Melanosis Circumscripta Praecancerosa (Dubreuilh)

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provided by Elsevier - Publisher Connector MELANOSIS CIRC[JMSCRIPTA PRAECANCEROSA (DUBRETJILIH)

A NON-NEVOID PIIEMELANOMA DISTINCT FROM JUNCTION NEVUS* YUTAKA MISHIMA, Ml).

Melanosis circumscripta praecancerosa of Du-monly black and by extension it may exceed the breuilh or infective senile freckle of Hutchinsonsize of the palm. The borders of the lesion are is a relatively uncommon lesion from which ma-irregular because the progression is not uniform lignant melanoma develops frequently. It is thethroughout the pigmented patch. Sometimes, while one part of the lesion is progressing, another purpose of this paper to examine the criteria bypart may show signs of regression. At the onset of which it can be distinguished from junction nevusmalignant transformation one observes thickening and to identify it as a non-nevoid prccanccrosis ofor induration in one portion of the patch which adult mclanocytcs. often produces pea to cherry-sized papules. It may become verrueous and may ulcerate and bleed CLINICAL REVIEW easily. The discoloration and thickness of the plaque is not uniform. The malignant melanoma arising from a pig- Mieseher (5) states that malignant melanomas mented plaque was first described clinically byoccur in about 30 per cent of the cases which Hutchinson. He named this pigmented plaqueincidence is considerably higher than that of infective pigment patch resembling superficialmalignant melanoma arising from junction nevus. melanosis (1) (1892) and lentigo-melanosis (2)On the other hand, Dubreuilh's melanosis is much (1894). less common than junction nevus. Dubreuilh gave it the name lentigo malin des Dubreuilh (4) observed an average period of vieillards (3) (1894) and mélanose circonscriteten years between the onset of the premalignant précancéreuse (4) (1912). Bayet (1895) termed itlesion and the development of malignant mela- "lentigo infectieux" and Miescber (5, 6) (1928)noma. Klauder and Beerman (15) recorded an called it "priicanceröse Melanose"; Hazen (7),average interval of 13 years; Mieseher (5), 29 "acquired mole"; Deckner (8) and Kumer andyears; Shaw (21), 31 years. In our group of 7 eases Lang (9), "tardive nevus"; Sachs (10), "junctionthe duration of the lesion was from 1 to 10 years nevus" and Allen (11), "dermoepidermal nevus".at the time of diagnosis. There were no malignant Becker, Sr. (12) termed it "lentigo maligna"changes in this lapse of time. classifying it as one type of junction nevus. Dubreuilh and Miescher stated that the Dubreuilh, Reese, Becker, Sr., Miescher,malignant melanoma is slow to develop from the Klauder-Beerman, and others reported a total ofpigmented lesion on the face, and lymph node about 50 cases. The following Table 1 shows theinvolvement does not occur early. Miescher localization and age of the patient at its onset. believed that generalization is very rare in the Dubreuilh's melanosis usually starts as a pin-case of facial lesions. Both authors agree that head sized, dark brown sepia spot. It is less com-on the extremities, malignant transformation develops more rapidly and generalization is also *Fromthe Departments of Dermatology, Wayne State University College of Medicine andmore frequent. Detroit Receiving Hospital (Hermann Pinkus, Klauder and Beerman (15) commented that M.D., Chairman) and the Detroit Institute ofafter appearance of the melanoma, particularly Cancer Research (William L. Simpson, M.D., Sci-on the face, regional lymph node involvement and entific Director), Detroit, Michigan. further metastasis is longer delayed than in the Supported in part by research grant RG-4435 and C-2072 from the National Institutes of Health,eases of malignant melanoma arising from junction U. S. Public Health Service, and in part by re-nevus. Dubreuilh's melanosis occurs frequently search contract DA-49-007-MD-584 from the Re-in older people, therefore it would appear many search and Development Division, Office of thepersons afflicted with this on the face may die of Surgeon General, Department of the Army. Abridgement of a portion of a thesis submittedother causes before malignant change takes place. by Dr. Mishima to the Faculty of the Postgraduate Reese (17—20) stated that Dubreuilh's melanosis School of Medicine, University of Tokyo, in partial of the conjunctiva pursues a more malignant fulfillment of the requirements for the degree ofcourse than that of the face and is more liable to Doctor of Philosophy in Dermatology and Syphi-undergo a malignant change than in the case of lology. Received for publication August 11, 1959. junction nevus. 361 TABLE 1 Clinical data on melanosis circumscripta praecancerosa Dubrenilh

