MELANOSIS CIRC[JMSCRIPTA PRAECANCEROSA (DUBRETJILIH)

A NON-NEVOID PIIEMELANOMA DISTINCT FROM JUNCTION NEVUS*

YUTAKA MISHIMA, Ml).

Melanosis circumscripta praecancerosa of Du-breuilh or infective senile freckle of Hutchinsonis a relatively uncommon lesion from which ma-lignant melanoma develops frequently. It is thepurpose of this paper to examine the criteria bywhich it can be distinguished from junction nevusand to identify it as a non-nevoid prccanccrosis ofadult mclanocytcs.

CLINICAL REVIEW

The malignant melanoma arising from a pig-mented plaque was first described clinically byHutchinson. He named this pigmented plaqueinfective pigment patch resembling superficialmelanosis (1) (1892) and lentigo-melanosis (2)(1894).

Dubreuilh gave it the name lentigo malin desvieillards (3) (1894) and mélanose circonscriteprécancéreuse (4) (1912). Bayet (1895) termed it"lentigo infectieux" and Miescber (5, 6) (1928)called it "priicanceröse Melanose"; Hazen (7),"acquired mole"; Deckner (8) and Kumer andLang (9), "tardive nevus"; Sachs (10), "junctionnevus" and Allen (11), "dermoepidermal nevus".Becker, Sr. (12) termed it "lentigo maligna"classifying it as one type of junction nevus.

Dubreuilh, Reese, Becker, Sr., Miescher,Klauder-Beerman, and others reported a total ofabout 50 cases. The following Table 1 shows thelocalization and age of the patient at its onset.

Dubreuilh's melanosis usually starts as a pin-head sized, dark brown sepia spot. It is less com-

* From the Departments of Dermatology,Wayne State University College of Medicine andDetroit Receiving Hospital (Hermann Pinkus,M.D., Chairman) and the Detroit Institute ofCancer Research (William L. Simpson, M.D., Sci-entific Director), Detroit, Michigan.

Supported in part by research grant RG-4435and C-2072 from the National Institutes of Health,U. S. Public Health Service, and in part by re-search contract DA-49-007-MD-584 from the Re-search and Development Division, Office of theSurgeon General, Department of the Army.

Abridgement of a portion of a thesis submittedby Dr. Mishima to the Faculty of the PostgraduateSchool of Medicine, University of Tokyo, in partialfulfillment of the requirements for the degree ofDoctor of Philosophy in Dermatology and Syphi-lology.

Received for publication August 11, 1959.

361

monly black and by extension it may exceed thesize of the palm. The borders of the lesion areirregular because the progression is not uniformthroughout the pigmented patch. Sometimes,while one part of the lesion is progressing, anotherpart may show signs of regression. At the onset ofmalignant transformation one observes thickeningor induration in one portion of the patch whichoften produces pea to cherry-sized papules. It maybecome verrueous and may ulcerate and bleedeasily. The discoloration and thickness of theplaque is not uniform.

Mieseher (5) states that malignant melanomasoccur in about 30 per cent of the cases whichincidence is considerably higher than that ofmalignant melanoma arising from junction nevus.On the other hand, Dubreuilh's melanosis is muchless common than junction nevus.

Dubreuilh (4) observed an average period often years between the onset of the premalignantlesion and the development of malignant mela-noma. Klauder and Beerman (15) recorded anaverage interval of 13 years; Mieseher (5), 29years; Shaw (21), 31 years. In our group of 7 easesthe duration of the lesion was from 1 to 10 yearsat the time of diagnosis. There were no malignantchanges in this lapse of time.

Dubreuilh and Miescher stated that themalignant melanoma is slow to develop from thepigmented lesion on the face, and lymph nodeinvolvement does not occur early. Miescherbelieved that generalization is very rare in thecase of facial lesions. Both authors agree thaton the extremities, malignant transformation de-velops more rapidly and generalization is alsomore frequent.

Klauder and Beerman (15) commented thatafter appearance of the melanoma, particularlyon the face, regional lymph node involvement andfurther metastasis is longer delayed than in theeases of malignant melanoma arising from junctionnevus. Dubreuilh's melanosis occurs frequentlyin older people, therefore it would appear manypersons afflicted with this on the face may die ofother causes before malignant change takes place.

