Lentigo Maligna and Lentigo-Maligna Melanoma Wallace H

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Lentigo Maligna and Lentigo-Maligna Melanoma Wallace H. Clark, Jr., M.D., and Martin C. Mihm, Jr., M.D.

PRIMARY HUMAN MALIGNANT MELANOMAS occur in thre clini- caIly and histologically distinct forms which have been designated superficial spreading melanoma, nodular melanoma, and lentigo-maligna melanoma."-2 One of these, lentigo-maligna melanoma, has been discussed infrequently outside dermatologic literature until recently.35 This paper will describe lentigo-maligna (L-M) melanoma (Hutchin- son's melanotic freckle or circumscribed precancerous melanosis of Du- breuilh). This Idnd of malignant melanoma begins as a small, irregular, freckle-like lesion and then evolves over many years in a distinctive way to become an invasive malignant melanoma distinguishable from the other forms of melanoma. The early, noninvasive stages of the process similar to a freckle will be referred to as lentigo maligna and the later invasive stages as L-M melanoma; this malignant melanoma occurs almost exclusively on exposed surfaces of the body and has a better prognosis than other forms of melanoma_.2' Our first objective will be the detailed description of lentigo maligna and L-M melanoma, differentiat- ing this process from other forms of malignant neoplasia affecting epidermal melanocytes. We will describe the clinical features, gross morphology, histogenesis, and differential diagnosis. Secondly, we will present a tabulation of all reported cases of L-M melanoma since Sir Johnathan Hutchinson's orginal descriptions appeared in a series of papers just before the turn of the century.7-" Materials and Methods Tlhis study is based upon 13 cases of lentigo maligna and 35 cases of L-M melanoma observed at the Massachusetts General Hospital since 1934. Prior to October 1965 the cases were selected on the basis of availability of good sections of the prnmary lesion and adequate follow-up data. Eight cases of lentigo maligna and nine cases of L-M ma observed between October 1965 and October 1967 have been studied in great detaiL Firstly, the primary lesion has been min by the authors in the Pigmented Lesion Clnic of the hospital Seoondly, the gross

From the Department of Pathology and of Dermatolgy, Massachusetts General Hospital and Harvard Medical SchooL Boston, Mass. Supported by Research Grant CA.06221 from the National Cancer Institute, and a grut from the Massachuset Division of the American Cancer Society. Accepted for publication Dec. 20, 1968. Address for reprint requests: Dr. Wallace H. Clark, Jr., Deprtment of Pathology, Temple University School of Medicine, 3400 N. Broad Street, Philadelphia, Penn. 19140. Present address: U. S. Public Health Servic HospitaL Staten Isln, N.Y. 39 40 CLARK AND MIHM Vol. 55, No. I specimen has been described by us and serially embedded in paraffin. From each paraffin block 20-40 contiguous sections have been stained with hematoxylin and eosin, Masson's trichome, and periodic acid-Schiff stains. Prior to dissection of the gross specimen, samples were taken for electron microscopy, the specimen photo- graphed, and a diagram of the various section levels made. The sections prepared for light microscopy were compared with the section diagram and with enlarged colored photographs; thus, microscopic interpretation was constantly related to the exact gross appearance. The histologic data were compared with clinical data derived from charts and patient examination, and much of the comparative data was analyzed by computer. Further details of methods employed are given in other publications.",2"12 Observations In the following descriptions lentigo maligna and L-M melanoma are at times considered separately, but in spite of this division for descriptive purposes, we regard these two lesions as representing the early and late stages of a single process. The sole criterion separating lentigo maligna from L-M melanoma is the presence of invasion in the latter. We have no evidence directly relating to the precentage of lentigenes maligna which become invasive, although Davis, Pack, and Higgins 4 cite a figure of about 30%, corresponding to the figure of 33%o proposed by Miescher in 1933.13 However, as Jackson, Williamson, and Beattie3 state: "ob- viously this is only a guess." Clinical Features Lentigo Maligna A total of 13 lesions were present on the sldn of 13 patients, one of whom had three additional L-M melanomas. Eight patients were male and five were female. The average age at the time of diagnosis was 65 years, and the average age at the time of onset 47 years. On casual in- spection the affected areas were irregular in outline, tan, and freckle-like (Fig. 1). More closely examined, the colors varied from tan to brown, and observations with a hand lens usually showed minute dark brown to black flecks. The average lesion occupied 2.7 sq. cm.; the smallest was 0.3 by 0.5 cm., and the largest 3.3 by 3.3 cm. All of the lesions were on the head and neck, excluding the scalp, except one located between the scapulas and another located on the foreann. L-M Melanoma A total of 37 lesions were diagnosed in 35 patients; one man had three such neoplasms. Of the patients, 19 were male and 16 were female. The lesions typically presented irregular, geographic borders, and their color varied from brown to dark blue to black, with even an occasional white or opalescent-blue/grey area (Fig. 2). Upon examination with the Apri 1969 STAGES OF LENTIGO MELANOMA 41 hand lens, the tan and brown areas often demonstrated black stippling or flecking, a feature often seen in lentigo maligna. The color placement was haphazard. The surface of these lesions was mainly flat, but in certain places slightly raised, indurated areas or even frank tumor nodules were evident; such areas were usually black and showed histologic invasion. Thus, the fully developed primary lesion was a large, multi- colored, hyperpigmented area, studded with an occasional nodule or nodules. The authors have observed a few examples of flat lesions with microscopic invasion. The average area occupied by the lesions was 8.4 sq. cm with the smallest and largest lesions measuring 0.2 by 0.2 cm. and 7.5 by 6.0 cm., respectively. The lesions were present primarily on exposed surfaces; all but five were on the head and neck Of these five, two were present on the pretibial area, two on the dorsum of the wrist, and one on the back The median age of the patients was 70 years at the time of histologic diagnosis. The average age at onset of the lesion was approximately 60.6 years. The youngest and oldest patients in the group were 45 and 96 years, respectively. In this series, according to the patients' recollections, the longest period of existence of lentigo maligna prior to the appearance of frank tumor nodules was 50 years, and the shortest duration was 4 months. A noteworthy aspect of the behavior of the primary lesion was the history strongly suggesting regression of the neoplasn. Previously hyperpigmented sites were described by patients as becoming white or of normal sldn color. Almost complete disappearance of the lesion has been observed.'3'14 Lesions diagnosed histologically as L-M melanoma with punch biopsy, but not removed because patients refused therapy, have been observed to disappear; this phenomenon has been documented photographically.14 Although these regressive phenomena occurred infrequently,8'9"4 the superimposition of white on a brown-black lesion was striking and virtually diagnostic of L-M melanoma, although a similar phenomenon may be seen occasionally in superficial spreading melanomas.

