Congenital nevi are benign proliferations that are present at birth and consist of cells that normally are present in the skin. Depending on the size and location, the presence of such lesions may cause great anxiety in a parent, who may seek medical attention for the afflicted child. Some nevi carry malignant potential or are part of a syndrome. Others are quite disfiguring and are a source of psychosocial impairment.
Smaller lesions may be excised and closed primarily. However, lesions that involve a substantial surface area or regions of aesthetic importance may not be amenable to simple excision and closure without compromising form or function. Excision of these lesions may require a more complex reconstructive technique, such as tissue expansion, skin grafts, or flaps.
A vast body of literature exists regarding pigmented congenital lesions. Less invasive modalities for treatment of congenital lesions have been explored. These treatments include laser ablation, dermabrasion, and bleaching agents. This review focuses on laser ablation of nonvascular congenital pigmented lesions.
LASER AND TERMINOLOGY
Light is a form of electromagnetic radiation that travels through space as waves and occurs at different wavelengths. The color of visible light corresponds to its wavelength, with violet having the shortest wavelength and red the longest. Laser is an acronym for “light amplification by stimulated emission of radiation.” It can produce light in the ultraviolet, visible, and infrared region of the electromagnetic spectrum.
Einstein developed the theory of stimulated emission in 1917. A photon is released from an atom whose electron is in an excited state and interacts with a similarly excited atom. The second atom de-excites itself by giving off a photon that is identical in frequency, energy, direction, and phase. The triggering photon goes on its way unchanged. There are now two photons, which go on to trigger more atoms through stimulated emission.
Stimulated emission can cause amplification of a number of photons traveling in a certain direction. Placing mirrors at opposite ends of an optical cavity can control the direction. The number of photons traveling along the axis of the two mirrors increases greatly, and light amplification by stimulated emission of radiation occurs.
Monochromicity, directionality, and coherence are three unique characteristics of laser light that differentiate it from other sources of light. Laser light is made of one (mono) color (chroma), a single color with a narrow range of wavelengths. Laser light diverges very little and travels in one direction. These traveling waves are in phase, or coherent, thereby giving the beam its strength and intensity.
The elements of a laser that give that beam its characteristics are the active medium, the excitation mechanism, the feedback mechanism, and the output coupler. The active medium may be a solid, liquid, gas, or semiconductor. The atoms of this medium will be stimulated, and when one emits a photon that travels perpendicular to the feedback mechanism, stimulated emission occurs. The excitation mechanism that provides this initial source of energy may be electrical energy from a power supply, light energy from a flash tube or lamp, or another laser. Two mirrors that are positioned at either end of the active medium are aligned to reflect back into the active medium. This is the feedback mechanism or optic cavity. As the light travels back and forth between the mirror and through the active medium, it is amplified. The output coupler is a partially transparent mirror that allows a portion of the intercavity beam to leave the laser and form the external beam.
Properties of a laser that determine its therapeutic effectiveness are wavelength, duration of exposure, and output power. The wavelength of the laser light determines its color if within the visible spectrum (400-760 nm). However, it may be longer (infrared light, 760-10,000 nm) or shorter (ultraviolet, 100-400 nm) than the visible spectrum. These wavelengths determine at what site the laser light will be absorbed and produce the resultant tissue changes.
The laser light may be delivered from the device in a continuous or pulsed wave. A continuous wave laser produces a constant flow of light, and the output remains constant over time. Pulsed lasers release light energy in short bursts, and the output changes greatly over a given period of time. The number of pulses in a given period of time is referred to as the pulse repetition rate (PRR). A quality-switch (Q-switch) is a shutter placed between the feedback mechanism mirrors that interrupt the release of the beam, causing the active medium to build energy that is then released as one intense pulse when the shutter opens.
The output power is expressed in watts or milliwatts. The degree of laser ablation is dependent on the energy density, or fluence, of the laser. The fluence is defined as the energy of the laser per unit area incident on the surface (Joules per square centimeter).
CONGENITAL PIGMENTED LESIONS
The development of pigment-specific lasers has presented possible clinical applications in the treatment of pigmented lesions. Among the congenital pigmented lesions that are being treated by laser ablation are nevus of Ota, nevus of Ito, café-au-lait macules, lentigines, and congenital melanocytic nevi.