Klauder-Beerman *Dubreuilh (4) Becker. Sr. (12, 14) Miescher (6) Reese (17) Mishima C Face 17 9 2 2 1 1 4 Ear 1 Eyelid 2 C Conjunctiva 4 1 17 Eyelid and conj 3 Mucous membrane.. 2 z Scrotum 1 0) Trunk 1 Extremities 7 1 4 1 Nucha 1 1 onset Age at between 18— be- between 19— average between 35- 65 average 40—50 40 48 between 30— 68 yrs.; tween 51; average about 70 70; average yrs. yrs. yrs. 66; average average 40 34—81 39 yrs. yrs. 56 yrs. 45 yrs. yrs. C * Of 35 cases C reported by Dubreuilh, 30 cases were compiledfrom the following author's reports: Boussion (1903), Bayet (1895), Thévenin (1898), Lamarque (1888), Hutchinson (1892, 1893), Claisse et Dartigues (1899), Nicolas et Durand (1909), Fox, W. (1911). In Dubreuilh's series the cases were almost equally distributed among males and females. TABLE 2 Clinical picture of melanosis circumscripta praecancerosa Dubreuilh

Case Age and Tumor Diameter Age at Beginning Clinical Diagnosis Recent Growth Remarks z No. Race Sex Site of (mm.) (Duration) Before Biopsy C _____ 02 02 1. White 54—M 1. cheek 18 x 21 48 yrs. old Melanotic freckle Quick growth and darker Dark brown with mottling. (4 yr.) within 1 yr. 2. White 60—M r. temple 12 x 11 57 yrs. old Senile keratosis Lately itching Brown papillomatous plaque (3 yr.) freckle 3. White 67—F r. cheek 24 x 19 66 yrs. old Melanotic freckle Recent darkening Large melanotic with hy- (1 yr.) perpigmentation at one edge reddish ele- 4. Japanese 52—M pre-auric- 16 x 11 42 yrs. old Pigmented seb- Within 4 mos. quick doubling \Terrucous, brown, ular (10 yr.) orrheic kera- growth, also heat flashes vated plaque on which 4 small tosis and itching during last 2 papular tumors are present. wks. 5. White 33—M r. arm (lat- 10 x 7 31 yrs. old 1. Pigmented No recent enlargement Dark brown; black pigmented eral sur- (2 yr.) nevus lesion, with slight elevation of ma- .5mm. face) 2. Possible C lignant mela- 01 noma 6. White 40—F post nuchal 13 x 8 37 yrs. old Junction nevus Late quick growth Flat, dark nevus area (3 yrs.) with 7. White 31—M shoulder 15 x 12 30 yrs. old Malignant mela- Few weeks before became Small, flat, pigmented lesion was sus- (1 yr.) noma larger and more papular a pole center, which pected to be undergoing activa- tion. 364 THEJOURNAL OF INVESTIGATIVE DERMATOLOGY

Fin. 1 (A). A 67 year old female. Lesion of one year's duration with recent darkening of color FIG. 1 (B). A 54 year old male with lesion of 3 years' duration. Both cases were confirmed histologically as Dubreuilh's melanosis circumscripta praecancerosa and treated by surgical excision.