Surviva Data of L-M Melanoma Of the 35 patients with L-M melanoma, 3 died of malignant melanoma: one at 8 years 2 months, another at 1 year 10 months, and the third at 1 year nine months following histologic diagnosis. Of the 18 patients alive and well without disease, the average follow-up time was 5.2 years, the shortest time being 2 weeks, and the longest 13 years 10 months. The median follow-up time calculated on 15 of the 18 patients was 4 42 CLARK AND MIHM Vol. 55, No. 1 years. Of the remainder of the patients, 9 have died of causes other than malignant melanoma. Five are lost to follow-up. In addition to the patients who died of metastatic malignant melanoma, 3 others have developed nodal metastases. One of these 3 died 2 years after diagnosis of causes other than malignant melanoma. The other 2 are living and well, 2 and 4 years, respectively, following nodal metastases, with no present evidence of malignant melanoma. Histologic Features We view the clinical evolution of this particular kind of malignant melanocytic tumor as being characterized by a centrifugally spreading hyperpigmented area that, in time, shows progressive changes in color; the color changes include progression from uniform tan to brown to reticulated black to black flecks and finally to solid black. Each new color or pattern of color is superimposed upon the previous colors; the new color does not replace the old, but becomes associated with it. Thus, the fully developed primary lesion of L-M melanoma has areas that are unifonnly tan, presumably of identical color with the tan freckle-like lesion that was the original grossly visible evidence of the neoplasm. Histologically, the various colors of a single lesion of L-M melanoma, or a series of lesions varying from tan to black, describes, therefore, the chronologic histogenesis of lentigo maligna and L-M melanoma. The appearance of uniform black color usually is followed by surface irregularity and frank tumor nodules. The histology associated with these topo- graphic changes is usually that of frankly invasive melanoma. In the following descriptions the histology of any particular color is applicable to both lentigo maligna and L-M melanoma; the presence or absence of invasion into the dennis is the only criterion separating one disease stage from the other.

Tan Areas There is an increased number of melanocytes in the basal regions of the epidermis (Fig. 3 and 4); the melanocytes may be normal (Fig. 4) or abnormal (Fig. 3). The abnormal forms have large nuclei, prominent or multiple nucleoli, and at times a decrease in cytoplasmic cross-sectional area relative to nuclear cross-sectional area (Fig. 5 and 6). Den- drites of the normal and abnormal cells may be prominent in tan, as well as in brown or black, areas (Fig. 7). Some abnormal cells may be multinucleated (Fig. 8). The cells of tan areas usually are individually disposed, being separated from each other by one or more keratinocytes (Fig. 3 and 4); the presence of nests is rare. If an entire lesion is uni- Apnl 1969 STAGES OF LENTIGO MELANOMA 43 formly t it is unlikely that imvasion will be observed on microscopic study; we have seen this, but in only a single case. The diagnosis of lentigo maligna cannot be made by demonstrating only an increase in the number of melanocytes. One can be confident of the diagnosis when normal and abnormal melanocytes are seen in the histologic prepara- tions; the abnormal forms should be distinctive and increased in number (Fig. 5 and 6), for in actinically damaged skin of older persons an occasional bizarre melanocyte may be observed.5

Brown Areas The changes are similar to those just described, except melanocytes are even more numerous (Fig. 9-11). Nest formation is still uncommon. Small strips of cells in the basal region may be composed entirely of normal and abnormal melanocytes; at some sites these cells completely replace the normal basal keratinocytes (Fig. 10).

Reticulated Black Areas and Areas With Black Flecks on a Brown Background The small black areas are due to the presence of a large number of mostly abnormal melanocytes disposed as a uni- or multilayered strip of cells immediately above the basement membrane, separating the keratinocytic epidermis from the underlying connective tissue (Fig. 12). The black flecks usually are caused by the formation of melanocytic nests with frankly bizarre cells (Fig. 13-15). Flat Black Areas These areas are due to confluence of cell patterns responsible for reticulated and flecked black areas; such black areas histologically demonstrate large accumulations of normal and abnormal melanocytes lying above the basement membrane disposed in cords, strips, and nests (Fig. 16 and 17).

