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

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

Contents thickness, biological behavior is not different among the four histogenetic types [16]. More- IV.2.1 Definition ...... 196 over, cutaneous melanomas not infrequently IV.2 IV.2.2 Clinical Features ...... 197 show overlapping histopathological features of IV2.3 Dermoscopic Criteria...... 198 the four types [36]. Ackerman repeatedly criti- cized the validity of the Clark’s classification IV.2.4 Relevant Clinical Differential and proposed the unifying concept of melano- Diagnosis...... 198 ma [1]. IV.2.5 Histopathology...... 199 Recently, Bastian and co-workers defined acral melanoma as melanoma occurring on the IV.2.6 Management...... 200 non-hair-bearing skin of the palms or soles or IV.2.7 Case Study...... 200 under the nails and found that this type of mel- References...... 202 anoma was unique in frequent amplifications of chromosomes 5p15, 5p13, 11q13, and 12q14 [4, 7]. Particularly, amplification of 11q13 was detected in ~50% of this type of melanoma. Cyclin D1 is the most important candidate gene located in this chromosome region. It is noteworthy IV.2.1 Definition that 5 of 36 acral melanomas defined by Bastian and co-workers were superficial spreading mel- Acral melanoma is a melanoma that affects ac- anoma according to Clark’s classification [7]. ral areas of the skin, which is the most prevalent Another characteristic of acral melanoma is site of melanoma in non-Caucasians [5, 10]. very low rate of mutation of the BRAF onco- Strictly speaking, acral lentiginous melanoma is gene, which is commonly found in superficial not a synonym for acral melanoma. Acral len- spreading melanoma [8, 18]. These findings tiginous melanoma, originally described by suggest that molecular pathogenesis of melano- Reed in 1976 [21], is one of the four histogenetic ma is different depending on anatomical loca- types defined by Clark et al. [6]. Almost all acral tions and/or degrees of sun exposure, irrespec- lentiginous melanomas occur on glabrous (non- tive of Clark’s types. In this chapter we use the hair-bearing) acral skin. Superficial spreading term acral melanoma according to the defini- melanomas also occur on acral skin, but they tion by Bastian and co-workers [7]. are mostly seen on non-glabrous portions such Proportions of acral melanoma in all mela- as dorsal aspects of the hands and feet; however, nomas are quite different among races [5, 10, superficial spreading melanomas can occur also 17]: more than 80% in black persons, ~40% in on glabrous skin [12]. Furthermore, nodular Asians, and ~5% in Caucasian; however, there melanomas are seen on both glabrous and non- seems to be no significant difference in absolute glabrous acral skin. If stratified by the tumor incidence of acral melanoma among races [35]. Chapter IV.2 Acral Melanoma Chapter IV.2 197

Fig. IV.2.1. Clinical, dermo- Acral Melanoma scopic (a), and histopathological (b) features of acral Toshiaki Saida, Hiroshi Koga, Yoriko Yamazaki, Masaru Tanaka IV.2 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 a is detected in the lower epidermis. 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)

IV.2.2 Clinical Features sion increases in size, and becomes irregular in shape and variegated in color (Fig. IV.2.1a, in- Acral melanomas occur in older patients. In a set), permitting differentiation from benign me- recent study of acral melanoma in Japan, a peak lanocytic nevus of the junctional type [23, 25]. of age distribution was in the seventh decade, Duration of this horizontal growth phase is and slight male preponderance was recognized variable: very long in some cases and transient [10]. Acral melanomas are most commonly seen in others. This macular stage is followed by the on the soles, followed by finger nails and then by vertical growth phase, which is characterized by toe nails. Palms are least frequently affected. appearance of indurated portions or elevated Clinically, most acral melanomas first appear nodules. In more advanced lesions, the indu- as a brownish macule on glabrous skin. The ini- rated or nodular portions are partly ulcerated tial stage may be difficult to recognize clinically [13]. Even in these advanced stages, macular because the lesion is small in size and is not so components are usually detected within or sur- irregular in shape and color [11]. In time, the le- rounding the lesions. Occasionally, small pale 198 T. Saida, H. Koga, Y. Yamazaki, M. Tanaka

