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CRITICAL EVALUATION OF THE SO-CALLED "JUNCTION NEVUS* S. WILLIAM BECKER, MS., M.D. The serious study of pigmented nevi was undertaken by many workers in the closing years of the 19th Century. All recognized that the microscopic picture of nevi differed from anything seen in other organs. The presence of nevus cells in both the epidermis and dermis led to concepts of origin at one or the other site, or at both sites. Dermal Origin: Demieville (1) believed that the nevus cells arose from adven- titial and endothelial cells of blood vessels. Bauer (2) and vonRecklinghausen (3) thought that the origin was from endothelium of lymph vessels rather than of blood vessels. Epidermal Origin: According to Abesser (4), Duranti, in 1871, was the first to suggest an epidermal origin of nevus cells. Kromayer (5) stated that the endo- thelium-like cells originate in the basal portion of the epidermis as "Bläschen- zellen", migrate to the dermis and develop connective tissue and elastic fibers, a change which he called "desmoplasia". Abesser (4) agreed that the cells origi- ated in the epithelium and lost their intercellular bridges, but migrated into the dermis as epithelium-like cells, and remained such. Unna (6) advanced the concept that the epithelial cells changed by losing their intercellular bridges and multiplied in groups, a process which he called "Ab- sonderung", then migrated as groups to the dermis, which he called "Abtrop- fung", thus forming pigmented nevi. Although previously supported by many workers, Unna's concept has few advocates at the present time. Lubarsch (7) stated that Unna's ideas were not proven, and that nevus cells do not correspond to epithelial cells in any way. Melanoblast-melanocyte: Pigment cells had been identified by some workers soon after discovery of the microscope had made such study possible. Waldeyer (8) may have been the first to identify stellate pigment cells, but Riehl (9) was the first to note that pigment cells in the superficial papillae send processes be- tween the basal cells. Ehrmann (10) and others believed they were of dermal origin, while Weiting and Hamdi (11) and others believed that they originate in the epidermis. The principal champion of melanoblasts as the source of nevus cells was Ribbert (12), who maintained that nevi and melanomas arose from melanoblasts (cells sui-gener'is, which he thought were of connective tissue origin), in the epidermis. He challenged Unna's concept by maintaining (13) that the cells described by Unna were melanoblasts, and had never had intercellular bridges. More recent work by Masson (14), Becker (15), Billingham (16) and Becker, Jr., et al (17) has established the identity beyond reasonable doubt of melanoblasts and melanocytes as cells sui generis. They are located at the Junc- tion of the epidermis and dermis, but are more intimately attached to the epider- mis, because their processes extend between the epidermal cells, and the cell *Fromthe Section of Dermatology, School of Medicine, Univ. of Chicago. Received for publication December 14, 1953. 217 218 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY bodies often lie between basal cells. Because of their location, the initial changes (benign to form nevi, and malignant to form melanoma) are first noted at the epidermo-dermal junction. This fact has given rise to the designation "junction nevus" and to the process as "junctional activity". Many of the early workers, especially Unna (6) noted, and recent workers, Lund and Stobbe (18) and Stegmaier and Montgomery (19) have reaffirmed the facts that 1. the younger the nevus, the more prominent the junctional activity, 2. the cells of smooth, brown nevi are predominantly in this location, and 3. elevated nevi may or may not show nevus cells in this area as a minimal part of their structure. Double origin: Masson (14), John (20) and Voss (21), suggested a double origin for pigmented nevi. Masson (14) suggested that the superficial portion originates in "cellules claires", which correspond to Kromayer's "Blaschenzellen", melano- blasts in the basal layer of the epidermis, and that the deeper portion originates in nerve structures in the dermis. John (20) thought that the epithelial portion comes from "Stalagmocytes", seen in silver-impregnated preparations, which Montgomery and Kernohan (22) could not identify, and Jaeger (23) believed are artefacts. Voss (21) thought that the superficial nevus cells are of neuroecto- dermal origin and the deeper cells are of neuromesodermal origin.