Areas with Surface Irreguarity and Tumor Nodules Surface irregularity usually is associated with the accumulation in the dermis of a mixture of malignant melanocytes, inflammatory cells, and melanophages (Fig. 18 and 19). These cells tend to be confined within the papillary dermis and, in most instances, show little tendency to protrude extensively between the collagen bundles of the reticular dermis. As the tumor cells in the papillary dermis increase in number, the apparent restriction by the upper border of the reticular dermis results in an irregular surface elevation. Thus, surface irregularity is frequently a sign of invasion (Fig. 19 and 20). 44 CLARK AND MIHM Vol. 55, No. 1 Relatively smooth, circumscribed nodules are composed of rather pure collections of malignant cells, which are situated beneath a flat- tened epidermis and show some tendency to stop at the papillary-reticular dermal interface. In the case of tumor nodules, however, the deeper cells may also invade the reticular dermis or even extend to the subcutaneous fat. Thus, L-M melanoma, in time, may show the same invasive patterns as any of the melanomas. We classify invasion in all of the melanomas into five levels, which we have described in detail else- where.1'2 Briefly, the invasion levels are as follows: Level I, all demon- strable tumor is above the basement membrane; Level II, there is invasion into the papillary dermis without extension to the reticular dermis; Level III, the tumor fills the papillary dermis and extends to, but not into, the reticular dermis; Level IV, the tumor extends into the reticular dermis; Level V, the tumor extends into the subcutaneous fat. Occasionally, striking keratinocytic hyperplasia and consequent surface hyperkeratosis may be observed in all three kinds of malignant melanoma (Fig. 20). One of us 1 previously had classified melanoma with such verrucous changes as a separate kind of melanoma, until it became clear that such associated keratinocytic hyperplasia was of little biologic significance and did not warrant the use of a separate category.

Translucent Blue Areas with Depigmentation The histology of the flat, translucent blue areas are characterized by a large number of melanophages and mononuclear inflammatory cells deep to a relatively normal epidermis (Fig. 21 and 22). In time, completely depigmented areas may be seen within and around the tumor, and these show a histologic structure virtually indistinguishable from the surrounding skin. Differentiation Between L-M Melanoma and Superficial Spreading Melanoma Clinical Features L-M melanoma must be distinguished from superficial spreading (SS) melanoma. The surface of the latter is principally raised. Its elevated nature results from the presence of numerous small, irregular, round, flat-topped, and confluent nodules. Additionally, SS melanoma exhibits an array of colors which include not only tan, brown, and black, but also pink, blue, grey, and even white. These various hues lie side by side in a haphazard fashion resulting in a lesion with a bizarre appearance. L-M melanoma also demonstrates variation in hue, but the variation mainly consists in different shades of brown, although white and blue may be observed occasionally. Flat, discolored areas usually form much Api 1969 STAGES OF LENTIGO MELANOMA 45 of the gross lesion of L-M melanoma, while flat areas often only form a peripheral rnm about the elevated portions of SS melanoma. Elevation and striking color variation, especially including shades of rose or pink, are the principal morphologic features which characterize SS melanoma. Several other clinical aspects of SS melanoma are distinctive. First, this tumor is usually somewhat smaller than L-M melanoma. It may occur anywhere on the body surface, but the commonest sites of distribution are on the leg, below the knee, on the sole of the foot, and on the neck, whereas L-M melanoma, in the vast majority of instances, occurs on the exposed surfaces, especially on the head and the neck. Finally, the peak incidence of SS melanoma occurs at median age 56.0 years and that of L-M melanoma at median age 70.0 years. Breaking down the figures for overall mortality due to metastatic disease, about 45%o is caused by SS melanoma and about 127c by L-M melanoma.2

Histologic Features The neoplastic cells of any kind of malignant melanoma invasive to Levels III, IV, or V may be similar, regardless of whether the entire lesion was classified as SS- melanoma, nodular melanoma, or L-M melanoma. However, lesions of lentigo maligna, a considerable portion of the primary lesions of L-M melanoma, and SS melanoma are located intra-epidermally. Multiple sections through these intra-epidermal portions are required to distinguish the processes from each other. Lentigo maligna and L-M melanoma commonly show almost contiguous intra-epidermal melanocytes that are strikingly pleomorphic (Fig. 23). Some of these cells are virtually normal, while others may be quite bizarre and multinucleated (Fig. 4-6, 8, 23, and 24). In SS melanoma, on the other hand, contiguous intraepidermal melanocytes, although quite abnormal in structure, are similar to each other; such similarity results in a relatively monomorphous appearance when compared with L-M melanoma (Fig. 25). In L-M melanoma a pagetoid distribution of melanocytes is relatively rare, while it is common in many portions of SS melanoma (Fig. 25). Melanocytic nest formation is present in virtually every section of SS melanoma (Fig. 26), but it is less common in L-M melanoma. In addition, the cells of the nests of L-M melanoma are pleomorphic (Fig. 5, 6, 8, and 17), whereas the cells in nests of SS melanoma are rather uniformly atypical (Fig. 25 & 26). Spindle cells are the most common form of melanoma cell seen in L-M melanoma (Fig. 19 and 20), and epithelioid cells are the dominant type in SS melanoma (Fig. 26). Finally, there are ultrastructural differences between the intra-epidermal cells of L-M melanoma and those of SS 46 CLARK AND MIHM Vol. 55, No. 1 melanoma, which have been described in detail in a separate publication.12 Briefly, the essence of these ultrastructural differences is as follows: The dominant cell of the intra-epidermal portion of SS melanoma is large, with an abundance of cytoplasm and a large nucleus; the cell is enlarged without significant alteration of the nucleocytoplasmic ratio. The nucleolus is prominent with some infolding of the nuclear membrane, but the striking abnormalities are cytoplasmic. The cytoplasm is crowded with abnormal melanosomes; these organelles comprise perhaps 50%o of the cross-sectional cytoplasmic area as compared with 10%o or less in normal cells. Each organelle is abnormal: They are spherical rather than ellipsoidal in outline; filaments with a distinctive 85 A helical pitch are formed as in the normal cell, but filament cross-linkage does not occur; melanization proceeds along certain filaments, but complete organelle melanization fails to take place. The abnormal organelles, so formed, are transferred to the keratinocytic system. The dominant cell of the intra-epidermal portion of L-M melanoma is quite different from the normal melanocyte and that of SS melanoma. The malignant melanocyte of L-M melanoma is large, but the increase in size is due almost entirely to increased nuclear size. Deep indenta- tions of the nuclear membrane are the rule. The cytoplasm is often only a narrow rim about the nucleus. Melanosomes may be decreased, normal, or increased in number; mnelanosomal filaments form, cross-linkage of filaments occurs, and melanization per organelle may approach normal.