Of Dubreuilh's 35 cases only three were fatal.neighboring cells. The nucleus of these cells is One of the patients who succumbed had con-large, vesicular and the protoplasm is light and junctival involvement and two had lesions of thehoneycombed. These cells may be pigmented or extremities. Involvement of lymph nodes wasentirely pigment free. Mitosis is absent. seen in only one patient who was well two years Corsi (24) pointed out the presence of large after their removal. pagetoid cells in Dubreuilh's melanosis which at Miescher (23) (1957) reported a case of morbusfirst might lead one to think that one was dealing Paget on the male genitals which had an intensivewith Bowen's disease, but closer examination pigmentation and resembled Dubreuilh's mela-showed these cells are in fact malignant melano- nosis. Steigleder (24) (1958) described a case ofblasts. Stout (25) noted that Paget cells sometimes Dubreuilh's melanosis on the scrotum and shafthad some resemblance to malignant melanoma of the penis which clinically and histologicallycells. resembled Miescher's case, however he classified Becker, Sr. (12) divided junction nevus and it as a superficial premalignant melanosis andjunctional activity into 3 distinct groups: 1.) pointed out that this is easily confused withquiescent, smooth, pigmented nevus, 2.) active, Paget's disease when it occurs in the genitalsmooth, pigmented nevus, 3.) lentigo maligna. region. Becker called Dubreuilh's melanosis, lentigo maligna, and noted lentigo maligna was the HISTOPATIIOLOGIC REVIEW advanced stage of junction nevus which had a Dubreuilh's melanosis has been described as alocation in the pathogenetic pathway from premelanomatous lesion or malignant melanomaquiescent junction nevus to malignant mela- in situ, the next step of which is penetration intonoma. He considered lentigo maligna different the dermis and the establishment of malignantfrom quiescent and active nevus in three respects: 1.) individual cells of the lesion show malignant melanoma.Klauder and Beerman (15) described the anaplasia rather than benign growth; 2.) the characteristic feature of the lesion as a change inmalignant cells are being worked through the the region of the basal cells, which is the precursorepidermis to the surface to be cast off with the of the segregation phenomenon of nevus cells.stratum corneum, and the dopa reaction is They adopted this from Dubreuilh, and addedstrongly positive in all these cells; 3.) round cell that individual cells of the basal layer seeminfiltration is present in the superficial dermis. larger and paler, and are separated by a gap from Miescher noted that the main histological TABLE 3

Dubreuilh'sMelanosisCircurnscripta Junction Nevus

1. Tendency to form well Rarely Almost always. circumscribed, massive cell nests 2. Dropping off phenomena No, not until changing to malignant Almost always shows a tendency melanoma to form intradermal or com- pound ncvus even though not changing to malignant melanoma. 3. Individual cells (1) protoplasma No syncytium-building, honey- Syncytium-building. homogene- combed and occasionally vaeuo- ous, oval or euboidal, usually lated; average size 10.2 px 6.3 p distinctly outlined. 18.6 p x 15.1 p (Quiescent), 16.5 ,.i x8.0ji (Active). (2) nucleus Irregular and shrunken Oval or round, predominately well outlined and compact. (3) size of nucleus Average 7.3 p x 3.9 p 8.6 p x 6.6 p (Quiescent), 8.9 p x 6.3 p (Active).

long axis of periearyon (4) ratio = . 1.40 2.16 (Quiescent), 1.85 (Active). long axis ofAverage nucleus

(5) nucleolus Cannot be identified Frequently can be identified; average 2.5 pdiameter. (6) melanin Carried in dendrites or honey- Carried in well outlined eyto- combed cytoplasm plasm. (7) general form Dendritie "clear cell" resemblingEpitheloid or activated nevus cell. normal melanoeyte (8) Comparison of pen- 1 4.4 (Quiescent) or 2.1 (Active). earyon size 4. Dopa reaction Strongly positive as hyperplastie Weakly or scarcely positive as less dendritie melanoeytes dendritie pigment cells. 5. Mitosis Occasionally found, two of our seven Rare. eases show it. 6. Malignant change fre- About 30—40% Infrequent. queney 7. Corium infiltration Chronic plasma cell infiltration with More mild and mainly composed lymphocytes. of lymphocytes. S. Malignancy of arisingLess malignant, metastasis and re- More malignant and metastasis malignant melanoma gional lymph node involvement very frequent. are very rarely observed. 9. Age at onset After middle age Usually before adolescence. 10. Clinical aspects Irregular, sepia brown, raisedSmooth, slightly raised, brown, plaques on which small tumors small, round or oval spot. frequently are found. The pig- Grows more slowly ment grouping of several spots by apposition of new elements. Spreads more rapidly, sometimes reaches the size of several centi- meters. 11. Changeability Progressive change, not only in Very stable. growth, but also in regression 12. Pathogenesis Segregation phenomena of melano- Segregated accumulation of nevus eytes cells.

365 366_sTHE JOURNALnat OF INVESTIGATIVE DERMATOLOGY r

S• ii;*W

FIG. 2. Melanosis circumscripta praecancerosa with hyperpiasia of the dendritic "clear cell" resembling normal melanocytes rather than nevus cells. Section stained with hematoxylin and eosin. X 913.