Nevus of Ota
Since being described by Ota in 1939, nevus fuscoceruleus ophthalmomaxillaris (nevus of Ota) has been identified around the world, with occurrences being most common among the Asian and African-American populations.1 The nevus of Ota is an oculodermal melanocytosis that usually presents as a unilateral, irregular, patchy blue-gray discoloration distributed along areas innervated by the first and second branches of the trigeminal nerve. Among reported cases, the female-to-male ratio is 3:1. Although its occurrence appears to be sporadic, rare cases of familial nevus of Ota have been reported.2 More than 50% of these lesions are present at birth, whereas 40% manifest during puberty. If the eye is affected by melanin pigment, as is noted in 46% to 65% of reported cases, the sclera is always involved. The other areas of the eye that may be involved are the iris, the conjunctiva, and the optic nerve in 50%, 40%, and 45% of cases, respectively.3 Secondary glaucoma has been reported in African-Americans and Asians between the ages of 20 and 40 years and is thought to be associated with melanocytes of the ciliary body of the angle of the anterior chamber.4
Four types of nevi exist: (1) unilateral orbital involvement with a tan-gray lesion over eyelids and/or zygoma; (2) slate-gray to brown densely spotted pigmentation on the eyes, over the zygoma, and at the base of the nose; (3) densely pigmented area of deep blue to purple on the side of the scalp and face down to the level of the zygoma; and (4) bilateral presentation, which is rare. Pigmentation on the mucous membranes of the pharynx, nose, and hard palate also is common.1 Intralesional or perilesional areas of blue papules may be found and may resemble blue nevi.5
The cause of the nevus is not fully known. Some have hypothesized that sex hormones play a role in its pathogenesis, given the female predominance, the appearance of the lesion at the onset of puberty in many cases, and reports of color variation with the menstrual cycle.1 Nevus of Ota is considered a benign dermatosis; however, some cases of melanoma have been reported as being associated with it, most occurring in Caucasians on the ipsilateral side.5-6
In the nevus of Ota, dendritic pigmented melanocytes are present in the deeper layers of the reticular dermis. Treatment of nevus of Ota with a Q-switched ruby or Alexandrite laser has been gaining favor during the past decade.7-11 These lasers have demonstrated the ability to selectively destroy dermal melanocytes while epidermal are either spared or recover from reversible injury.12,13 The number of treatments required to achieve excellent to good results are dictated by the depth and color of the lesion.11,14 Predominantly brown lesions achieve an excellent to good cosmetic result with as few as three treatments, whereas the blue-green lesions require six or more treatments to achieve similar cosmetic results.11
Nevus of Ito
The nevus of Ito (nevus fuscoceruleus acromiodeltoideus) likely represents the same pathologic process as the nevus of Ota; however, it is found in a unilateral distribution over the supraclavicular, deltoid, or scapular regions. This lesion may vary in coloration from a light brown to a blue or blue-purple patch. Similar to the nevus of Ota, a nevus of Ito is considered benign.1 Its response to Q-switched ruby laser has been similar to that of the nevus of Ota.15,16
Café-au-lait macules (CALMs) are sharply demarcated, round or oval, uniformly light tan to brown pigmented lesions that may range from a few millimeters to 20 cm in diameter. Solitary lesions are nonspecific and have been reported to be present in 10% to 28% of normal individuals, with their prevalence increasing during infancy and decreasing in adult life.15,17-19 Although they may occur anywhere on the body, they are found at birth most often on the buttocks region.20 When multiple CALMs are present (more than three in Caucasians and more than five in other races), it is no longer as common, and associated syndromes must be considered15 (Table 1). The lesion itself is considered benign.
The response of CALMs to laser treatment seems difficult to predict when the cases reported are reviewed, with results ranging from total disappearance to no change and recurrence rates at follow-up ranging from zero to 67%.18,21-26 Apparently, facial CALMs may be more responsive to laser treatment.16,24 The best reported results came from the largest series available. Alster18 reported 34 CALMs on 30 patients were treated with a pulsed dye laser set at 510-nm wavelength. The average number of treatments was 8.4 (range, 4-14). The series reports complete elimination of the lesions with no recurrence at follow-up after 12 months.18
An example of less impressive results is the series from Shimbashi and Kojima,21 in which 21 CALMs were treated with long-pulsed ruby laser (450 μs) at 694-nm wavelength for fewer treatments than Alster. The response of the 21 lesions treated was reported as 5 with remarkable fading, 12 with slight fading, 3 little change, and 1 lesion was aggravated. After an average follow-up of 8 months (range, 3-20 months), there was a recurrence of 14 lesions.