Histologic Differentiation Between Melanocytic Nevi and Lentigo Maligna and L-M Melanoma In order to present the histologic differences between melanocytic nevi and L-M melanoma, one must clearly define a melanocytic nevus. The true melanocytic nevi are developmental phenomena of the human melanocytic system, usually arising between the second and sixth year of life; they demonstrate an increased number of melanocytes, which are disposed in a specific way in a localized area of the skin. It is conceptually unfortunate that moles are regarded as benign neoplasms by some, and as nevi by other observers; a benign neoplasm implies a growth abnormality of a cellular system, and nevus implies a developmental malformation. Although we use the term melanocytic nevus because of its almost universal application to moles, we feel that such usage is inaccurate. One of the difficulties in the field of nevi and melanomas lies in the careless use of the terms "junctional activity" and "junctional nevus." Many microscopists call virtually any intra-epidernal nest of melanocytes a junctional nevus or junctional activity; for ex- April 1969 STAGES OF LENTIGO MELANOMA 47 ample, the nests shown in Fig. 14 and 17, although a part of lentigo maligna and L-M melanoma, would be called junctional activity by many observers, and the lesion would be called an active junctional nevus. Such use of the term junctional activity, therefore, may imply that virtually every neoplasm affecting epidermal melanocytes arises from a junctional nevus. However, if one compares the histology of the true melanocytic nevus (mole) with the histology of the processes described in this paper, the similarities between the two disorders are quite superficial to us. Such melanocytic nevi show, in their early stages, intra- epidermal melanocytes. The nuclei of these cells are spherical and uniformly blue when stained with hematoxylin; they possess a single small nucleolus, and are uniform in their relationship with each other. The intra-epidermal melanocytes may be disposed in nests and may be pagetoid in distribution, but the nuclei are normaL The dermal com- ponent of melanocytic nevi (moles) shows a series of orderly changes as one progresses into deeper levels of the dermis. Just below the basement membrane, the melanocytes may be large and pigmented as in the epidermis; in deeper portions of the dermis, however, they are smaller in size, show a pigment-free clear cytoplasm, and at times exhibit the neuroid patterns described by Masson.L Inlammatory cells are not commonly associated with nevi (moles). Inflammatory infiltrates only rarely accompany dermal accumulations of nevus cells. The study of the epidermal and dermal components of L-M melanoma, comparing them with the structures just emphasized, permits one to easily distinguish these melanocytic neoplasms from nevi (moles). The epidermal melanocytes of L-M melanoma possess pleomorphic nuclei; some are large and dark with prominent nucleoli and others are multinucleated. These atypical changes persist as the cells extend into the dermis; the cells do not go through a series of progressive, orderly changes as seen in nevi (moles). Inflammatory cells usually are associated with the accumulation of malignant melanocytes in the dermis in L-M melanoma, and there are usually many melanophages associated with the invasive cells.

Discussion Cdteda for Dignos L-M melanoma occurs primarily on the exposed surfaces of the body of elderly people of Caucasian extraction, most of whom have a fair com- plexion. Lentigo maligna, a premalignant lesion, is an irregular, tan, freclde-like process, usually about 0.5-1.5 cm. i diameter. Microscop- 48 CLARK AND MIHM Vol. 55, No. 1 ically, it demonstrates a distinct increase in the number of epidernal melanocytes, which vary from normal, to distinctly atypical, to frankly bizarre in structure. L-M melanoma, the malignant derivative of lentigo maligna, is irregular in outline and exhibits in its fully developed form a haphazard combination of colors, including tan, brown, and black, as well as elevated, dark, blue-black nodules, and occasionally depigmented or translucent blue areas. Histologically, the process is identical with lentigo maligna except for the presence of invasion of the dermis by malignant melanocytes. L-M Melanoma and Exposure to Sunlight There can be no question that this form of malignant rmielanoma occurs predominantly on the exposed surfaces of the body. We have observed this phenomenon consistently, as have other students of this disorder.9"10,18,"7'19 A few neoplasms occur, however, on nonexposed surfaces.5"0 The observations relating incidence to exposure implicate sunlight as an etiologic factor. Davis et al.2* in Australia, have discussed at length the relationship between sunlight and all forms of malignant melanoma. They point out a progressive increase in incidence of melanoma as one approaches the equator and then state that if "there were a direct cause and effect relationship between sunlight and this tumor one would expect the sites of melanoma and squamous and basal cell carcinomas to correspond but they do not." 20 These workers, however, did not distinguish L-M melanoma from other forms of melanoma in that particular publication; in our study, however, the distribution of lentigo maligna and L-M melanoma is similar to basal and squamous cell carcinoma. This clinical finding, the invariable histologic observation of dermal changes due to solar radiation, and the occasional histologic finding of solar keratosis and basal cell carcinoma, are all strong evidence that sunlight plays a significant role in the etiology of this melanocytic neoplastic disorder. Blologic Behavior of L-M Melanoma We have reasonable evidence that the evolution of L-M melanoma- from clinically normal skin, through lentigo maligna, to the invasive neoplasm-may last as long as 50 years. It is not uncommon, however, to find a lapse of 10-15 years between onset of a lesion and the appearance of frank malignancy. 10"1721'22 Such observations reasonably warrant the conclusion that there is intra-epidermal melanocytic proliferation for many years prior to the onset of overt melanocytic malignancy. Once L-M melanoma has developed, death due to metastasis is less com- April 196 STAGES OF LENTIGO MELANOMA 49 mon in other forms of melanoma.59J0"18"19'2 In our series, 12%o of persons with L-M melanoma died of metastatic melanoma. Jackson, Williamson, and Beattie 3 suggest, however, that L-M melanoma be- haves no differently than any other kind of melanoma; they observed and cite as evidence 8 deaths from the disease in 21 cases. Sportaneous _eressio of L-M Melanoma Dubreuilh 17 clearly recognized regression as an important aspect of the biology of this neoplasm. Several other authors, including Miescher,18 Justitz,M2 and Mishima,"4 have noted this phenomenon. The evidence for regression includes the appearance of translucent blue areas, white areas, and irregular white halos in and around the primary lesion. Histo- logically, such blue areas demonstrate melanophages deep to an essentially normal epidermis; wbite areas may have virtually normal microscopic appearance; white halos peripheral to the lesion are characterized by an absence of melanin in the epidermis. The phenomenon of partial regression does not necessarily indicate the onset of an inexorable series of changes that will lead to disappearance of the entire lesion; at times, in fact, there may be extension of the process in one area while regression takes place in another; rarely, the entire tumor clinically may disappear, only to be followed by a nodule of frank melanoma at the same site months or even years later.23 The significance of these regressive phenomena is obscure. Possibly they represent an expression of host resistance or some self-limiting mechanism within the neoplastic cells. If regression is a result of host resistance, it is possible that such resistance influences the primary neoplasm in a selectional way, resulting in the outgrowth of progres- sively more malignant groups of cells. In earlier publications 1,2 we have discussed host resistance acting in a selectional way on primary melanomas.