TERMINOLOGY The designations "junction nevus" and "junctional activity" have been used for three distinct lesions, as follows: 1. Quiescent, smooth pigmented nevus. Smooth nevi are found on various parts of the body. Nevi on the genitalia, lower extremities, and especially the feet, are predominantly of that type (18). The clinical features remain constant, and, microscopically, the nevus cells showr a minimal degree of anaplasia (Fig. 1). The masses of nevus cells remain in or attached to the epidermis, Type A (24), with occasionally a few islands in the superficial dermis, Type AB. No cells, or very few cells, are being worked through the epidermis to the surface, and little or no lymphocytic infiltrate is present in the dermis, the two earliest signs of malignancy. Pigmentation is slight to moderate, and is confined chiefly to the nevus cells. From the quiescent nevus, there is gradual transition to: 2. Active, smooth, pigmented nevus. Clinically, the brown, active nevus is enlarging and/or becoming darker. Microscopically, (Fig. 2), the benign neo- plastic nevus cells are hyperpigmented, as is the surrounding epidermis. The stratum corneum contains many pigmented cell remnants, but no definite iso- lated or grouped tumor cells are seen in that location. Mild lymphocytic infiltrate may be present in the dermis. 3. Lentigo maligna. This term was first used by Dubreuilh (25) for ITutchin- son's (26) "senile freckle" or "infective senile freckle". This lesion differs clin- ically from quiescent and active nevi by its slow, steady enlargement. Darier (27) stated that lentigo maligna may appear at any age, enlarge slowly, then, sooner or later, give rise to melanoma. Microscopically, it differs from a nevus in three JUNCTION NEVUS 219

FIG.1. Quiescent smooth brown nevus (Type AB) from sole of woman, aged 32. There had been no clinical change for years. There is no sign of activity or malignancy. (H & E stain) respects (Fig. 3). a. The so-called nevus cells show malignant anaplasia, rather than benign growth. The nuclei and cell bodies are larger than those of nevus cells. They may be oval or fusiform, and their pigment, which varies from a small to moderate amount in the slightly to moderately pigmented plaques to pro- nounced pigmentation in the darkest ones, is present in the form of small, often dust-like particles, of the same size in a given cell. Mitotic figures are rarely seen. b. The malignant cells are being worked through the epidermis to the surface to be cast off with the stratum corneum, as observed by Waelsch (28), Darier (27) and others. The dopa reaction is strongly positive in all these cells. c. Round cell infiltrate is present in the superficial dermis. Lentigo maligna has been classed as melanoma in situ or as a premelanomatous lesion. The next step in the malignant process is penetration into the dermis, which Allen and Spitz (29) consider the first sign of malignancy. Lentigo maligna of the mucosae is called precancerous melanosis of the conjunctiva by Reese (30) and melanoplakia of the oral mucosa by Breuckmann (31). The course of events is essentially the same, whether on the skin or mucosa. Sooner or later, after a few months or years, a tumor develops in lentigo maligna, which all workers agree is a melanoma. de Morgan (32) stated that appearance of this tumor heralds imminent metastasis. The cells of the tumor (33) may be more anaplastic than those of the lentigo maligna in which it arose. 220 THEJOURNAL OF INVESTIGATIVE DERMATOLOGY % ti. 1. 'S 'I;' .4 -I 4 , ' I-... /

Fio. 2. Active black nevus (Type A or AB) of four months' duration from the cheek of a girl, aged 8. Nevus cell groups and epidermis are intensely pigmented, with pigmented melanophages in the dermis. Mild dermal lymphoeytic infiltrate is the only suggestion of malignancy. (H & E stain, courtesy of Dr. F. V. Hauser)

DIFFERENTIAL DIAGNOSIS Clinical diagnosis can often be made in typical lesions. However, it is now generally accepted that biopsy is essential. The microscopic features have already been given. Difficulty may be experienced in distinguishing lentigo maligna from metastatic lesions, where cells may also penetrate into the epidermis as they do in a primary lesion, to which attention has been directed by Nicolau (34), Acker- man (35) and Caeiro Carrasco (36). This feature may have been the basis for the diagnosis of multiple primary melanomas by Pack et al (37) and Allen and Spitz (29). Other disorders from which superficial nevi and lentigo maligna must be differentiated are lentigo, seborrheic keratosis, melanotic carcinoma, thrombosed angioma, and angiofibroma with hemorrhage. These are discussed elsewhere (38).

TREATMENT OF "JUNCTION NEVUS" A quiescent smooth nevus that has not enlarged or darkened can be removed safely with only a few millimeters of peripheral normal tissue. An active nevus, usually in a child, can be removed in the same way. Lentigo maligna, ordinarily in an adult, should be treated as melanoma by wide and deep excision and re- moval of the regional lymph nodes. JUNCTION NEVUS 221

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kr I FIG.3. Lentigo maligna of four and one-half years' duration from the leg of a woman, aged 49. Malignantly anaplastic melanoma cells are being worked through to the surface. Abundant lymphocytic cells are present in the superficial dermis. (H & E stain. From BECKER, S. W.: The Changing Mole, Minnesota Medicine, 34: 1153, 1951.)

