoma can be cured with total excision of the nail apparatus, and the tissue defect is easily covered with skin grafting, preserving the func- tion of the digit [27].

In a recent study of a total of 801 acral mela- nomas in Japan, 5-year survival rates according to the present UICC/AJCC staging were as fol- lows: stage IA, 98.1%; stage IB, 95.8%; stage IIA, 93.8%; stage IIB, 73.4%; stage IIC, 64.2%;

stage IIIA, 48.0%; stage IIIB, 39.4%; stage IIIC, 44.1%; and stage IV, 16.0% (unpublished data).

The survival rates in stages IIA, IIB, IIC and IIIC seem to be better than those reported by Balch et al. [2], whose patients were mainly Cau- casians suffering from superficial spreading melanoma.

IV.2.7 Case Study

A 56-year-old Japanese woman noticed a brown- ish macule on her left sole 6 years previously. At her first visit to us, the pale brown macule was 21¥16 mm in size, and not so irregular in shape and color (Fig. IV.2.3a, inset). These findings suggested benign melanocytic lesions such as lentiginous nevus or volar melanotic macule.

Dermoscopically, however, this lesion exhibited the typical features of the parallel ridge pattern (Fig. IV.2.3a), strongly suggesting that this was melanoma in situ, and we excised the lesion to- tally.

Histopathologically, in tissue sections cut

perpendicularly to the skin markings, random

proliferation of melanocytes was recognized

in the lower epidermis, which was more promi-

nent in the crista profunda intermedia under-

lying the surface ridge of the skin marking

(Fig. IV.2.3b, arrows).

Comments

Using conventional clinical and histopathologi- cal criteria, we diagnosed this case as possible lentiginous melanocytic nevus; however, if we consider all the findings, including dermoscop- ic features of the typical parallel ridge pattern, we could diagnose this lesion as an early lesion of acral melanoma in situ [11, 29, 30]. This case demonstrates that dermoscopy is very helpful in detecting early melanoma on glabrous skin.

Preferential proliferation of melanocytes in the epidermal rete ridges underlying the surface ridges, which corresponds to the dermoscopic parallel ridge pattern, strongly suggests the di- agnosis of early acral melanoma.

C

Core Messages

■ The parallel ridge pattern is a highly sensitive and specific dermoscopic pattern of acral melanoma, including early evolving lesions, and thus, using this dermoscopic finding, we can effectively detect acral melanoma in early, curable stages.

■ In addition, recent studies suggest that acral melanoma is unique in molecular pathogenesis, which could be used in developing molecular diagnosis and molecular targeting therapy.

Fig. IV.2.3. Case Study

a

b

202 T. Saida, H. Koga, Y. Yamazaki, M. Tanaka

IV.2

References

1. Ackerman AB (1980) Malignant melanoma: a uni- fying concept. Hum Pathol 11:591–595

2. Balch CM, Buzaid AC, Soong S-J, et al. (2001) Final version of the American Joint Committee on cancer staging system for cutaneous melanoma. J Clin On- col 19:3635–3648

3. Bastian BC (2003) Understanding the progression of melanocytic neoplasia using genomic analysis:

from fields to cancer. Oncogene 22:3081–3086 4. Bastian BC, Kashani-Sabet M, Hamm H, et al.

(2000) Gene amplifications characterize acral mela- noma and permit the detection of occult tumor cells in the surrounding skin. Cancer Res 60:1968–1973 5. Bellows C, Belafsky P, Fortgang IS, et al. (2001) Mel-

anoma in African-Americans: trends in biological behavior and clinical characteristics over two de- cades. J Surg Oncol 78:10–16

6. Clark WH Jr, Goldman L, Mastrangelo MJ (1979) Human malignant melanoma. Grune and Stratton, New York

7. Curtin JA, Fridlyand J, Kageshita T, et al. (2005) Distinct set of genomic alterations in melanoma. N Engl J Med 353:2135–2147

8. Davies H, Bignell GR, Cox C, et al. (2002) Muta- tion of the BRAF gene in human cancer. Nature 417:949–954

9. Ferrara G, Argenziano G, Soyer P (2003) Melano- cytic nevi of palms and soles. Am J Surg Pathol 27:411–412

10. Ishihara K, Saida T, Yamamoto A (2001) Updated statistical data for malignant melanoma in Japan.

Int J Clin Oncol 6:109–116

11. Ishihara Y, Saida T, Miyazaki A, et al. (2006) Early acral melanoma in situ: correlation between the parallel ridge pattern on dermoscopy and micro- scopic features. Am J Dermatopathol 28:21–27 12. Kato T, Suetake T, Tabata N, et al. (1999) Epidemiol-

ogy and prognosis of plantar melanoma in 62 Japa- nese patients over a 28-year period. Int J Dermatol 38:515–519

13. Kato T, Tabata N, Suetake T, et al. (1997) Non-pig- mented nodular plantar melanoma in 12 Japanese patients. Br J Dermatol 136:207–211