FIG. 3. Melanosis circumscripta praecaneerosa showing the hyperplasia of numerous strongly dopa- positive dendritic melanocytes at dermo-epidermal junction. Section stained with "combined dopa- premelanin reaction". X 1034. MELANOSIS CIRCUMSCRIPTA PRAECANCEROSA (DTJBRETJILH) 367 ?- a4 '4 a I. p V.-—--, FIG.4. Numerous hyperplastic and ameboid-shaped melanocytes (indicated by arrow) of melanosis circumscripta praecancerosa. Combined dopa-premelanin reaction. X 957.

TABLE 4 Individual cells of snelanoszs circumscripta praccancerosa

Pericaryon Nucleus No, Nucleolus Long axis Short axis Long axis Short axis

1. 10.5/1 5.9/1 7.1 , 2.2/2 Can't identify 2. 9.0 6.7 6.3 5.7 Can't identify 3. 12.6 8.8 7.4 5.3 Can't identify 4. 12.0 8.9 8.6 4.1 Can't identify 5. 8.7 4.8 6.6 3.7 Can't identify 6. 11.6 5.5 6.7 3.3 Can't identify 7. 10.9 4.9 6.6 3.6 Can't identify 8. 9.6 7.9 8.6 4.0 Can't identify 9. 7.2 4.5 6.2 3.4 Can't identify 10. 9.9 5.4 8.5 3.8 Can't identify

Total 102.0 63.3 72.6 39.1 Average 10.2/2 6.3/2 7.3/2 3.9j L. A/S. A.: 1.62 1.87 S2(L. A. X S. A.): 64.26/22 28.47/22 368 THEJOURNAL OF INVESTIGATIVE DERMATOLOGY

TABLE 5 TABLE 6 Individual cells of junction nevus Individual cells of junction nevu.s (Quiescent nest type) (Active premalignant type)

Pericaryon Nucleus Nucle- Pericaryon Nucleus Nucleolus; No. olus; Long No. Axis(Di- Long Axis Long Short Long Shoit ameter) Long Short Long 5hort(Diameter) axis axis axis axis axis axis axis axis

1. 16.9 16.7 ,9.6 7.7 /2.6 , 1. 10.5 L9.3 /7.7 5.9 2.4 L 2. 16.2 12.3 8.2 6.9 3.0 2. 11.8 8.0 7.4 6.8 2.1 3. 18.3 15.7 7.9 6.2 2.8 3. 10.5 9.2 8.8 7.6 3.4 4. 21.7 13.9 9.9 7.1 2.2 4. 11.4 7.9 9.3 5.6 1.9 5. 21.1 13.3 7.8 6.3 2.3 5. 15.1 8.910.5 6.9 3.1 6. 25.2 20.1 8.8 6.9 2.1 6. 13.1 9.2 7.2 6.5 2.3 7. 15.9 15.6 6.9 5.9 3.0 7. 18.5 6.610.2 7.4 2.8 8. 14.3 12.9 8.05.5 2.2 8. 31.2 8.4 9.7 6.3 2.6 9. 16.8 13.8 8.9 6.1 2.9 9. 28.9 5.5 8.4 4.8 2.3 10. 19.7 16.810.2 6.9 2.1 10. 14.1 6.5 9.3 5.2 2.2

Total 186.1 151.0 86.2 65.5 25.2 Total 165.1 79.5 88.5 63.0 25.1 Average 18.6 i15.1,8.6 ,z6.6 r 2.5 Average 16.5 8.0 ,8.9s6.3 2.5,.