Lentigines are smaller lesions measuring 1 to 2 mm in diameter. They are described as small, flat, dark, brown, circular, or oval lesions that may involve any cutaneous surface, including the conjunctiva and oral mucosa, in a spotty distribution.15 They are the result of an increase in the number of melanocytes at the dermoepidermal junction without formation of nests.27 Unlike freckles, which they resemble, their coloration is unaffected by sunlight. Histologic evaluation reveals elongation of the rete ridges, an increase in the concentration of melanocytes in the basal layer, and the presence of melanophages in the upper dermis.28
Lentigines present at birth may be a distinctive clue to one of several syndromes. Peutz-Jeghers syndrome is an autosomal-dominant disorder that is characterized by pigmented legions on the buccal mucosa, the gingiva, the hard palate, and the lips. These pigmentary changes around the nose and mouth may be present at birth or develop in early childhood. Gastrointestinal polyps are also associated with this syndrome. The LEOPARD syndrome is also an autosomal-dominant disorder associated with lentigines. LEOPARD is an acronym for lentigines, electrocardiographic abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth, and deafness. The lentigines may be present at birth or appear soon after. The syndrome characterized by lentigines, atrial myxoma, mucocutaneous myxoma, and blue nevi, or LAMB syndrome, should also be considered when the lentigines are present on the face.
No treatment is necessary for these lesions. However, if the patient desires treatment, laser is an option to be considered (Fig 1). Because of their location in the epidermis, the CO2 or the erbium-YAG can prove effective.16 These lasers allow for resurfacing after a nonselective epidermal destruction.
Congenital Melanocytic Nevi
Congenital melanocytic nevi (CMNs) are collections of melanocytes that may present as macular, papular, or plaque-like pigmented lesions in various shades of brown with foci that are black or blue.15 Presence of hair and texture may vary. CMNs occur in 1% of all neonates.29 CMNs are categorized by their size and the assumed adult size.30 CMNs with a diameter that measures less than 1.5 cm are small, 1.5 to 20 cm are intermediate, and greater than 20 cm are large or giant.
Although most CMNs are small or intermediate, the incidence of giant CMN is one in 500,000 neonates.29 Suggested criteria for defining a CMN as “giant” include nevi greater than 20 cm at the largest diameter, nevi greater than 2% body surface area, and nevi that cannot be excised in a single procedure.31-33 Because these lesions typically grow in proportion to the patient, one should allow for expected proportionate growth. A useful guideline for classifying a CMN in the neonate is if the nevus measures approximately 9 cm on the head or 6 cm on the body, it may be considered a “giant” CMN.15
These CMNs are clinically significant because of their potential for melanoma. Most studies conclude that there is a 3% to 5% lifetime risk of developing melanoma in a giant CMN.34 The New York University Large Congenital Melanocytic Nevi Registry (NYU-LCMN Registry) was created in 1979 with the mission to determine the risk of melanoma in patients with large CMNs. A report from 2000 revealed data on 194 patients, reporting that of the 194 patients entered, 160 were followed up prospectively for an average of 5.5 years.35 Among these, no melanoma developed within the large CMN; however, three extracutaneous melanomas occurred: two in the central nervous system and one retroperitoneal. These numbers do not include patients who had the diagnosis of melanoma on initiation of the prospective study. When all 194 registry patients were included, 15 were identified as having melanoma. Interestingly, 14 of those patients had nevi larger than 50 cm in diameter.35
Treatment modalities are targeted at early removal of as many melanocytes as possible. The standard and most effective method of removal is excision. However, in recent years, several clinicians and investigators have looked to laser ablation as an option in treating congenital melanocytic nevi.36-46
Imayama and Ueda report up to 8 years follow-up with patients treated with normal-mode ruby laser for congenital nevi.33 Their histologic studies show that there is immediate thermal damage to the superficial nests of nevus cells and a subsequent remodeling of superficial connective tissue after multiple treatments with the normal-mode ruby laser. Although the papillary dermal structure was maintained, scar tissue would develop, which, once greater than 1 mm in thickness, would mask underlying residual nevus cells. This histologic finding was consistent in patients with a good cosmetic result. There were no cases of melanoma in these patients.33