Reese (17—20) stated that Dubreuilh's melanosisof the conjunctiva pursues a more malignantcourse than that of the face and is more liable toundergo a malignant change than in the case ofjunction nevus.

TA

BL

E 1

Clin

ical

dat

a on

mel

anos

is c

ircu

msc

ript

a pr

aeca

ncer

osa

Dub

reni

lh

*Dub

reui

lh

(4)

Bec

ker.

Sr.

(12

, 14

) M

iesc

her

(6)

Kla

uder

-Bee

rman

R

eese

(17

) M

ishi

ma

Face

17

9

2 2

1 1

4 E

ar

1 E

yelid

C

onju

nctiv

a E

yelid

and

con

j M

ucou

s m

embr

ane.

.

2 4 3 2

1 17

Scro

tum

1

Tru

nk

1 E

xtre

miti

es

7 1

4 1

1 N

ucha

1

Age

at o

nset

be

twee

n 18

—

be-

betw

een

19—

av

erag

e be

twee

n 35

- 68

yrs

.; tw

een

51;

aver

age

abou

t 70

70

; ave

rage

av

erag

e 40

34—

81

39 y

rs.

yrs.

56

yrs

. yr

s.

65

C

C z 0)

C

C

betw

een

30—

66;

aver

age

45 y

rs.

* O

f 35

case

s re

port

ed b

y D

ubre

uilh

, 30

case

s w

ere

com

pile

d fro

m th

e fo

llow

ing

auth

or's

rep

orts

: Bou

ssio

n (1

903)

, Bay

et (

1895

), T

héve

nin

(189

8),

Lam

arqu

e (1

888)

, Hut

chin

son

(189

2, 1

893)

, Cla

isse

et D

artig

ues

(189

9), N

icol

as e

t Dur

and

(190

9), F

ox, W

. (1

911)

. In

Dub

reui

lh's

ser

ies

the

case

s w

ere

alm

ost e

qual

ly d

istr

ibut

ed a

mon

g m

ales

and

fem

ales

.

yrs.

av

erag

e 40

—50

40

48

yr

s.

yrs.

Site

of T

umor

TA

BL

E 2

Clin

ical

pic

ture

of m

elan

osis

cir

cum

scri

pta

prae

canc

eros

a D

ubre

uilh

Dia

met

er

Age

at B

egin

ning

(m

m.)

(D

urat

ion)

A

ge a

nd

Sex

54—

M

60—

M

67—

F

52—

M

Clin

ical

Dia

gnos

is

Bef

ore

Bio

psy

1. c

heek

r. t

empl

e

r. c

heek

Rec

ent G

row

th

Cas

e N

o.

1.

2.

3.

4.

5.

6.

7.

Rac

e

Whi

te

Whi

te

Whi

te

Japa

nese

Whi

te

Whi

te

Whi

te

Rem

arks

18 x

21

12 x

11

24 x

19

16 x

11

10 x

7

13 x

8

15 x

12

48 y

rs.

old

(4 y

r.)

57 y

rs.

old

(3 y

r.)

66 y

rs.

old

(1 yr

.)

42 y

rs.

old

(10

yr.)

31 y

rs.

old

(2 y

r.)

37 y

rs.

old

(3 y

rs.)

30

yrs

. ol

d (1

yr

.)

pre-

auri

c-

ular

33—

M r

. ar

m (

lat-

er

al s

ur-

face

)

40—

F po

st n

ucha

l ar

ea

31—

M s

houl

der

Mel

anot

ic fr

eckl

e

Seni

le k

erat

osis

Mel

anot

ic fr

eckl

e

Pigm

ente

d se

b-

orrh

eic

kera

- to

sis

1. P

igm

ente

d ne

vus

2.