Importance of Disfnction Between L-M and SS Melanomas The observer who only occasionally sees primary malignant melanoma, either clinically or histologically, may have difficultv in distinguishing between L-M and SS melanomas. In this paper and in previous publications we have attempted to describe the features which diferentiate these neoplasms. We have discussed the differential points and compared gross and microscopic photographs with McGovern,23 Davis,24 and Milton 25 (Australian workers with extensive experience in the study of primary melanomas). These workers agree with us that SS and L-M melanomas are quite different entities, and further agree that there is 50 CLARK AND MIHM Vol. 55, No. 1 a nodular form of melanoma. They do not use the tern superficial spreading melanoma. McGovern originally called such tumors premalignant melanoses and now refers to them as pagetoid melanoma.23 As these tumors are different in prognosis, age incidence, regional distribution, and, probably, etiologic mechanisms, they should be distinguished in all studies of melanoma.

Rationale for Use of "Lentigo Maligna" and "Lentigo-Maligna Melanoma" A quite satisfactory historical case can be made for applying the term lentigomelanosis of Hutchinson 10,11 or circumscribed precancerous melanosis of Dubreuilh to the disorder described in this report. The use of the term lentigomelanosis of Hutchinson or the melanotic freckle of Hutchinson 4'5 has one great disadvantage-it does not permit one to distinguish between the noninvasive and the invasive stages of the neoplasm. Dubreuilh's term, on the other hand, implies that the process is entirely premalignant; in addition, the name is quite cumbersome. Al- though dermatologists, by nature, easily gravitate to the use of circumscribed precancerous melanosis of Dubreuilh, pathologists can hardly be compelled to use such a term in routine reports. Lentigo maligna and lentigo-maligna melanoma, terms derived in part from Dubreuilh26 and Hutchinson 10,11 are simple and easily defined. Conceptually, lentigo maligna is to lentigo-maligna melanoma as solar keratosis is to squamous cell carcinoma.

Analysis of the Literature: Lentigo Maligna and L-M Melanoma A recent article5 reviews extensively the publications concerning L-M melanoma; consequently, we will only tabulate (Table 1) all the reported cases of lentigo maligna and L-M melanoma that we have found, enu- merating the various authors and the cases they have contributed to the literature. With the inclusion of the recent series of Reese and Morgan 27 describing cases affecting the conjunctiva, there have been over 500 cases reported since the original observation of Hutchinson. Summary We have attempted to delineate the clinical features and gross and microscopic characteristics which distinguish lentigo maligna and lentigo-maligna melanoma from other forms of melanoma. Lentigo maligna and lentigo-maligna melanoma are names applied to early and late stages of the same neoplastic system affecting melanocytes; lentigo maligna applies to the noninvasive stage and lentigo-maligna melanoma to the invasive neoplasm. The lentigo-maligna melanoma disorder Apnl 1969 STAGES OF LENTIGO MELANOMA 51