14. Kawabata Y, Ohara K, Hino H, et al. (2001) Two kinds of Hutchinson’s sign, benign and malignant. J Am Acad Dermatol 44:305–307

15. Kawabata Y, Tamaki K (1998) Distinctive derma- toscopic features of acral lentiginous melanoma in situ from plantar melanocytic nevi and their his- topathologic correlation. J Cutan Med Surg 2:199–

16. Koh HK, Michalik E, Sober AJ, et al. (1984) Lentigo 204 maligna melanoma has no better prognosis than other types of melanoma. J Clin Oncol 2:994–1001

17. Kuchelmeister C, Schaumburg-Lever G, Garbe C (2000) Acral cutaneous melanoma in Caucasians:

clinical features, histopathology and prognosis in 112 patients. Br J Dermatol 143:275–280

18. Maldonado JL, Fridlyand J, Patel H, et al. (2003) De- terminants of BRAF mutations in primary melano- mas. J Natl Cancer Inst 95:1878–1890

19. Miyazaki A, Saida T, Koga H, et al. (2005) Anatomi- cal and histopathological correlates of the dermo- scopic patterns seen in melanocytic nevi on the sole:

a retrospective study. J Am Acad Dermatol 53:230–

20. Oguchi S, Saida T, Koganehira Y, et al. (1998) Char-236 acteristic epiluminescent microscopic features of early malignant melanoma on glabrous skin: a vid- eomicroscopic analysis. Arch Dermatol 134:563–

21. Reed RJ (1976) Acral lentiginous melanoma. In: 568 Hartmann W, Kay S, Reed RJ (eds) New concepts in surgical pathology of the skin. Wiley, New York, pp 89–90

22. Ronger S, Touzet S, Ligeron C, et al. (2002) Dermo- scopic examination of nail pigmentation. Arch Der- matol 138:1327–1333

23. Saida T (1989) Malignant melanoma in situ on the sole of the foot: its clinical and histopathologic characteristics. Am J Dermatopathol 11:124–130 24. Saida T (1992) Heterogeneity of the site of origin of

malignant melanoma in ungual areas: “subungual”

malignant melanoma may be a misnomer. Br J Der- matol 126:529

25. Saida T (2000) Malignant melanoma on the sole:

how to detect the early lesions efficiently. Pigment Cell Res 13 (Suppl 8):135–139

26. Saida T (2005) Lessons learned from studies of the development of early melanoma. Int J Clin Oncol 10:1371–1374

27. Saida T, Oshima Y (1989) Clinical and histopatho- logic characteristics of early lesions of subungual malignant melanoma. Cancer 63:556–560

28. Saida T, Miyazaki A, Grin CM (2005) Acro-lentigi- nous melanoma. In: Marghoob A, Braun R, Kopf A (eds) Atlas of dermoscopy. Taylor and Francis, Lon- don, pp 221–233

29. Saida T, Miyazaki A, Oguchi S, et al. (2004) Sig- nificance of dermoscopic patterns in detecting malignant melanoma on acral volar skin: results of a multi-center study in Japan. Arch Dermatol 140:1233–1238

30. Saida T, Oguchi S, Ishihara Y (1995) In vivo obser- vation of magnified features of pigmented lesions on volar skin using videomicroscope: usefulness of epiluminescence technique in clinical diagnosis.

Arch Dermatol 131:298–304

31. Saida T, Oguchi S, Miyazaki A (2002) Dermoscopy for acral pigmented skin lesions. Clin Dermatol 20:279–285

32. Seiji M, Takematsu H, Hosokawa M, et al. (1983) Acral melanoma in Japan. J Invest Dermatol 80 (Suppl):56s–60s

33. Signoretti S, Annessi G, Puddu P, et al. (1999) Mela- nocytic nevi of palms and soles: a histological study according to the planes of section. Am J Surg Pathol 23:283–287

34. Soon SL, Solomon AR, Papadopoulos D, et al. (2003) Acral lentiginous melanoma mimicking benign dis- eases: the Emory experience. J Am Acad Dermatol 48:183–188

35. Stevens NG, Liff JM, Weiss NS (1990) Plantar mela- noma: Is the incidence of melanoma of the sole of foot really higher in blacks than whites? Int J Can- cer 45:691–693

36. Weyers W, Euler M, Diaz-Cascajo C, et al. (1999) Classification of cutaneous malignant melanoma: a reassessment of histopathologic criteria for the dis- tinction of different types. Cancer 86:288–299 37. Yamaura M, Takata M, Miyazaki A, et al. (2005)

Specific dermoscopy patterns and amplifications of the cyclin D1 gene to define histopathologically unrecognizable early lesions of acral melanoma in situ. Arch Dermatol 141:1413–1418

38. Zalaudek I, Argenziano G, Soyer P, et al. (2004) Dermoscopy of subcorneal hematoma. Dermatol Surg 30:1229–1232