Poss

ible

ma-

lig

nant

mel

a-

nom

a Ju

nctio

n ne

vus

Mal

igna

nt m

ela-

no

ma

Qui

ck

grow

th

and

dark

er

with

in 1

yr

. L

atel

y itc

hing

Rec

ent d

arke

ning

With

in 4

mos

. qui

ck d

oubl

ing

grow

th,

also

hea

t fl

ashe

s an

d itc

hing

dur

ing

last

2

wks

. N

o re

cent

enl

arge

men

t

Lat

e qu

ick

grow

th

Few

w

eeks

be

fore

be

cam

e la

rger

and

mor

e pa

pula

r

z C

____

_ 02

02

Dar

k br

own

with

mot

tling

.

Bro

wn

papi

llom

atou

s pla

que

Lar

ge m

elan

otic

frec

kle

with

hy-

pe

rpig

men

tatio

n at

on

e ed

ge

\Ter

ruco

us,

redd

ish

brow

n,

ele-

va

ted

plaq

ue o

n w

hich

4 s

mal

l pa

pula

r tu

mor

s ar

e pr

esen

t.

Dar

k br

own;

bl

ack

pigm

ente

d le

sion

, with

slig

ht e

leva

tion

of

.5m

m.

C

01

Fla

t, da

rk n

evus

Smal

l, fl

at, p

igm

ente

d le

sion

with

a

pole

ce

nter

, w

hich

was

sus

-

pect

ed t

o be

und

ergo

ing a

ctiv

a-

tion.

364 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

Fin. 1 (A). A 67 year old female. Lesion of one year's duration with recent darkening of colorFIG. 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.One of the patients who succumbed had con-junctival involvement and two had lesions of theextremities. Involvement of lymph nodes wasseen in only one patient who was well two yearsafter their removal.

Miescher (23) (1957) reported a case of morbusPaget on the male genitals which had an intensivepigmentation and resembled Dubreuilh's mela-nosis. Steigleder (24) (1958) described a case ofDubreuilh's melanosis on the scrotum and shaftof the penis which clinically and histologicallyresembled Miescher's case, however he classifiedit as a superficial premalignant melanosis andpointed out that this is easily confused withPaget's disease when it occurs in the genitalregion.

HISTOPATIIOLOGIC REVIEW

Dubreuilh's melanosis has been described as apremelanomatous lesion or malignant melanomain situ, the next step of which is penetration intothe dermis and the establishment of malignantmelanoma.Klauder and Beerman (15) described thecharacteristic feature of the lesion as a change inthe region of the basal cells, which is the precursorof the segregation phenomenon of nevus cells.They adopted this from Dubreuilh, and addedthat individual cells of the basal layer seemlarger and paler, and are separated by a gap from

neighboring cells. The nucleus of these cells islarge, vesicular and the protoplasm is light andhoneycombed. These cells may be pigmented orentirely pigment free. Mitosis is absent.

Corsi (24) pointed out the presence of largepagetoid cells in Dubreuilh's melanosis which atfirst might lead one to think that one was dealingwith Bowen's disease, but closer examinationshowed these cells are in fact malignant melano-blasts. Stout (25) noted that Paget cells sometimeshad some resemblance to malignant melanomacells.

Becker, Sr. (12) divided junction nevus andjunctional activity into 3 distinct groups: 1.)quiescent, smooth, pigmented nevus, 2.) active,smooth, pigmented nevus, 3.) lentigo maligna.Becker called Dubreuilh's melanosis, lentigomaligna, and noted lentigo maligna was theadvanced stage of junction nevus which had alocation in the pathogenetic pathway fromquiescent junction nevus to malignant mela-noma. He considered lentigo maligna differentfrom quiescent and active nevus in three respects:1.) individual cells of the lesion show malignantanaplasia rather than benign growth; 2.) themalignant cells are being worked through theepidermis to the surface to be cast off with thestratum corneum, and the dopa reaction isstrongly positive in all these cells; 3.) round cellinfiltration is present in the superficial dermis.

Miescher noted that the main histological

TABLE 3

Dubreuilh'sMelanosisCircurnscripta Junction Nevus

1. Tendency to form well Rarely Almost always.circumscribed, massivecell nests

2. Dropping off phenomena No, not until changing to malignant Almost always shows a tendencymelanoma to form intradermal or com-

pound ncvus even though notchanging to malignant mela-noma.