L. A./S. A.: 1.23 1.30 L. A./S. A.: 2.06 1.41 S2 (L.A. X S. A.): 56.76 S2 (L. A. X S. A.): 56.07 2 280.86 132.002

differences between Dubreuilh's melanosis and benign junction nevus were the high degree ofone was on the right arm; one on the shoulder; pigment dropping resulting in many chromato-and one on the back of the neck. phores in the upper cutis and chronic plasma and Clinical Diagnosis: The clinical picture is fre- lymph cell infiltration as in other precanceroses.quently that of a brown sepia or bluish-black He maintained that after the occurrence of thepapillomatous plaque rather than a nevoid len- dropping off phenomenon of the tumor cells, ittigo (Fig. 1). Therefore the clinical diagnosis is was already a malignant melanoma. often pigmented senile keratosis or seborrheic keratosis with beginning malignancy. Six cases CASEREPORTS out of the seven show recent growth or darkening Clinicaldata and histologic material wereof the region and were sometimes suspected as an available on seven cases which are listed in Tableactive junction nevus becoming a malignant mela- 2. Dubreuilh's melanosis or lentigo maligna hasnoma, but the onset of the lesion was relatively two meanings as Lund (26) stated: "a pre-malig-late in life, and the size of the macule was larger nant lentigo and fully developed but superficialthan the usual pigmented mole. Configuration malignant melanoma". In order to avoid con-was irregular, and regression was observed with fusion it would seem better to limit it to theprogression. former designation. Histologic Aspects Clinical Aspects Sections stained with hematoxylin and eosin Age: Five of seven patients were 40 years orand with acid orcein and Masson's ammoniated older. The average age was 48 years. silver nitrate were available in all cases. Two Sex: There were five males and two females. cases were examined with a new technic of com- Duration: Most lesions had been present forbined dopa-premelanin reaction (27) and tyrosi- from 1 to 3 years, and the age at onset in all casesnase reaction. The histopathologic findings of the was past 30 years. specimens are shown in Table 3, in comparison Site: In more than half of my cases the lesionswith junction nevus. The lesions consist of an in- were situated on the face, frequently on the cheek;creased number of hyperplastic dendritic "clear MELANOSIS CIRCTJMSCRIPTA PRAECANCEROSA (DUErEUILII) 369

TABLE7 Comparative data of melanosis circumseripta praecancerosa and nevus cell

Junction Nevus Junction Nevus Melanosis Ciccumsccipta Praecancecosa (Quiescent Nest (Active, Pcernalig- Type) nant Type)

A. Pericaryon 1. L. A. 10.2 18.6 p 16.5 p 2. S.A. 6.3p l5.lp S.Op 3.S2(L. A. XS. A.) 64.26 p2 280.86 p2 132.00 p2 4.Comparison (52) 1 4.4 2.1 B.Nucleus 1.L.A. 7i&p 8.6p 8.9p 2. S. A. 3.Op 6.€lp G.3p 3.S2(L. A. X S. A.) 28.4'7p2 56.76 p2 S6.07 p2 4. Comparison (82) 1 2.0 2.0 C.Ratio L. A. (Pericaryon) 1 R,= 1.62 1.23 2.06 S.A. (Pericaryon) L. A. (Nucleus) 2. R2 = 1.87 1.30 1.41 s.A. (Nucleus) L. A. (Pericaryon) 3 R2= 1.40 2.16 1.85 L.A. (Nucleus) 5. A. (Periearyon) 4 144= 1.62 2.29 1.27 S.A. (Nucleus) S (Periearyon) 5. 115 = 2.26 4.95 2.35 52(Nucleus) cells" resembling normal melnnocytes in the lowercytium as nevus cells do, and their cytoplasm, epidermis, i.e., at the epidermal-dermal junctionnucleus, nucleolus appear different in certain and in the outer sheath of hair follicles with hy-ways which are listed in Table 4. perpigmentation, (Figs. 2, 5A, 6A). There are no Furthermore, micro-measurement of each com- nevus cell nests. The change is sharply limited toponent was done to establish their quantitative an area in which highly dopa positive melano-differences in 10 p hematoxylin-eosin sections. eytes proliferate and also increase in size (Figs. 3, There are two types of junction nevi of which, 4).Thisis different from the usual picture ofhowever, there are transitions. In one type, nevus junction nevus, where theques of nevus cells oftencells are present largely as well circumscribed occur at some distance beyond the body of thenests within the lower epidermis; while, in the main lesion. other type, the nevus cells are scattered diffusely Dubreuilh's melanosis showed a negative or in-through the lower epidermis. This latter type of hibited tyrosinase reaction. Pigment is present injunction nevus has been called active premalig- the form of small, often dust-like particles of evennant junction nevus by Allen and Spitz (28). size. These are found in the neoplastic melano-Therefore, the measurement was done in com- eytes and also in the Malpighian cells, and fre-parison with these two types of junction nevus quently in the horny layer. These epidermaland Dubreuilh's melanosis (Tables 4, 5, 6, 7). changes are accompanied by a large collection ofActual measurement showed the average value of melanophores and inflammatory reaction consist-10.2 p for the long axis (L. A.) of the pericaryon, ing of lymphocytes and plasma cells. 6.3 p for the short axis and an L. A./S. A. index Individual cells of the lesion do not form a syn-of 1.62 in Dubreuilh's melanosis. This compares 370 THEJOURNAL OF INVESTIGATIVE DEHMATOLOGY

