Fibrous Papule of the Nose: a Clinicopathological Studyf James H

FIBROUS PAPULE OF THE NOSE: A CLINICOPATHOLOGICAL STUDYF JAMES H. GRAHAM, M.D.,t JOHN B. SANDERS, M.D.,t WAINE C. JOHNSON, M.D.t AND ELSON B. HELWIG, M.D.t The usual history of a patient with a fibrousmethods: periodic acid-Schiff (PAS) reaction, with papule of the nose is that of a middle-agedand without diastase digestion; colloidal iron re- person who consults a physician because ofaction (1), with and without bovine testicular hyaluronidase and ribonuelease digestion; Feulgen recent color changes in the lesion or to requestreaction; Fontana-Masson stain for argentaffin removal for cosmetic reasons. These dome-granules (melanin); Snook's reticulum stain; shaped papules are often interpreted clinicallyMovat's pentaehrome I stain (2); Bodian's method as cellular nevi; but their configuration, firmfor nerve fibers and nerve endings; Gomori's iron reaction; Gomori's aldehyde-fuehsin technic; and consistency, and vaseularity may cause confu-the aleian blue method. The pH of the working sion with fibrous proliferations and vascularsolutions, and the methods used in the aldehyde- lesions. fuchsin and alcian blue teehnics and detailed The purpose of this paper is to report ourinterpretation of the results were similar to those described by Johnson and Helwig (3), and John- elinieopathologieal observations of a distinctson, Graham and Helwig (4). Formalia-fixed tissue isolated fibrous papule of the nose, stressingfrom 3 fibrous papules and 2 cellular nevi was used histogenesis, pathogenesis, histoehemical char-for preparing frozen sections for the following fat acteristics, and possible relationship to cellularstains: oil red 0; osmium tetroxide; sudan black B; and the nile blue sulfate stain for neutral fats nevi of the nasal region. and fatty acids. With the exceptions given, the procedures were carried out as outlined in the MATERIALS AND METHODS "Manual of Histologic and Special Staining Tech- nies" (5). The study was conducted on 42 fibrous papules of the nose removed from 40 patients. Tbe ma- CLINICAL DATA terial from 6 of the 40 patients was from The Armed Forces Institute of Pathology (AFIP). The Fibrous papule.—The fibrous papule oc- files of the AFIP include case material from mili-curred predominantly in the Caucasian race. tary, veterans administration and civilian sources. Clinical and pathological observations were sup-Twenty-two patients were men, and 15 were plemented by clinical records, surgical reports,women. The only Negro patients were 2 men. questionnaires, and/or personal interview and ex-The median age of the 40 patients at first amination of the patient. Follow-up data was ob-biopsy or treatment was 41 years. The young- tained from 34 patients. For comparative purposes, est was 14, and the oldest 65 years. The dura- 70 cellular nevi removed from the nose of 65 patients were studied. For purposes of this paper,tion of 2S lesions in 26 patients from stated the term cellular nevus is used to indicate a nevusonset to time of biopsy removal or treatment cell nevus. All specimens were fixed in 10% neutral varied from 3 months to 16 years. The median buffered formalin and the tissue was processed forduration was 3 years, i.e. half of the patients routine paraffin-blocked sections. Multiple sections stained with hematoxylin and eosin were examined had a biopsy diagnosis established within 3 in all eases. Sections from 15 fibrous papules andyears after recognized onset. 10 cellular nevi were prepared by the following The fibrous papule usually appeared dome- shaped and was flesh-colored, pigmented or This investigation was supported in part by re- search training grant no. 2A-5289 (C2), from theangiomatous (Fig. 1). A few of the lesions National Institute of Arthritis and Metabolicwere sessile, polypoid or papillomatous. The Diseases, U. S. Public Health Service, Bethesda, Maryland 20014. majority of the lesions were firm and indurated, Presented by title at the Twenty-fith Annualbut a few were soft. The size of the lesions Meeting of The Society for Investigative Derma-varied from 1 to 5 mm in diameter; the median tology, Inc., San Francisco, Calif., June 21—23, 1964. Received for publication September 25, 1964. was 3 mm. Most patients stated the lesion * From the Skin and Cancer Hospital of Phila-was asymptomatie, although a few mentioned delphia, Department of Dermatology, Templeepisodes of erosion and bleeding usually associ- University School of Medieine,t Philadelphia, Pa. 19140, and The Armed Forces Institute of Pa-ated with trauma. Forty-two lesions from 40 thology4 Washington, D. C. 20305. patients involved the nose as illustrated in 194 FIBROUS PAPULE OF THE NOSE 195 Figure 2. The majority of the lesions were lo- .. cated on the ala nasi. Thirty-eight patients had a single lesion and the other 2 patients had 2 lesions each. The initial clinical diagnosis in 18 patients was cellular nevus. Other diagnoses were: fibrous papule, 7; fibroma, 2; telangiectasia, 2; hemangioma, 2; and keratosis, epithelioma, neurofibroma, verruca, granuloma pyogenicum, ulceration, epidermoid cyst, papilloma, and milia, 1 each. Family history was not significant. Six patients had cellular nevi of the head and neck region confirmed by biopsy examination. One patient had a primary malignant melanoma of the scalp. This latter patient and 1 other had basal cell carcinoma of the skin. Treatment of the fibrous papule was by surgical excision in 34 patients, excision and desiccation of the base of the lesion in 5, and FIG. 2. Anatomic distribution of42 fibrous pap- desiccation and curettement in 1. Surgical exci-ules on the nose. sion was by sharp blade removal of the lesion flush with the surface of the surrounding skin. the first biopsy diagnosis of the fibrous The follow-up period for 34 patients, frompapule to the last known status, ranged from 2 months to 9.3 years. The median was 17 months. None of the patients have had recur- rences. Only 1 patient is known to be dead and death was caused by malignant melanoma with widespread metastasis. Six of the 40 patients in the study were lost to follow-up. Cellular nevi.—Cellular nevi of the nose oc- curred predominantly in the Caucasian race. Only 5 of the 65 patients were Negro. Forty- two patients were women, and 23 were men. The median age of the 65 patients at the time of first biopsy or treatment was 37 years. The youngest patient was 13, and the oldest 84 years. The duration of 44 lesions in 41 patients from stated onset to biopsy examination varied from 3 weeks to 78 years; the median was 5 years. Clinically, the majority of the 70 cellular nevi of the nose appeared dome-shaped, smooth, and flesh-colored to brown. A few of the nevi were sessile, polypoid or papillomatous. The consistency of the lesions varied from firm to soft. The size of the lesions varied from 1 to 9 mm in diameter; the median was 4 mm.