3. Individual cells(1) protoplasma No syncytium-building, honey- Syncytium-building. homogene-

combed and occasionally vaeuo- ous, oval or euboidal, usuallylated; average size 10.2 px 6.3 p distinctly outlined.

18.6 p x 15.1 p (Quiescent), 16.5 ,.ix 8.0ji (Active).

(2) nucleus Irregular and shrunken Oval or round, predominately welloutlined 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 x6.3 p (Active).

long axis ofperiearyon(4) ratio = . Average 1.40 2.16 (Quiescent), 1.85 (Active).long axis ofnucleus

(5) nucleolus Cannot be identified Frequently can be identified; aver-age 2.5 p diameter.

(6) melanin Carried in dendrites or honey- Carried in well outlined eyto-combed cytoplasm plasm.

(7) general form Dendritie "clear cell" resembling Epitheloid 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 lessdendritie 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 composedlymphocytes. of lymphocytes.

S. Malignancy of arising Less malignant, metastasis and re- More malignant and metastasismalignant 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, raised Smooth, slightly raised, brown,plaques on which small tumors small, round or oval spot.frequently are found. The pig- Grows more slowlyment grouping of several spots byapposition of new elements.Spreads more rapidly, sometimesreaches 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 nevuseytes cells.

365

366 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

FIG. 2. Melanosis circumscripta praecancerosa with hyperpiasia of the dendritic "clear cell" resem-bling 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.

_s natr

• WS ii;*

MELANOSIS CIRCUMSCRIPTA PRAECANCEROSA (DTJBRETJILH) 367

FIG. 4. Numerous hyperplastic and ameboid-shaped melanocytes (indicated by arrow) of melanosiscircumscripta praecancerosa. Combined dopa-premelanin reaction. X 957.

TABLE 4Individual cells of snelanoszs circumscripta praccancerosa

No,Pericaryon Nucleus

Nucleolus

Long axis Short axis Long axis Short axis

1.

2.3.4.5.

6.7.8.9.

10.

10.5/19.0

12.612.08.7

11.610.99.67.29.9

5.9/16.78.88.94.85.54.97.94.55.4

7.1 ,6.37.48.66.66.76.68.66.28.5

2.2/25.75.34.13.73.33.64.03.43.8

Can't identifyCan't identifyCan't identifyCan't identifyCan't identifyCan't identifyCan't identifyCan't identifyCan't identifyCan't identify

TotalAverage

102.010.2/2

63.36.3/2

72.67.3/2

39.13.9j

L. A/S. A.: 1.62S2(L. A. X S. A.): 64.26/22

1.8728.47/22

V.-

—--

,

a I. '4

p a4

?-

368 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

differences between Dubreuilh's melanosis andbenign junction nevus were the high degree ofpigment dropping resulting in many chromato-phores in the upper cutis and chronic plasma andlymph cell infiltration as in other precanceroses.He maintained that after the occurrence of thedropping off phenomenon of the tumor cells, itwas already a malignant melanoma.

CASE REPORTS

Clinical data and histologic material wereavailable on seven cases which are listed in Table2. Dubreuilh's melanosis or lentigo maligna hastwo meanings as Lund (26) stated: "a pre-malig-nant lentigo and fully developed but superficialmalignant melanoma". In order to avoid con-fusion it would seem better to limit it to theformer designation.

Clinical Aspects

Age: Five of seven patients were 40 years orolder. The average age was 48 years.

Sex: There were five males and two females.Duration: Most lesions had been present for

from 1 to 3 years, and the age at onset in all caseswas past 30 years.

Site: In more than half of my cases the lesionswere situated on the face, frequently on the cheek;

one was on the right arm; one on the shoulder;and one on the back of the neck.

Clinical Diagnosis: The clinical picture is fre-quently that of a brown sepia or bluish-blackpapillomatous plaque rather than a nevoid len-tigo (Fig. 1). Therefore the clinical diagnosis isoften pigmented senile keratosis or seborrheickeratosis with beginning malignancy. Six casesout of the seven show recent growth or darkeningof the region and were sometimes suspected as anactive junction nevus becoming a malignant mela-noma, but the onset of the lesion was relativelylate in life, and the size of the macule was largerthan the usual pigmented mole. Configurationwas irregular, and regression was observed withprogression.