brownish macules not continuous to the main nomas, and thus this pattern is very much help- lesion are detected in the periphery (skip mac- ful in detecting early lesions of acral melanoma ules), which may be explained by the “field cell” [11]. Irregular diffuse pigmentation is another theory by Bastian [3]. dermoscopic finding of acral melanoma Most melanomas affecting nail apparatus are (Fig. IV.2.1a), which is detected in more ad- initially seen as longitudinal pigmented bands vanced macular portions [15, 29]. Moreover, of the nail plate (see Chap. IV.11) [24, 27]. In dermoscopic patterns observed in melanocytic time, the pigmented band of the nail plate in- nevus on acral volar skin, such as the parallel creases in width and becomes variegated in col- furrow pattern, the lattice-like pattern, or the or from tan to black. Later, pigmented macules fibrillar pattern, could be also detected in acral on the nail folds (Hutchinson’s sign) may devel- melanoma (see Chap. III.2) [28, 31]; however, op [32]. Still later, deformity of the nail plate is they are just focally detected within the lesion of recognized, and finally, the nail plate is de- acral melanoma, in contrast to overall regular stroyed, producing nodular lesions often ac- distribution of the patterns in melanocytic ne- IV.2 companied by ulceration. vus. Acral melanomas are not infrequently hy- Characteristic dermoscopic findings of pig- popigmented; 10~20% of acral melanoma in mented bands of the nail-apparatus melanoma Japanese was reported to be partly or completely have not yet been fully clarified [22] (see amelanotic [13]. Clinical diagnosis of amelanot- Chap. IV.11). If hyponychial volar skin is in- ic melanoma is difficult and often misdiagnosed volved by nail apparatus melanoma, the charac- as other neoplastic or non-neoplastic lesions teristic parallel ridge pattern is detected there, (see Chap. IV.3) [34]. which helps us to determine the diagnosis [14, 28]. In addition, dermoscopy enables us to recognize tiny pigmentation on the cuticle not dis- IV2.3 Dermoscopic Criteria cernible with the naked eye (micro-Hutchinson sign) [14, 22]. This sign strongly suggests evolv- Dermoscopic features of advanced primary le- ing lesions of melanoma of nail apparatus sions of acral melanoma are common to those (Fig. IV.2.2); however, even by use of dermosco- affecting other anatomical sites: diffuse pig- py, it is still difficult for us to differentiate pigmentation with variegated shades of brown mented bands of the nail plate caused by early from tan to black; abrupt edge; blue whitish veil; melanoma from those due to benign condi- and regression structures with whitish or gray- tions. ish color. In addition to irregular streaks found at the periphery, dots/globules of variable sizes are randomly distributed within a lesion [30, IV.2.4 Relevant Clinical Differential 31]. Ulceration is also common in advanced le- Diagnosis sions. In macular portions of acral melanoma, a Differentiation of early acral melanoma from very unique dermoscopic finding, termed the melanocytic nevus on glabrous skin is impor- parallel ridge pattern, is frequently detected tant. Melanocytic nevus is not uncommon on (Fig. IV.2.1a). This pattern is characterized by the glabrous skin: about 7% of Japanese general band-like pigmentation on the ridges of the skin populations have melanocytic nevi on their markings, which run in a parallel fashion on soles [25]. In general, melanocytic nevus on gla- glabrous skin [20, 31]. More importantly, the brous skin is regular in shape, usually oval or parallel ridge pattern is also frequently detected spindle-shaped, up to 7 mm in maximum di- in the lesions of melanoma in situ [28]. The sen- ameter, and homogeneous in color. In contrast, sitivity and specificity of the parallel ridge pat- most acral melanomas are seen as large, irregu- tern to acral melanoma are 86 and 99%, respec- lar lesions; however, we often encounter diffi- tively [29]. The sensitivity and specificity are culties in clinical differentiation of the two bio- almost same between invasive and in-situ mela- logically distinct entities. Dermoscopy is Acral Melanoma Chapter IV.2 199