Other investigators have reported better clinical results when combining the normal-mode ruby laser and the Q-switched ruby laser.38,42-44 The Q-switched ruby laser has been found to be effective at selective photothermolysis of superficial pigmented cells; however, deeper dermal melanocytic cells persist.39,47 When the lesion is treated first with the normal-mode ruby laser, then followed by treatment with the Q-switched ruby laser, Kono and investigators found that the nevomelanocytes in the epidermis, papillary dermis, and upper reticular dermis were completely disrupted.40 This combination laser therapy of CMNs is reported to yield good cosmetic results.38,42-44 The CO2 laser, which is nonselective, has also been reported by one group to have a good outcome in a series of seven patients with the longest follow-up being 6 years, with no report of malignancy in any of the seven patients.45
Because of the potential for malignant conversion of CMNs, surgical excision remains the standard of care for treatment of these lesions.32 The persistence of residual nevus cells and its potential for malignant transformation also generates concern regarding the treatment of CMNs, particularly giant CMNs, with laser ablation.48,49
The decision to use laser ablation to treat a congenital nevus should be based on the size and location of the lesion, the lesion's histology and malignant potential, and the surgeon's experience. If a lesion is small enough to be excised and repaired with an inconspicuous scar and without deformity, surgical removal may be prudent. Although it may require more than one treatment, ablation of a small lesion that has low malignant potential is also reasonable, so long as the appropriate laser is selected. Lesions that are multiple or that cover a large surface area may be amenable to laser treatment, particularly when excision and reconstruction may result in mutilation. The physician should educate the patient and parents regarding the potential for recurrence and hyper-or hypopigmentation.
Histology of the lesion should influence the surgeon's decision concerning which laser will be appropriate. CO2 lasers are nonselective for melanin because all water-containing cells absorb its wavelength. It may be useful for treatment of superficial epidermal pigmented lesions. The erbium-YAG laser is also nonselective but may be useful in ablation of epidermal lesions. More highly selective laser options include flashlamp-pumped pulsed dye, Q-switch Nd:YAG, Q-switch ruby, and Q-switch Alexandrite lasers. The Q-switch ruby and Q-switch Alexandrite lasers are particularly effective for pigmented lesions within the dermal layer.
The malignant potential of a pigmented lesion must be a factor when considering laser ablation. Although surgical excision is the standard for treatment of CMN, investigations into laser photothermolysis of melanocytes in large CMN introduce the possibility of treatment without the associated morbidities of excising large areas of integument.36-46 This modality in treatment of CMN is relatively new. The longest follow-up in the literature at this point is just more than 8 years.36 Although lasers selective for melanin may obliterate melanocytes, some melanocytic cells in the deeper dermis may be left behind. Theoretically, reduction in the melanocyte load may reduce the presence of cells that have malignant potential. However, it is unknown whether there is a higher intrinsic malignant potential in CMN melanocytes or the malignant potential is a function of the higher number of melanocytic nevi.16 Concern has been expressed that the tissue changes resulting from laser photothermolysis of CMNs may result in difficulty with monitoring for signs of malignant transformation in pigmented cells left behind in the deeper dermal layers.50
Clinical acumen is necessary when using laser to treat congenital pigmented lesions. If the number of passes or the laser settings are selected inappropriately, irreparable damage may occur. Accurate diagnosis of the lesion with an understanding of any possible associated pathology is imperative before treatment (Fig 2). Although surgical excision may be more appropriate with certain lesions, laser ablation is an effective modality in the surgical armamentarium for treatment of congenital pigmented lesions.