Histologic Aspects

Sections stained with hematoxylin and eosinand with acid orcein and Masson's ammoniatedsilver nitrate were available in all cases. Twocases were examined with a new technic of com-bined dopa-premelanin reaction (27) and tyrosi-nase reaction. The histopathologic findings of thespecimens are shown in Table 3, in comparisonwith junction nevus. The lesions consist of an in-creased number of hyperplastic dendritic "clear

TABLE 5Individual cells of junction nevus

(Quiescent nest type)

Pericaryon Nucleus

TABLE 6Individual cells of junction nevu.s

(Active premalignant type)

No.

1.2.

3.

4.

5.6.7.8.9.

10.

Longaxis

16.916.218.321.721.125.215.914.316.819.7

Shortaxis

16.7 ,12.3

15.713.913.320.115.612.913.816.8

Longaxis

9.68.27.99.97.88.86.9

8.08.9

10.2

Shoitaxis

7.7 /6.9

6.27.16.36.95.95.56.16.9

Nucle-olus; LongAxis (Di-ameter)

2.6 ,3.0

2.82.22.32.13.02.22.92.1

No.

Pericaryon NucleusNucleolus;Long Axis(Diameter)Long

axisShortaxis

Longaxis

5hortaxis

1.2.3.4.5.6.7.8.9.

10.

10.5 L11.810.511.415.113.118.531.228.914.1

9.3 /8.09.27.98.99.26.68.45.56.5

7.77.48.89.3

10.57.2

10.29.78.49.3

5.96.87.65.66.96.57.46.34.85.2

2.4 L2.13.41.93.12.32.82.62.32.2

TotalAverage

165.1 79.5

16.5 8.0 ,88.5

8.9 s63.0

6.3

25.1

2.5 ,.

L. A./S. A.: 2.06S2 (L. A. X S. A.):

132.00 2

1.4156.07 2

Total

Average

186.1 151.0

18.6 i 15.1 ,

86.2

8.6 ,z

65.5

6.6 r

25.2

2.5

L. A./S. A.: 1.23

S2 (L.A. X S. A.):

280.86

1.30

56.76

MELANOSIS CIRCTJMSCRIPTA PRAECANCEROSA (DUErEUILII) 369

TABLE 7

Comparative data of melanosis circumseripta praecancerosa and nevus cell

Melanosis Ciccumsccipta PraecancecosaJunction Nevus(Quiescent Nest

Type)

Junction Nevus(Active, Pcernalig-

nant Type)

A. Pericaryon1. L. A.2. S.A.3. S2(L. A. X S. A.)4. Comparison (52)

B. Nucleus

1. L.A.2. S. A.3. S2(L. A. X S. A.)

4. Comparison (82)

C. Ratio

1 R,L. A. (Pericaryon)=S. A. (Pericaryon)

10.26.3p

64.26 p21

7i&p3.Op

28.4'7p21

1.62

18.6 pl5.lp

280.86 p24.4

8.6p6.€lp

56.76 p22.0

1.23

16.5 pS.Op

132.00 p22.1

8.9pG.3p

S6.07 p22.0

2.06

L. A. (Nucleus)2. R2 =

s. A. (Nucleus)1.87 1.30 1.41

3 R2L. A. (Pericaryon)=L. A. (Nucleus)

1.40 2.16 1.85

4 1445. A. (Periearyon)=S. A. (Nucleus)

1.62 2.29 1.27

S (Periearyon)5. 115 =

52 (Nucleus)2.26 4.95 2.35

cells" resembling normal melnnocytes in the lowerepidermis, i.e., at the epidermal-dermal junctionand in the outer sheath of hair follicles with hy-perpigmentation, (Figs. 2, 5A, 6A). There are nonevus cell nests. The change is sharply limited toan area in which highly dopa positive melano-eytes proliferate and also increase in size (Figs. 3,4). This is different from the usual picture ofjunction nevus, where theques of nevus cells oftenoccur at some distance beyond the body of themain lesion.