Table 1. Cases of Lentigo Maligna and Lentigo-Maligna (L-M) Melanoma Previously Reported No. of cases Lentigo L-M Author mnaligna melanoma Hutchinson (1894) X 10 Dubreuilh (1912) w 7 8* Lane (1930)X 1 Shaw (1931) 1 Justitz (1935) 3 7 Miescher, Hiberlein, & Guggenheim (1936) - 2 Corsi (1938-1939) 3 Becker (1954) 0 4 Klauder & Beerman (1955) 5 Schuerrnann (1955) U 16 9 Grinspan & Abulafia (1956) 10 Herzberg (1956) 11 Walther (1956) - 2 Costello, Fisher, & DeFeo (1959) 10 Sulzberger, Kopf, & Witten (1959) 1 Mishima (1960) U 7 Moroni (1962) U 8 Petersen, Bodenham, & Uoyd (1962) U 7t Trapl et at. (1964) * 81 Schreus (1965) 2 Jackson, Williamson, & Beattie (1966)' 21 Fnederich & Schneider (1966) o 32 29 Mishima (1966) X 1 2 Hadida et al. (1966) X 2 Ollstein et al. (1966) i 18t Reese & Morgan (1967) 83 62 Wayte & Helwig (1968) ' 40 45 Clark & Mihm (1969, present report) 13 35 Total cases 202 396 * Dubreuilh included 25 cases in all: 10 we thom reported by Hutchinson, 10 were taken from other authors, and 5 cases he himself observed. t Seven cases we definitely rcognized as lenfigo-rnaligna melanoma. t We assume that aU cases were bgnt-inaligna melanoma. occurs primarily on the exposed cutaneous surfaces of the elderly. The tumor evolves slowly over many years, and tis evolution is characterized by changes in form and the superimposition of various hues of brown and black on an originally tan lesion. Late in the evolution of the tumor, and approximately coinciding with the change from lentigo maligna to lentigo-maligna melanoma, surface irregularities and frank tumor nodules appear. The histologic features associated with the various colors and surface irregularities are described in detaiL Lentigo- maligna melanoma is distinguished from superficial spreading melanoma. The relationship of lentigo-maligna melanoma to prolonged sunlight exposure is discussed, as is the phenomenon of spontaneous regression 52 CLARK AND MIHM Vol. 55, No. 1 of the neoplasm. Finally, all cases of lentigo maligna and lentigo-maligna melanoma reported in the literature have been tabulate-d. References 1. CLARK, W. H. "A Classification of Malignant Melanoma in Man Correlated with Histogenesis and Biological Behavior." In Advances in Biology of the Skin Vol. 8: The Pigmentary System. MoNTAGNA, W., and Hu, F., Eds. Pergamon, New York, 1967, pp. 621-647. 2. CLARK, W. H., FROM, L., BERNARDINO, E., and MImM, M. C. Histogenesis and biological behavior of primary human malignant melanomas of the skin. Cancer Res, 1969. 3. JACKSON, R., WILLIAMSON, G. S., and BEATrIE, W. G. Lentigo maligna and malignant melanoma. Canad Med Ass 1 95:846-851, 1966. 4. DAVIS, J., PACK, G. T., and HIGGINS, G. K. Melanotic freckle of Hutchinson. Amer J Surg 113:457-463, 1967. 5. WA1rE, D. M., and HELWIG, E. B. Melanotic frecle of Hutchinson. Cancer 21:893-911,1968. 6. MISiMA, Y. Melanocytic and nevocytic malignant melanomas. Cancer 20: 632-649, 1967. 7. HUTCHINSON, J. Notes on the cancerous process and on new growths in general. Arch Surg (London) 2:83-86, 1890. 8. HUTCH[NSON, J. On tissue dotage. Arch Surg (London) 3:315-322, 1892. 9. HUrCHINSON, J. On cancer. Arch Surg (London) 4:61-65, 1892. 10. HuVrcImSON, J. Lentigo-melanosis. A further report. Arch Surg (London) 5:253-256, 1894. 11. Hu-rciNSON, J. President's address at the Third International Congress of Dermatology. Arch Surg (London) 7:297-317, 1896. 12. CLARK, W. H., and BRETTON, R. "A Comparative Fine Structural Study of Melanogenesis in Normal Human Epidermal Melanocytes and Certain Human Malignant Melanoma Cells." In International Academy of Pathology Monograph: The Skin. HELWIG, E. B., Ed. Williams & Wilkins, Baltimore. In press. 13. MIESCHER, G. "Praecanceroeses Vortstadium des Melanoms, Praecanceroese Melanose." In Handbuch der Haut- und Geschlechtskrankheiten (Vol. 12, No. 3), JADAssoHN, J., Ed. Springer Verlag, Berlin, 1933, pp. 1005-1135. 14. Mismm, Y. Prophylaxis of malignant melanomas-melanosis circumscripta praecancerosa Dubreuilh distinct from junction nevus. Cutis 2:588-591, 1966. 15. MrrcHiLL, R. E. The effect of prolonged solar radiation on melanocytes of the human epidermis. J Invest Derm 41:199-212, 1963. 16. MASSON, P. My conception of cellular nevi. Cancer 4:9-38, 1951. 17. DUBREUn.E, W. De la m6lanose circonscrite pr6canc6reuse. Ann Derm Syph (Paris) 3 (ser. 5):129-151, 205-230, 1912. 18. KLAUDER, J. V., and BEERMAN, H. Melanotic freckle (Hutchinson), m6lanose circonscrite pr6canc6reuse (Dubreuilh). Arch Dermat Syph 71:2-10, 1955. 19. MISHIMA, Y. Melanosis circumscripta praecanoerosa (Dubreuilh): A non- nevoid premelanoma district from junction nevus. J Invest Derm 34:361- 375, 1960. April 1969 STAGES OF LENTIGO MELANOMA 53