1. Mishima Y, Mevorah B. Nevus
of Ota and nevus
of Ito in American Negroes. J Invest Dermatol 1961;36:133-154
2. Trese MT, Petit TH, Froos RY, et al. Familial nevus
of Ota. Ann Ophthalmol 1981;13:855-857
3. Haim T, Meyer E, Kerner H, et al. Oculodermal melanocytosis (nevus
of Ota) and orbital malignant melanoma. Ann Ophthalmol 1982;14:1132-1136
4. Liu JC, Ball SF. Nevus
of Ota with glaucoma: report of three cases. Ann Ophthalmol 1991;23:286-289
5. Hartmann LC, Oliver GF, Winkelmann RD, et al. Blue nevus
of Ota associated with dermal melanoma. Cancer 1989;64:182-186
6. Shaffer C, Walker K, Weiss GR. Malignant melanoma in a Hispanic male with nevus
of Ota. Dermatology 1992;185:146-150
7. Alster TS, Williams CM. Treatment of nevus
of Ota by the Q-switched Alexandrite laser
. Dermatol Surg 1995;21:592-596
8. Goldberg DJ, Nychay SG. Q-switched ruby laser
treatment of nevus
of Ota. J Dermatol Surg Oncol 1992;18:817-821
9. Geronemus RG. Q-switched ruby laser
therapy of nevus
of Ota. Arch Dermatol 1992;128:1618-1622
10. Chan HH, King WW, Chan ES, et al. An in vivo trial comparing the patients' tolerability of Q-switched Alexandrite (QS Alex) and Q-switched neodymium: yttrium-aluminum-garnet (QS Nd-YAG) lasers in the treatment of nevus
of Ota. Laser
Surg Med 1999;24:24-28
11. Lu Z, Chen JP, Wang SX, et al. Effect of Q-switched Alexandrite laser
irradiation on dermal melanocytes of nevus
of Ota. Chin Med J 2000;113(l):49-52
12. Lu Z, Chen JP, Wang XS, et al. Effect of Q-switched Alexandrite laser
irradiation on epidermal melanocytes in treatment of nevus
of Ota. Chin Med J 2003;116(4):597-601
13. Ueda S, Isoda M, Imayama S. Response of naevus of Ota to Q-switched ruby laser
treatment according to lesion colour. Br J Dermatol 2000;142:77-83
14. Kopera D, Hohenleutner U, Stolz W, et al. Ex vivo quality-switched ruby laser
irradiation of cutaneous melanocytic lesions: persistence of S-100-, HMB-45-, and Masson-positive cells. Dermatology 1997;194(4):344-350
15. Dohil MA, Baugh WP, Eichenfield LF. Vascular and pigmented birthmarks. Pediatr Clin North Am 2000;47(4):783-812
16. Carpo BG, Grevelink JM, Grevelink SV. Laser
treatment of pigmented lesions in children. Semin Cutan Med Surg 1999;18(3):233-243
17. Hurwitz S. Clinical Pediatr Dermatol (ed 2). Philadelphia: Saunders, 1993
18. Alster RS. Complete elimination of large café-au-lait birthmarks by the 510-nm pulsed dye laser
. Plast Reconstr Surg 1995;96:1660-1664
19. McLean DI, Gallagher RP. ‘Sunburn’ freckles, café-au-lait macules, and other pigmented lesions of schoolchildren: The Vancouver Mole Study. J Am Acad Dermatol 1995;32:565-570
20. Landau M, Krafchik BR. The diagnostic value of café-au-lait macules. J Am Acad Dermatol 1999;6:877-890
21. Shimbashi T, Kojima T. Ruby laser
treatment of pigmented skin lesions. Aesth Plas Surg 1995;19:225-229
22. Tan OT, Morelli JG, Kurban AK. Pulsed dye laser
treatment of benign cutaneous pigmented lesions. Lasers Surg Med 1992;12:538-542
23. Fitzpatrick RE, Goldman MP, Ruiz-Esparza J. Laser
treatment of benign pigmented epidermal lesions using a 300-ns pulse and 510-nm wavelength. J Dermatol Surg Oncol 1993;18:341-347
24. Grekin RC, Shelton RM, Geisse JK, et al. 510-nm pigmented lesion dye laser
: its characteristics and clinical uses. J Dermatol Surg Oncol 1993;19:380-387
25. Shimbashi T, Kamide R, Hashimoto T. Long-term follow-up in treatment of solar lentigo and café-au-lait macules with Q-switched ruby laser
. Aesth Plast Surg 1997;21:445-448
26. Walton RG, Jacobs AH, Cox AJ. Pigmented lesions in newborn infants. Br J Dermatol 1976;95:389-396
27. Gari LM, Kopf AW. Melanomas arising in large congenital