Dubreuilh's melanosis showed a negative or in-hibited tyrosinase reaction. Pigment is present inthe form of small, often dust-like particles of evensize. These are found in the neoplastic melano-eytes and also in the Malpighian cells, and fre-quently in the horny layer. These epidermalchanges are accompanied by a large collection ofmelanophores and inflammatory reaction consist-ing of lymphocytes and plasma cells.

Individual cells of the lesion do not form a syn-

cytium as nevus cells do, and their cytoplasm,nucleus, nucleolus appear different in certainways which are listed in Table 4.

Furthermore, micro-measurement of each com-ponent was done to establish their quantitativedifferences in 10 p hematoxylin-eosin sections.

There are two types of junction nevi of which,however, there are transitions. In one type, nevuscells are present largely as well circumscribednests within the lower epidermis; while, in theother type, the nevus cells are scattered diffuselythrough the lower epidermis. This latter type ofjunction nevus has been called active premalig-nant junction nevus by Allen and Spitz (28).Therefore, the measurement was done in com-parison with these two types of junction nevusand Dubreuilh's melanosis (Tables 4, 5, 6, 7).Actual measurement showed the average value of10.2 p for the long axis (L. A.) of the pericaryon,6.3 p for the short axis and an L. A./S. A. indexof 1.62 in Dubreuilh's melanosis. This compares

370 THE JOURNAL OF INVESTIGATIVE DEHMATOLOGY

Fin. 5. Comparison of melanosis circumscripta praecancerosa (A) and junction nevus (B). Both sec-tions stained with hcmatoxylin and cosin. Note differences between the neoplastic clear cell and thenevus cell listed on Table 3. Magnification A: X 225, B: X 75.

MELANOSIS CIRCUMSCRIPTA PRAECANCEROSA (DTJBREUILH) 371

TABLE 8Sources of molignant melanoma

(Miescher (29), 1933)

Malignant melanoma fromnevi

1. Face2. Other parts

Malignant melanoma fromDubreuilh's melanosis

1. Face2. Other parts

Malignant melanoma fromnormal skin

1. Face2. Other parts

Dubreuilh's melanosis. This compares with 8.6 bL. A. and 6.6 S. A. and 1.30 L. A./S. A. forquiescent, nest type junction nevus, and 8.9 /2L. A., 6.3 b' S. A. and 1.41 L. A./S. A. for activepremalignant type.

The value of average periearyons of individualwith 18.6 L. A., 15.1 j.t S. A., and 1.23 L. A./S. A. for the quiescent, nest forming type of junctionnevus, and 16.5 L. A., 8.0 t S. A., and 2.06L. A./S. A. for the active, pre-malignant type ofjunction nevus. The average length of the nucleusis 7.3 L. A., 3.9 . S. A., and 1.87 L. A./S. A. forcells is 64.3 p2 for Dubreuilh's melanosis and280.9 p2 for quiescent type and 132.0 ft2 for activepre-malignant type junction nevus. The ratioL. A. (pericaryon) equals 1.4 in Dubreuilh s mela-

L. A. (nucleus)nosis, 2.2 in quiescent junction nevus, and 1.9 inthe active pro-malignant type.

DiscussioN

The term "clear cell" therefore has been usedby many authors indiscriminately for normalmelanocytes and for nevus cells at the dermo-epi-dermal junction. The histopathologic findings ofDubreuilh's melanosis may, in this sense, be de-scribed as an increased number of clear cells.Closer examination and measurement of thesecells, as set forth in Tables 3—7, reveals importantdifferences between the hyperplastic melanoeytesof this disease and junctional nevus cells (Fig. 5).

Also, some investigators do not distinguish be-tween Dubreuilh's melanosis and junction nevuswhere the origin of malignant melanoma is eon-

eerned. Dubreuilh's melanosis has been consid-ered by some authors (10, 11, 12) as an advancedstage of junction nevus in the pathologic pathwayfrom quiescent junction nevus to malignant mela-

Uncurednoma.

Micscher (29) and others, on the other hand,listed three sources of malignant melanoma: june-tion nevus, Dubreuilh's melanosis, and origind'emblee in normal skin (Table 8).