Fin. 5. Comparison of melanosis circumscripta praecancerosa (A) and junction nevus (B). Both sections stained with hcmatoxylin and cosin. Note differences between the neoplastic clear cell and the nevus cell listed on Table 3. Magnification A: X 225, B: X 75. MELANOSIS CIRCUMSCRIPTA PRAECANCEROSA (DTJBREUILH) 371

TABLE 8 eerned. Dubreuilh's melanosis has been consid- Sources of molignant melanoma ered by some authors (10, 11, 12) as an advanced (Miescher (29), 1933) stage of junction nevus in the pathologic pathway from quiescent junction nevus to malignant mela- Total CuredUncured Sources noma. Malignant melanoma from Micscher (29) and others, on the other hand, nevi listed three sources of malignant melanoma: june- 1. Face 6 6 tion nevus, Dubreuilh's melanosis, and origin 2. Other parts 6 3 d'emblee in normal skin (Table 8). Malignant melanoma from Lutz (30) divided malignant melanoma into 1.) Dubreuilh's melanosis melanosis circumscripta praecancerosa, 2.) nevo- 1. Face 8 7 carcinoma, and 3.) nevosarcoma. 2. Other parts — Lund(31) stated that late appearing lentigo or Malignant melanoma from late appearing junction nevus (nevus tardus) is normal skin the major source of malignant melanomas. The 1. Face 4 3 malignant growth is not a transformation of be- 2. Other parts 3 1 2 nign mature nevus cells, but an abnormal proliferation of the junctional pigmentary components. Dubreuilh's melanosis. This compares with 8.6 bPerhaps in a majority of eases, malignant mela- L. A. and 6.6S. A. and 1.30 L. A./S. A. fornoma arises from non-nevoid premelanomatous quiescent, nest type junction nevus, and 8.9 /2lesions. L.A., 6.3 b' S. A. and 1.41 L. A./S. A. for active The vagueness of the distinction between Du— premalignant type. brcuilh's melanosis and junction nevus is related The value of average periearyons of individualto the nature of the difficulty in defining nevus with 18.6L. A., 15.1 j.tS.A., and 1.23 L. A./and nevus cell, and distinguishing them from neo- S. A. for the quiescent, nest forming type of junction plasms. A discussion of this complex question nevus, and 16.5L. A., 8.0 tS.A., and 2.06would lead too far. It may suffice to state that L. A./S. A. for the active, pre-malignant type ofDubreuilh's melanosis does not fit the definition junction nevus. The average length of the nucleusof a nevus as a congenital malformation, nor does is 7.3 L. A., 3.9 .S.A., and 1.87 L. A./S. A. forit contain nevus cells. cells is 64.3 p2 for Dubreuilh's melanosis and The individual tumor cell of Dubreuilh's mela- 280.9 p2 for quiescent type and 132.0 ft2 for active nosis is different from the cell of the junction no- pre-malignant type junction nevus. The ratiovus in size, shape, distribution, enzyme activity and several other properties as described above L. A. (pericaryon)equals 1.4 in Dubreuilh s mela- L. A. (nucleus) (Figs. 6, 7). nosis, 2.2 in quiescent junction nevus, and 1.9 in In conclusion, it may be said that the basic pat- the active pro-malignant type. tern of Dubreuilh's melanosis circumscripta praecaneerosa is considerably different from that of DiscussioN junction nevus. The principal change of Dubreu- The term "clear cell" therefore has been usedilh's melanosis is the segregation and proliferation by many authors indiscriminately for normalof neoplastic melanocytes tending to form malig- melanocytes and for nevus cells at the dermo-epi-nant melanoma. The junction nevus is accepted dermal junction. The histopathologic findings ofas a segregated accumulation of nevus cells tend- Dubreuilh's melanosis may, in this sense, be de-ing to form a dermal nevus, though having the scribed as an increased number of clear cells.ability in exceptional cases to change to malignant Closer examination and measurement of thesemelanoma. cells, as set forth in Tables 3—7, reveals important In a previous paper, a non-nevoid tumor char- differences between the hyperplastic melanoeytesacterized by benign proliferation of epidermal of this disease and junctional nevus cells (Fig. 5).melanocytes in combination with malpighian hy- Also, some investigators do not distinguish be-perplasia was set apart as melanoacanthoma tween Dubreuilh's melanosis and junction nevus(Mishima and Pinkus (32), 1960). Dubreuilh's where the origin of malignant melanoma is eon-melanosis may be defined a non-nevoid precan- 372 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