Fig. IV.2.2. Dermoscopic and histopathological features cuticle and proximal nail fold (withe asterisk) was well of early melanoma in situ affecting nail apparatus. This -le recognized (Hutchinson’s sign). These findings prompted sion was from the right little finger of a 28-year-old Japa- us to excise this lesion. Histopathologically, random pro- nese woman. She had noticed the nail pigmentation more liferation of solitary arranged atypical melanocytes was than 10 years before. The longitudinal pigmented bands detected in the lower epithelium of the nail matrix and were 4.1 mm in width. Dermoscopically (inset), the pig- nail bed, confirming the diagnosis of melanoma in situ. mented bands were not so irregular, but the nail plate was In addition, solitary melanocytes were detected in the partly destroyed at the distal tip (arrowhead). Moreover, epidermis corresponding to the cuticle (circle) proximal to the pigmented bands, pigmentation on the immensely helpful in this differentiation; the duced by ill-fitted shoes of athletes, is included parallel ridge pattern is unique to acral mela- in clinical differential diagnosis of acral melanoma and the parallel furrow and the lattice- noma. This condition is definitely diagnosed by like patterns are characteristic of melanocytic the unique dermoscopic findings termed the nevus (see Chap. III.2) [29]. Regularly distrib- reddish black “pebbles on the ridges” [31] and uted fibrillar pattern also strongly suggests me- homogeneous pigmentation [38]. lanocytic nevus. Pigmented macules seen in Peutz–Jeghers syndrome and Laugier–Hunziker syndrome IV.2.5 Histopathology show the parallel ridge pattern [28, 31], but these conditions are easily diagnosed clinically: mul- Histopathologically, in macular portions of ac- tiple tiny macules on the fingers and toes as well ral melanoma, melanocytes randomly prolifer- as on the lips. In our evaluation, brown macules ate in the lower epidermis, which shows acan- induced by cytotoxic drugs such as 5-fluoroura- thosis and is often accompanied by elongated cil also show the parallel ridge pattern on der- rete ridges [23]. Preferential proliferation of me- moscopy. But this condition also can be clini- lanocytes in the crista profunda intermedia, an cally diagnosable, as multiple lesions on the epidermal rete ridge underlying the surface background of grayish red atrophic skin. Volar ridge, can be recognized (Fig. IV.2.1b). The pro- melanotic macules commonly seen in black per- liferating melanocytes are usually round or oval sons may show the parallel ridge pattern. So- in shape but occasionally spindle-shaped or called black heel, i.e., calcaneal petechiae in- dendritic. The nuclei are often large and hyper- 200 T. Saida, H. Koga, Y. Yamazaki, M. Tanaka