COMMENT When the term "junction nevus" is used, it is necessary to determine, if possible, whether quiescent nevus, active nevus or lentigo maligna is meant. The presentation by Sachs et al (39) implied that the designation "junctional nevus" is practically synonymous with "melanoma". However, Stegmaier and Mont- gomery (19) stated that junction nevus does not necessarily giverise to melanoma. Lund and Stobbe (18) stated that added criteria are necessary. Traub (40) stated that junction nevus cannot be called precancerous, because melanoma is rare contrasted with the frequency of junction nevi. I-fe added that junction nevi ap- pearing lnter in life are more serious, which is a pro pos, because the type appear- ing at that age is most apt to be the lentigo maligna variety. The smooth brown nevus is the type most apt to give rise to melanoma (38) in the small percentage (about 25 per cent) of such tumors which arise in nevi. However, nevuscells probably do not become malignant, because pathologic principle statesthat malignant cells do not arise from those which are benignly neoplastic, butrather arise do novo. Lever's (41) statement that junction nevi are always active, hence potentially dangerous, does not correspond to my experience. The confusion that has resulted from recent popularization of the term "junc- tion nevus" is an indication for more cautious use of the designation, or, perhaps, better, its discontinuance, since other adequate descriptive terms areavailable. 222 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

SUMMARY AND CONCLUSIONS A brief history of the study of pigmented nevi is presented, with pathogenetic theories. "Junction nevi" include 1. quiescent nevi, 2. active nevi and 3. lentigo maligna, which are described. The designation "junction nevus" is confusing, and could advantageously be abandoned. REFERENCES 1. DvrsvrraiE, P.: Ijeber die Pigmcntflecke der Haut, Arch. path. Anat., 81: 333, 1889. 2. BAUEa, C.: Ueber endotheliale Rautwarzen und ihre Beziehungen zum Sarkom, Arch. path. Anat., 142: 407, 1895. 3. v. RECKLINGHAU5EN, F. D.: Uebcr die multiplcn Fibrome der Haut und ihre Bezie- hungen zu den multiplen Neuromen, Berlin, A. Hirschwald, 1882. 4. ABE5SER, M.: Ueber die Herkunft und Bedeutung der in den sogenanten Nnevi der Haut vorkommenden Zelihaufen, Arch. path. Anat., 166:40, 1901. 5.KROMAYEE, E.: Zur Histogcnesc der weichen Nautnaevi. Mctaplasie von Epithel zur Bindcgewebe. Dermat. Ztschr., 3:263,1896. 6.UNNA,P. C.: Naevi und Naevocarcinoma, Berlin. kim. Wchnschr., 30: 14, 1893. 7. Lun.utsc, 0.: Hyperpiasic und Ccschwulstc, in LUBAaSCI-r, 0. UND OSTEaTAG, R.: Ergebnissc der allgemeincn Pathologic, Morphologic und Physiologic, Wiesbaden, J.F. Bergmann, 1895. S.WALDEYER, H. W.G.: Xanthelasma palpebrarum, Arch. path. Anat., 52: 318, 1871. 9.RIERL, C.: Zur Pathologic des Morbus Addisoni, Ztschr. f. klin. Mcd., 10: 521, 1886. 10. EHRMANN, S.: Physiologic und Pnthologie des Hautpigmcntcs, Vicrtcljahrschr. Dcrmat. u. Syph., 17: 507, 1885 and 18: 57, 1886. 11. WRITING AND HAMDI: Ucbcr die physiologischc und pathologische Melaninpigmen- ticrung uud den cpithclialcn Ursprung dcr Melanoblastome, Bcitr. path. Anat. u. aug. Path.,42: 23, 1907. 12.RIBBERT, H.:Ucbcrdas Mclanosarkom, Bcitr. path. Anat. u alig. Path., 21: 471, 1897. 13. RIBBERT, H.: Discussion of UNNA, P. C.: Ueber weiche Nacvi dcr Neugchorcn, Zentralbi. nllg. Path., 6: 712, 1895. 14. MAssoN, P.: My conception of cellular nevi. Cancer, 4:9, 1951. 15. BECKER, S. W.: Dermatological Investigations of Melanin Pigmentation, in The Bi- ology of Melanomas, New York, New York Academy of Sciences, 1948. 16. BILLINGRAM, H. E.: Dendritic cells in pigmented human skin, J.Anat.,83: 109, 1949. 17. BECKEa, S. W., JR., FITZPATRICK, T. B., AND MONTGOMERY, H.: Human mclanogenesis: Cytology and histology of pigment cells (melanodendrocytcs), Arch. Dcrmat. & Syph., 65: 511, 1952. 18. LUND, H. Z.,ANDSTOBBE, C. D.: The natural history of the pigmented ncvus; factors of age and anatomic location, Am. J.Path.,25: 1117, 1949. 19. STEGMAIER, 0.Ja., ANDMONTGOMERY, H.: Histopathologic studies of pigmented ncvi in children, J.Invest.Dermat., 20: 51, 1953. 20. JoHN, F.: Studien zur Histogencsc der Naevi, Arch. Dermat. u Syph., 178: 607, 1938. 21. Voss, C.: Zum Nacvusproblcm, Arch. Dermat. u Syph., 194: 30, 1952. 22. MONTGOMERY, H., AND KERNOHAN, J.W.:Pigmented nevi, with special studies regard- ing a possible rleurocpithclial origin of the nevus cell, J.Invest.Dermat., 3:465, 1940. 23. JAEGER, H.: Recherches histologiqucs sur les naevi cellulaires et pigmentaires a l'aidc de l'impreguation argentiquc, Dermatologica, 92: 165, 1946. 24. BECKER, S. W.: Diagnosis and treatment of pigmented nevi. Arch. Dermat. & Syph., 60:44, 1949. JUNCTION NEVUS 223