S V 1 4 ;4 4rrb pI i'

Fio. 6. A. Melanosis circumseripta praecancerosa showing dendritic "clear cells" resembling normal melanocytes in the lower epidermis and in the outer sheath of the hair follicle. Hematoxylin and eosin stain. X 340. B. Normal clear cells at junction. Hematoxylin and eosin stain.)< 790. C. Usual dopa reaction of melanosis cireumscripta praecancerosa. X 30. MELANOSIS CIRCUMSCRIPTA PRAECANCEROSA (DUBRETJILH) 373

FIG. 7. Comparethese nevus cells (A) and melanoma cells (B) with the cells of melanosis circumscripta praecancerosa in fig. 2. Both stained with hematoxylin and eosin and reproduced at identical magnification. X 1100. 374 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

TABLE 9 Non-nevoid benign and malignant tumors of the epidermis

Keratinocyte Melanocyte

Benign Neoplasm Seborrheic Keratosis Melanoacanthoma Precancerous Neoplasm Senile Keratosis Melanosis Circumseripta Praeeancerosa Malignant Neoplasm Prickle Cell Carcinoma Malignant Melanoma cerous proliferation of epidermal melanocytes. tisehen Pracancerose und zur senilen Warze, Arch. f Dermat. u. Syph., 174: 105—125, 1936. Melanoacanthoma and melanosis circumscripta 7. HAZEN, H. H.: Malignant moles. South. M. J., praecancerosa may be compared by analogy to 13: 345, 1920. the benign and precancerous tumors of the other S. DEcKNER, K.: ZurKlinik der Melanome. Beitr. z. klin. Chir., 154: 159—166, 1931. component of the epidermis, the malpighian cell 9.KUMEE, L. AND LANG, F. J.: Die bosartigen or keratinocyte (Table 9). Just as keratosis se- Geschwtilst der Haut, in Arzt, L., andZieler, K.,Editors: Die Haut- und Geschlechts- ailis leads to squamous cell carcinoma in a high krankheiten, Vol. 2. Berlin, Urban & percentage of cases, so precancerous melanosis Schwarzenberg, 1935. leads to malignant melanoma. It should be added10. SAcH5, W., MACKEE, G. M., SCHWARTZ, 0. D. AND PIERsoN, II. S.: Junction nevus-nevo- to the list of obligate precanceroscs together with carcinoma (the so-called melanoma group). keratosis senilis (actinic and other etiology), J. A. M. A., 135: 216—218, 1947. Bowen's disease, and leukoplakia of mucous11. ALLEN, A. C.: Survey of pathologic studies of cutaneous disease during WorldWar II. membranes. Arch. Dermat. & Syph., 57: 19—56, 1948. 12.BECKER, S. W.: Critical evaluation of the so- SUMMARY called junction nevus. J. Invest.Dermat., 22: 217—223, 1954. Seven cases of Dubreuilh's melnnosis eireum- 13. JU5TITZ,H.:Melanotische Pracancerose, Dis- seripta praecancerosa are presented which clini- sertation,Zurich, 1935. 14. BECKER, S. W.: Pitfalls in the diagnosis and cally resemble pigmented senile keratosis or mela- treatment of melanoma. Arch. Dermat. & noma in situ, while their histologic characteristics Syph., 69: 11—30, 1954. superficially resemble junction nevus. Closer ex-15. KLAL'DEE, J. V. AND BEEEMAN, H.: Melanotic freckle (Hutchinson), Melanose circonscrite amination reveals them to be different in their precancereuse(Dubreuilh). Arch. Dermat. basic pattern of pathogenesis and also clinically. & Syph., 71: 2—10, 1955. Dubreuilh's tumor can be considered as a precan- 16. STEIGLEDER, G.:Pseudo-Paget des Skrotums: Melanotische Praeeancerose unter dem cerous non-nevoid melanoeytoma which is de- klinischenBildeines superfiziellen Car- rived from the junctional mature melanocyte and cinoms, die histologisch einen Morbus Paget nachahmt. Dermatologica, 117: 165—172, shows the segregation phenomenon of these cells. 1958. It represents an alternate pathway by which ma-17. REEsE, A. B.: Precancerous melanosis and the lignant melanoma can originate without the inter- resulting malignant melanoma (cancerous melanosis) of conjunctiva and skin of lids. mediate formation of nevus cells. Arch. Opth., 29: 737—746, 1947. 18. REESE, A. B.: Precancerous melanosis and REFERENCES diffuse malignant melanoma of the con- 1. RUTCHIN5ON, J.: Senile freckles (Cases III, junctiva. Arch.Ophth.,19: 354—365, 1938. IV, V, VI), Arch.Surg.,3: 319—322, 1892. 19. REESE, A. B.: Pigmented tumors. Am. J. 2. HuTcmNsoN, J.: Lentigo-melanosis (Plate Ophth., 30: 537—565, 1947. CVI). Arch.Surg.,5: 252—256, 1894. 20. REESE, A. B.: Precancerous and cancerous 3. DUBREUTLH, M. W.: Lentigo maIm des vieil- melanosis of the conjunctiva. Am. J. Ophth., lards, Société de Dermatologie, 4 aodt, 1894. 39: 96—100, 1955. 4. DunaEuiLis, M. W.: De la mélanose circons-21. SHAW, H. C.: Lentigomaligna: report of one crite précancéreuse. Ann. de dermat. et casetreated With radium. Am. J. Cancer, 15: syph., 3: 129—151 and 205—230, 1912. 1557—1569,1931. 5. Misscmert, 0.: PrdcancerOses Vorstadium des 22.LANE, C.W.: Senile freckle. Arch. Dermat. & Melanoms, präcancerOse Melanose, in Jadas- Syph., 21: 494—495, 1930. sohn, J.: Handbuch der Haut und Gesch-23. MIESCHEE, 0.:Morbus Paget der Genital lechtskrankheiten, Vol. 12, Pt. 3, p. 1085. region mit Beteiligung von Haut und Berlin, Springer-Verlag, 1933. Sehweissdrdsen mit Pigmentierungen vom 6. MIE5cHER, 0., HABERLIN, L. AND GUGGEN Aussehen der melanotischen PrSkanzerose. HElM, L.: Uber fleckformige Alterspigmen- Dermatologicn, 114: 193—198, 1957. tierungen: IhreBeziehungen zur melano- 24. COESI,H.:Three cases ofmélanose eircons- MELANOSIS CIRCUMSCRIPTA PRAECANCEROSA (DIJBREUILH) 375