chromatic. Near the invasive portions, the de- 5 mm free margin. Suspicious lesions whose di- grees of melanocytic proliferation become more agnosis cannot be definitely determined, even pronounced: atypical melanocytes are often with dermoscopy, should be excised and evalu- distributed throughout the entire epidermis ated histopathologically. In this case, the tissue [17]. In the invasive areas, growth of atypical specimen should be cut perpendicularly to the melanocytes is seen in the dermis, usually ar- skin markings. ranged in densely packed nests or in sheets, of- If nail-apparatus melanoma is detected early ten accompanied by lymphocytic infiltration. in the in-situ stage, amputation of the digit is In more advanced lesions, epidermis is de- not necessary. Such an early nail-apparatus mel- stroyed by infiltration of atypical melanocytes, anoma can be cured with total excision of the producing necrotic, ulcerated areas. nail apparatus, and the tissue defect is easily Histopathological features of melanoma covered with skin grafting, preserving the func- in situ affecting glabrous skin are similar to tion of the digit [27]. those of macular portion of acral melanoma. It In a recent study of a total of 801 acral mela- IV.2 is noteworthy that, corresponding to the der- nomas in Japan, 5-year survival rates according moscopic parallel ridge pattern, proliferation is to the present UICC/AJCC staging were as fol- prominent in crista profunda intermedia, an lows: stage IA, 98.1%; stage IB, 95.8%; stage IIA, epidermal rete ridge underlying the surface 93.8%; stage IIB, 73.4%; stage IIC, 64.2%; ridge [11, 20, 21, 26, 28]. This is in contrast to stage IIIA, 48.0%; stage IIIB, 39.4%; stage IIIC, histopathological findings of melanocytic ne- 44.1%; and stage IV, 16.0% (unpublished data). vus showing the parallel furrow pattern, in The survival rates in stages IIA, IIB, IIC and which proliferation of melanocytes (nevus cells) IIIC seem to be better than those reported by are mostly confined to crista profunda limitans, Balch et al. [2], whose patients were mainly Cau- an epidermal rete ridge underlying the surface casians suffering from superficial spreading sulcus [19]. To recognize these important find- melanoma. ings, excised tissues must be cut perpendicularly to the skin markings [9, 11]. If the tissue of melanocytic nevus is cut parallel to the skin mark- IV.2.7 Case Study ings, continuous, irregular proliferation of melanocytes is seen in the lower epidermis, which A 56-year-old Japanese woman noticed a brown- mimics the features of melanoma in situ [33]. ish macule on her left sole 6 years previously. At We occasionally see acral pigmented lesions her first visit to us, the pale brown macule was which exhibit the parallel ridge pattern on der- 21¥16 mm in size, and not so irregular in shape moscopy, but their histopathological features and color (Fig. IV.2.3a, inset). These findings are too subtle to diagnose as melanoma in situ: suggested benign melanocytic lesions such as only slight increase of melanocytes in the basal lentiginous nevus or volar melanotic macule. layer of the crista profunda intermedia [11]. In Dermoscopically, however, this lesion exhibited about 40% of these subtle lesions, we have found the typical features of the parallel ridge pattern amplification of cyclin D1 by fluorescent in-situ (Fig. IV.2.3a), strongly suggesting that this was hybridization analysis, which strongly supports melanoma in situ, and we excised the lesion to- that these subtle lesions are evolving melanoma tally. in situ [37]. Histopathologically, in tissue sections cut perpendicularly to the skin markings, random proliferation of melanocytes was recognized IV.2.6 Management in the lower epidermis, which was more prominent in the crista profunda intermedia under Primary lesions of acral melanoma without lying the surface ridge of the skin marking metastatic lesions should be surgically excised (Fig. IV.2.3b, arrows). with the free margin of 1–2 cm. Acral melanoma in situ is cured by simple excision with only Acral Melanoma Chapter IV.2 201

Fig. IV.2.3. Case Study

Comments C Core Messages Using conventional clinical and histopathologi- ■ The parallel ridge pattern is a highly cal criteria, we diagnosed this case as possible sensitive and specific dermoscopic lentiginous melanocytic nevus; however, if we pattern of acral melanoma, including consider all the findings, including dermoscop- early evolving lesions, and thus, using ic features of the typical parallel ridge pattern, this dermoscopic finding, we can we could diagnose this lesion as an early lesion effectively detect acral melanoma in of acral melanoma in situ [11, 29, 30]. This case early, curable stages. demonstrates that dermoscopy is very helpful in ■ In addition, recent studies suggest that detecting early melanoma on glabrous skin. acral melanoma is unique in molecular Preferential proliferation of melanocytes in the pathogenesis, which could be used in epidermal rete ridges underlying the surface developing molecular diagnosis and ridges, which corresponds to the dermoscopic molecular targeting therapy. parallel ridge pattern, strongly suggests the diagnosis of early acral melanoma. 202 T. Saida, H. Koga, Y. Yamazaki, M. Tanaka

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