nevocytic nevi: a prospective study. Pediatr Dermatol 1998;5:151-158
28. Kopf AW, Bart RS, Hennessey P. Congenital
nevocytic nevi and malignant melanomas. J Am Acad Dermatol 1979;1:123-130
29. Quaba AA, Wallace AF. The incidence of malignant melanoma (0 to 15 years of age) arising in ‘large’ congenital
nevocellular nevi. Plast Reconstr Surg 1986;78:174-181
30. Pilney FT, Broadbent TR, Woolf RM. Giant pigmented nevi of the face: surgical management. Plast Reconstr Surg 1967;40:469-474
31. Lawrence CW. Treatment options for giant congenital
naevi. Clin Dermatol 2000;25:7
32. Bittencourt FB, Marghoob AA, Kopf AW, et al. Large congenital melanocytic nevi
and the risk for development of malignant melanoma and neurocutaneous melanocytosis. Pediatrics 2000;106(4):736
33. Imayama S, Ueda S. Long-and short-term histological observations of congenital
nevi treated with the normal-mode ruby laser
. Arch Dermatol 1999;135:1211-1218
34. Lapiere K, Ostertag J, Van De Kar T, et al. A neonate with a giant congenital
naevus: new treatment option with the erbium:YAG laser
. Br J Plast Surg 2002;55:440-442
35. Kono T, Ercocen AR, Kikuchi Y, et al. A giant melanocytic nevus
treated with combined use of normal mode ruby laser
and Q-switched Alexandrite laser
. J Dermatol 2003;30:538-542
36. Kopera D, Hohneleutner U, Stolz W, et al. Ex vivo quality-switched ruby laser
irradiation of cutaneous melanocytic lesions: persistence of S-100-, HMB-45-, and Masson-Positive cells. Dermatology 1997;194:344-350
37. Michel JL. Laser
therapy of giant congenital melanocytic nevi
. Eur J Dermatol 2003;13:57-64
38. Nelson JS, Kelly KM. Q-switched ruby laser
treatment of a congenital
. Dermatol Surg 1999;25:274-276
39. Kono T, Ercocen AR, Chan HHL, et al. Effectiveness of the normal-mode ruby laser
and the combined (normal-mode plus Q-switched) ruby laser
in the treatment of congenital melanocytic nevi
: a comparative study. Ann Plast Surg 2002;49:476-485
40. Kono T, Nozaki M, Chan HHL, et al. Combined use of normal mode and Q-switched ruby lasers in the treatment of congenital
melanocytic naevi. Br J Plast Surg 2001;54:640-643
41. Noordzij MJ, van den Broecke DG, Alting MC, et al. Ruby laser
treatment of congenital melanocytic nevi
: a review of the literature and report of our own experience. Plast Reconstr Surg 2004;114:660-667
42. Reynolds N, Kenealy J, Mercer N. Carbon dioxide laser
dermabrasion for giant congenital melanocytic nevi
. Plast Reconstr Surg 2003;111:2209-2214
43. Grevelink JM, van Leeuwen RL, Anderson RR, et al. Clinical and histological responses of congenital melanocytic nevi
after single treatment with Q-switched lasers. Arch Dermatol 1997;133:349-353
44. Nelson JS, Applebaum J. Treatment of superficial cutaneous pigmented lesions by melanin-specific selective photothermolysis using the Q-switched ruby laser
. Ann Plast Surg 1992;29:231-237
45. Burd A. Laser
treatment of congenital melanocytic nevi
. Plast Reconstr Surg 2004;113:2232-2233
46. Woodrow SL, Burrows NP. Malignant melanoma occurring at the periphery of a giant congenital
naevus previously treated with laser
therapy. Br J Dermatol 2003;149:886-888
47. Gosain AK, Santoro TD, Larson DL, et al. Giant congenital
nevi: a 20-year experience and an algorithm for their management. Plast Reconstr Surg 2001;108:622-636
48. Grossman MC, Anderson RR, Farinelli W, et al. Treatment of café-au-lait macules with lasers: a clinicopathologic correlation. Arch Dermatol 1995;131:1416-1420
49. Elder D. Lever's histopathology of the skin. Philadelphia: Lippincott-Raven, 1997, 624-684
50. Caputo R, Gelmetti C. Pediatric Dermatology and Dermatopathology: A Concise Atlas. London: Martin Dunitz, 2002, 204