crite précancéreuse. Proc. Roy. Soc. Mcd.,29. MIE5cHEE, G.: Melanom, in Jadassohn, J.: 32:261—263, 1938—1939. Handbuch der Haut und Geschlechtskrank- 25. STOUT, A. P.: Relationship of malignant heiten, Vol. 12, Pt. 3, p. 1005—1135. Berlin, melanoma(nevocarcinoma) to extra-mam- Springer-Verlag, 1933. mary Paget's disease. Am. J. Cancer, 33:30. LUTZ, W.: Lehrbuch der Haut- nod Gesch- 196—204, 1938. 26. LUND, H. Z. : Protocol of the clinico-pathologic lechtskrankheiten, p. 168—170. Basel, S. conference of the American Academy of Karger Co., 1957. Dermatology and Syphilogy Meeting in Chi-31. LUND, H. Z.: Persooal communication. cago, December 10, 1958. 32. MI5HJMA, Y. AND PINKUS, H.: Benign mixed 27. MI5IIIMA, Y.: New technic for comprehensive tumor of melanocytes and malpighian cells. demonstration of melanin, premelanin and Melanoacanthoma:itsrelationshipto tyrosinase sites. Combined dopa-premelaoin reaction, J. Invest. Dermat., 1960. In press. Bloch's benign non-nevoid melanoepitheli- 28. ALLEN, A. C. AND SPITZ, S.: Malignant mela- oma. Arch. Dermat. & Syph., 81: 539—550, noma. Caocer, 6: 1—45, 1953. 1960.