20. DAvis, N. C., HEmoN, J. J., and McLEan, G. R. Malignant melama M Queensland-. Analysis of 400 skin lesions. Lancet 2:407-410, 196. 21. Coramo, M. J., FISHEB, S. B., and DEFEo, C. P. Melanotic freckle. Lentigo maligna. Arch Derm (Chicago) 80:753-771, 1959. 22. Jusrriz, H. Melanotishe Pricancerose. Dissetation. Druckereigenossens- chaft Aarau, Zmch, 1935. 23. McGovER, V. J. Personal communication. 24. DAvis, NEVLLE. Personal communicatin 25. MILTON, G. Psonal communication. 26. Dxnasunii, W. Lentigo main des viellards. Ann Derm Syph (Paris) 5 (ser. 3): 1092-1099, 1894. 27. RmEsz, A. B., and MoncAN, W. E. HI -Preanceo and Cancerous Meano- sis of Sin and Mucous Membranes." In Proceedings of the Internationa Workshop on Cancer of the Head and Neck, CoNL, J., Ed. Buttoth, Washinton, 1967, pp. 253-256. 28. LANE, C. W. Seni freckl& Arch Dema Syph 21:494-495, 1930. 29. Svw, H. C. Lentigo maligna: Report of one case treated with radium. Amer I Caew 15:1557-1569, 1931. 30. Mzscm, G., Hi Iw, L, and GuCMEM, L tYber flecktrmige Alterspigmentierungesi. Ihre Beziehungen zur meaanotero Pfnose und zur senilen Warze. Arch Dermat Syph 174:105-125, 1936. 31. Con, H. Three cases of mnltnose circonscite pr6cancereuse. Proc Roy Soc Med 32:261-263, 1938-1939. 32. Bxcm, S. W. Critical evalution of the so-calEd junctio nevus. J Invest Dem 22:217-223, 1954. 33. SCUEDANN, H. Melanosis circuinscripta praecancrosa- Aerztl Wschr 10: 49-53, 1955. 34. Gm.sAN, D., and ABuLAFIA, J. L go maligno de Hutchinson (melaii rc precan de Dubreuilh). Caracteres histopatol6gi cos y dia difeenial Arch Argent Dern 6:351-387, 1956. 35. HEbZBIG, J. J. Zur Diagnostik und Tlerapie der Melanocytoblastome. Arch KRin Exp Derm 203:142-202, 1956. 36. WALIn, VON D. tber die Melnosis circusaipta praecncerosa (Dubre- uiilh). Z Haut Gechlechtskr 20:286-290, 1956. 37. SuLmKz, M. B., KoPF, A. W., and Wrrrr.N, V. H. Pigmented nevi, benign juvenile melana and circumscribed precancerous melanois. Post- grad Med 26:617-631, 1959. 38. MoRoNI, P. Considerazioni suIla cura dei nevi pigmentati dei melanomi maligni e dela melanosi precancosa di DubreuihL Arch Ital Dern Vener 32:124-141,1962. 39. PrrzEw, N. C., BoDENRAM, D. C., and IoYD, 0. C. Malignant melanomas of tie scin. A study of the origin, development, aetiology, spread, treatment, and prognosis. Brt J Plast Surg 15:49-94, 97-116, 1962. 40. TiffpL, J., PALE&, L, ED3m, J., and Ku6iuA, M. Origin and development of skdn melanoblastoma on the basis of 300 cases. Acta Dermatovener (Stockholm) 44:377-380, 1964. 41. Scmyais, H. T. Melas sa et proliferativa Hutchinson Dubreuilh. Denn Wwhr 151:1015-1031, 1965. 54 CLARK AND MIHM Vol. 55, No. 1

42. FRiEDERICH, H. C., and SCHNEIDER, H. J., JR. Ergebnisse der operativen Behandlung der Melanosis circumscripta praeblastomatosa Dubreuiilb. Vorlaufige Mitteilung. Med Welt 17:2495-2500, 1966. 43. HADIA, E., BERANGER, J., SAYAG, J., and SAYAG, J. Naevo-carcinome sur m6lanose de Dubreuilh. BuU Soc Franc Derm Syph 73:519-520, 1966. 44. OLLSTEIN, R. N., KAPLAN, H. S., CRIaAIR, G. K., and LATTEs, R. Is there a malignant freckle? Cancer 19:767-775, 1966.

Legends for Figures The diagnosis assigned to the specimen is given at the beginning of each legend and is based upon the examination of all sections of the specimen and not just the section illustrated in the photomicrograph. For example, the section illustrated in Fig. 4 does not show invasion, but a nearby section did show invasion; thus, the legend to the micrograph begins "tan area, lentigo-maligna melanoma." Figures 3-20, when viewed in continuity, show our concept of the histogenesis of this neoplastic disorder of melanocytes histogenesis in time and thus in color from tan through black nodule. Fig. 1. Lentigo maligna. This lesion was located on the left forearm of a 53-year-old, fair-skinned female of Irish extraction (S.B.). It was 2.0 X 1.8 cm. in its greatest dimensions and had been developing slowly .for about 5 years. The irregular outline and haphazard combination of colors, from tan to dark brown-black, disposed in a flat lesion, are quite characteristic of lentigo maligna. Fig. 2. Lentigo matigna melanoma. This lesion developed on the right side of the neck of an 81-year-old rather dark male of Italian extraction (S.G.). It had been evolving over a 55-year period. Figure depicts the fully developed stage of lentigo-maligna melanoma. There are tan, brown, brown with black flecks, reticulated black, depigmented, and translucent blue areas. Histologic appearance of these various colors from this and similar specimens are shown in the ensuing photomicrographs. April 1969 STAGES OF LENTIGO MELANOMA 55

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Material in Fig. 3-26 was stained with hematoxylin and eosin. Fig. 3. Tan area, lentigo maligna. (I.P., 66-14,656 D.) Melanocytes are increased in number and vary considerably in size. There is a relative decrease in melanocytic cytoplasm. Nuclei are hyperchromatic, and show some variation in outline. X 256. Fig. 4. Tan area, lentigo-maligna melanoma. (C.B., 66-14,655 0.) Area is characterized by an increased number of large, but otherwise normal, melanocytes. Melanocytes are in the basal region and have an abundance of relatively clear cytoplasm. Illustrated area is about 0.6 cm. away from a site of frank invasion (shown in Fig. 18). X 256. April 1969 STAGES OF LENTIGO MELANOMA 57

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Fig. 5. Tan to brown area, lentigo-maligna melanoma. (S.G., 65-12,870 C.) Gross appearance of this lesion is illustrated in Fig. 2. In central portion of photomicrograph, near dermo-epidermal interface, there are several atypical melanocytic nuclei. X 640. Fig. 6. Tan to brown area, lentigo maligna. (D.G., 67-4081 K.) Frankly bizarre melanocytic nuclei are shown just above dermo-epidermal interface. X 640. Fig. 7. Dark brown to flat black area, lentigo-maligna melanoma. (C.B. 66-14,655 W.) In right lower portion of photomicrograph, there is a broad dendrite, which extends from basal region toward epidermal surface. Several less well resolved and smaller dendrites are also seen. X 640. Fig. 8. Tan to brown area, lentigo-maligna melanoma. (S.G., 66-12,870 D.) Gross lesion from which this section was prepared is illustrated in Fig. 2. In central portion of photomicrograph, just above the basement membrane, there is a giant, multinucleated melanocyte. X 640. April 1969 STAGES OF LENTIGO MELANOMA 59