25.DUHRRUILH, W.: Lentigo maim des vieillards, Ann. dermat. et syph., 5: 1092, 1894. 26. HUTCHJNSON, J.:Onsenile moles and senile freckles and on their relation to cancerous processes, Arch. Surg., 2: 218, 1890—91. 27. DARIER, J.:Precisde dermatologie, Paris, Masson & Cie., 1928. 28. WAEL5CH, L.: Ueber die aus Wcichcn Ncvis entstandencn bosartigen Geschwtilstc, Arch. Dermat. u Syph., 49:249,1899. 29. ALLEN, A. C. AND SPiTZ, SOPHIE: Malignant melanoma. A clinico-pathological analysis of the criteria for diagnosis and prognosis, Cancer, 6: 1, 1953. 30. REESE, A. B.: Precancerous mclanosis and diffuse malignant melanoma, Arch. Ophth., 19:354, 1938. 31.BHEUCKMANN,H.:Ijeher Mclanome der Mundschlcimhaut, Dermat. Wchnschr., 110: 36, 1940. 32. DRMOROAN, C.:On the origin of cancer, Lancct, 518—588, 1871. 33.BECKER, S. W.: Microscopic Analysis of Normal Melanoblasts, Nevus Cells and Mela- noma Cells, in GORDON, M.: Pigment Cell Growth, New York, Academic Press, Inc., 1953. 34.NICOLAU, S.: Sur Ic phcnomencdemigration cellulaire, intracpidermique dans Ic naevocarcinoma (a propos de l'ctude des tumcurs de metastase) Ann dermat. et syph., 1:746, 1930. 35. ACKERMAN,L.V.:Malignant melanoma of the skin, Texas State J.Mcd., 45: 735, 1949. 36. CARIROCARRASCO, M.:0melanoma pediculado acromico. Aspectos anatomicos, Gazeta Medica Portoguesa, 2:931, 1949, abstr.Excerpt. Med., (XIII) 4: 493, 1950. 37. PACK, C.T., SCJJARNAORL,ISABRLM., AND HILLYRR, R.A.: Multipleprimary melanoma: A report of 16 cases, Cancer, 5: 1110, 1952. 38. BECKER, S. W., AND OBERHAYER, M. E.: Modern Dermatology and Syphilology, 2nd cd., Phila., J. B. Lippincott Co., 1947. 39.SACNS,W.,MACKEE,C.M., SCHWARTZ,0.D., ANDPIERSON, H.S.:Junctional ncvus- nevocarcinoma (the so-called melanoma group), J.A. M. A., 135: 216, 1947. 40. TRAUB,E. F.: Ncvi, Med. Clin. N. A., 35: 301, 1951. 41.LEVER,W.:Histopathologyof the Skin, Phila., J. B. Lippincott Co.,1949.