Lutz (30) divided malignant melanoma into 1.)melanosis circumscripta praecancerosa, 2.) nevo-carcinoma, and 3.) nevosarcoma.

— Lund (31) stated that late appearing lentigo orlate appearing junction nevus (nevus tardus) isthe major source of malignant melanomas. The

2malignant growth is not a transformation of be-nign mature nevus cells, but an abnormal prolifer-ation of the junctional pigmentary components.Perhaps in a majority of eases, malignant mela-noma arises from non-nevoid premelanomatouslesions.

The vagueness of the distinction between Du—brcuilh's melanosis and junction nevus is relatedto the nature of the difficulty in defining nevusand nevus cell, and distinguishing them from neo-plasms. A discussion of this complex questionwould lead too far. It may suffice to state thatDubreuilh's melanosis does not fit the definitionof a nevus as a congenital malformation, nor doesit contain nevus cells.

The individual tumor cell of Dubreuilh's mela-nosis is different from the cell of the junction no-vus in size, shape, distribution, enzyme activityand several other properties as described above(Figs. 6, 7).

In conclusion, it may be said that the basic pat-tern of Dubreuilh's melanosis circumscripta prae-caneerosa is considerably different from that ofjunction nevus. The principal change of Dubreu-ilh's melanosis is the segregation and proliferationof neoplastic melanocytes tending to form malig-nant melanoma. The junction nevus is acceptedas a segregated accumulation of nevus cells tend-ing to form a dermal nevus, though having theability in exceptional cases to change to malignantmelanoma.

In a previous paper, a non-nevoid tumor char-acterized by benign proliferation of epidermalmelanocytes in combination with malpighian hy-perplasia was set apart as melanoacanthoma(Mishima and Pinkus (32), 1960). Dubreuilh'smelanosis may be defined a non-nevoid precan-

Sources Total Cured

66

8

43

63

7

31

372 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

Fio. 6. A. Melanosis circumseripta praecancerosa showing dendritic "clear cells" resembling normalmelanocytes in the lower epidermis and in the outer sheath of the hair follicle. Hematoxylin and eosinstain. X 340. B. Normal clear cells at junction. Hematoxylin and eosin stain.)< 790. C. Usual dopa reac-tion of melanosis cireumscripta praecancerosa. X 30.

V;4 4rr

S

14

bpI i'

MELANOSIS CIRCUMSCRIPTA PRAECANCEROSA (DUBRETJILH) 373

FIG. 7. Compare these nevus cells (A) and melanoma cells (B) with the cells of melanosis circum-scripta praecancerosa in fig. 2. Both stained with hematoxylin and eosin and reproduced at identicalmagnification. X 1100.

374 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

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

Keratinocyte Melanocyte

Benign NeoplasmPrecancerous Neoplasm

Malignant Neoplasm

Seborrheic KeratosisSenile KeratosisPrickle Cell Carcinoma

MelanoacanthomaMelanosis Circumseripta PraeeancerosaMalignant Melanoma

cerous proliferation of epidermal melanocytes.Melanoacanthoma and melanosis circumscriptapraecancerosa may be compared by analogy tothe benign and precancerous tumors of the othercomponent of the epidermis, the malpighian cellor keratinocyte (Table 9). Just as keratosis se-ailis leads to squamous cell carcinoma in a highpercentage of cases, so precancerous melanosisleads to malignant melanoma. It should be addedto the list of obligate precanceroscs together withkeratosis senilis (actinic and other etiology),Bowen's disease, and leukoplakia of mucousmembranes.

SUMMARY

Seven cases of Dubreuilh's melnnosis eireum-seripta praecancerosa are presented which clini-cally resemble pigmented senile keratosis or mela-noma in situ, while their histologic characteristicssuperficially resemble junction nevus. Closer ex-amination reveals them to be different in theirbasic pattern of pathogenesis and also clinically.Dubreuilh's tumor can be considered as a precan-cerous non-nevoid melanoeytoma which is de-rived from the junctional mature melanocyte andshows the segregation phenomenon of these cells.It represents an alternate pathway by which ma-lignant melanoma can originate without the inter-mediate formation of nevus cells.

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