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Fig. 9. Brown area, lentigo-maligna melanoma. (W.T., 67-12,473 A.) Basal region of epidermis is largely made up of melanocytes which have irregular and hyperchromatic nuclei. X 256. Fig. 10. Brown area, lentigo-maligna melanoma. (W.T., 67-12,473 A.) Keratinocytic epidermis is separated from the dermis by a rather broad strip of melanocytes. X 256. Fig. 11. Brown area, lentigo maligna. (D.G., 67-4081 K.) Almost every cell in basal region is a large, and somewhat atypical, melanocyte. X 256. Fig. 12. Dark brown area, lentigo-maligna melanoma. (B.C., 66-8504 I.) Almost half of the cells comprising the epidermis are melanocytes. There is a tendency to nest formation in left portion of photomicrograph. Solar degeneration of the dermis is advanced. X 256. Fig. 13. Brown area with black flecks, lentigo maligna. (L.H., 67-1786 I.) A nest of poorly cohesive melanocytes protrudes from the epidermis into the superficial dermis. We do not judge this to represent a site of invasion. Detailed structure of melanocytes comprising the nest is somewhat obscured by the large amount of melanin. This kind of melanocytic nest is common in the lentigo-maligna melanoma process, but is not seen in superficial spreading melanoma. Compare with Fig. 25 and 26. X 256. April 1969 STAGES OF LENTIGO MELANOMA 61

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Fig. 14. Brown area with black flecks. (B.C., 66-8504 J.) Melanocytes are disposed in large nests, which protrude well into the dermis. Within each nest there is considerable variation in structure of the melanocytic nuclei, and the cells are poorly cohesive. X 256. Fig. 15. Dark brown area with black flecks, lentigo-maligna melanoma. (S.G., 65- 12,870 S.) Melanocytic nests similar to those illustrated here are common in lentigo- maligna melanoma. The cells are spindle-shaped and again show some lack of cohesion. X 160. Fig. 16. Flat black area, lentigo maligna melanoma. (C.B., 66-14,655 J.) Entire dermo- epidermal interface is composed of continuous strips of atypical melanocytes or of confluent nests of melanocytes associated with a considerable amount of melanin. At left is a continuous strip of melanocytes extending along the external root sheath of a pilar unit-a common observation in lentigo maligna and lentigo-maligna melanoma. X 256. Fig. 17. Flat black area, lentigo-maligna melanoma. (C.B., 66-14,655 K.) The majority of cells above a scalloped basement membrane region are bizarre, heavily melanized melanocytes disposed in irregular confluent nests. X 256. April 1969 STAGES OF LENTIGO MELANOMA 63

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Fig. 18. Black elevated area with superficial tumor invasion, lentigo-maligna melanoma. (C.B., 66-14,655 J.) Distinctive basement membrane region separating atypical melanocytes from the dermis is no longer present. Central portion of figure shows an ill-defined nest of melanocytes merging with connective tissue of the dermis. x 256. Fig. 19. Black, nodule of invasive tumor, lentigo-maligna melanoma. (B.C., 66-8504 G.) Major portion of figure is composed of spindle-shaped melanocytes, which are the superficial portion of a deeply invasive nodule. X 256. Fig. 20. Black area with tumor invasion, verrucous surface, lentigo-maligna melanoma. (B.C., 66-8504 L.) In addition to spindle-shaped melanocytes similar to those in Fig. 19, there is also extensive keratinocytic hyperplasia with hyperkeratosis. X 160. April 1%96 STAGES OF LENTIGO MELANOMA 65

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Fig. 21. Flat, translucent blue area, lentigo-maligna melanoma. (S.G., 65-12,870 I.) This area was near center of lentigo-maligna melanoma seen in Fig. 2. There is an essentially normal epidermis except for a central focus of hyperpigmentation, and a dermis studded with melanophages and mononuclear inflammatory cells. x 256. Fig 22. Flat, translucent blue area, lentigo-maligna melanoma. (B.C., 66-8504 I.) Epi- dermis is essentially normal. Dermis shows numerous dark melanophages and advanced solar "degeneration;" such degeneration is associated invariably with the lentigo-maligna melanoma process. x 256. Fig. 23. Intra-epidermal melanoma cells with nest formation, lentigo-maligna melanoma. (R.W., 68-3748.) Pleomorphic melanocytes tend to ble disposed along dermo-epidermal interface and rarely show the strikingly pagetoid growth so characteristic of superficial spreading melanoma. Compare with Fig. 25 and 26. x 256. Fig 24. Intra-epidermal melanoma cells, lentigo-maligna melanoma. (S.G., 65-12,870 F.) Intra-epidermal melanocytes are pleomorphic and have relatively scant amount of cytoplasm when compared with superficial spreading melanoma. Compare Fig. 23 and 24 with Fig. 25 and 26. x 256. Fig 25. Intra-epidermal melanoma cells, superficial spreading melanoma. (P.G.. 64-5178 A.) Melanoma cells have distinctly pagetoid distribution, are relatively large with abundant cytoplasm, and, in relationship with each other, tend to be monomorphous. x 256. Fig. 26. Intra-epidermal melanoma cells, superficial spreading melanoma. (P.G., 64-5178.) Photomicrograph shows epithelioid melanoma cells, the kind commonly seen in superficial spreading melanoma and easily distinguished from the spindle-shaped melanoma cell so commonly seen in lentigo-maligna melanoma. Compare with Fig. 19 and 20. x 256.