Fio. 1. Fibrous papules of the nose. One lesion HI5TOPATHOLOGIC AND HISTOCHEMICAL is located near the rounded eminence of the ala nasi and the other at the superior aspect of the OBSERVATIONS nasolabial fold. Both lesions are dome-shaped, but one is flesh-colored, and the other pigmented and Fibrous papule: In hematoxylin- and eosin- angiomatous. stained preparations, the fibrous papules showed a 196 THEJOURNAL OF INVESTIGATIVE DERMATOLOGY dome-shaped or papular to polypoid configura-centric or laminated pattern (Figs. 6 and 7a). In tion, fibrosis and vascular ectasia (Fig. 3). ilyper-a few lesions, the perifollieular fibrosis was asso- keratosis and acanthosis was seen in some exam-ciated with atrophy of the lanugo hairs (Figs. 6 ples, and a few lesions showed superficial erosionand Ia). In the upper eorium, the fibrous prolifera- of the epidermis. Variable numbers of vacuolatedtion showed a tendency to run in wavy fibrillar cells were seen in the epidermis in 34 of the 42strands at right angles to the overlying epidermis lesions (Fig. 4). An increased amount of melanin(Figs. 3 and 4a). A few of the lesions showed pigment was present in the basal layer of the epi-myxomatous features as a part of the fibrous pro- dermis in many specimens. Melanoeytes were lo-liferation. Sebaeeous glands were present in 29. of cated at the dermoepidermal junction, and inthe lesions, and these often appeared rudimentary several specimens these cells were increased inand compressed by the surrounding fibrosis. All number (Fig. 4). The melanocytes in some areasof the lesions showed dilated vessels (Figs. 3, 4a, were grouped in small clusters and others showedand 6), and in some examples there were focal nuclei arranged in a peripheral ring about a cen-areas of eapillary-endothelial proliferation and tral mass of cytoplasm. Sections from 5 of theextravasated red blood cells. lesions showed single theques of nevus cells at the Results of bistoehemical studies were as fol- dermoepidermal junction (Fig. 4), and 1 showedlows: The Fontana-Masson stain for melanin changes resembling senile lentigo. A few lesionsshowed an abundance of pigment in the basal layer showed areas of an indistinct basement membraneof the epidermis and in the lanugo hair follicles at the dermoepidermal junction associated with(Fig. 6). In the eorium, the melanin granules were incontinence of melanin pigment. Focal areas offree, within giant cells and/or melanophages (Fig. inflammation were present in the corium and com-5). The colloidal iron reaction demonstrated re- posed of variable numbers of lymphocytes, histio-active material in the large cutaneous nerves, cyto- cytes, and plasma cells (Fig. 4a). Thirty-six of theplasm of the giant cells, interfibrillar ground sub- lesions contained multinucleated giant cells. Moststance, outer root sheath and dermal papilla of of these giant cells showed a peripheral ring oflanugo hair follicles, mast cells, and particulate nuclei arranged about a distinct mass of cyto-granules in the epidermis and corium. The ma- plasm, but others varied in size and shape, andority of the reactive substance in the cutaneous appeared stellate, fusiform, spindled or dendritienerves, interfibrillar ground substance and outer (Figs. 5, 7b and 7c). These giant cells were seenroot sheath of the hair follicles was hyaluronidase- most often in the papillary corium, but were ob-labile, and interpreted as byaluronie acid. The served at all levels in the fibrous stroma. Lanugovarious colloidal iron reactive sites wese Feulgen hairs were observed in 33 of the lesions and fibro-negative and were not altered by ribonuclease di- sis was striking, because the proliferation wasgestion. There is a possibility that the acid sub- arranged about these structures in a unique eon-stance in the giant cells and about particulate

t Fic. 3. Fibrous papule showing dome-shaped configuration, fibrosis and vascular ectasia. II & E,)< 38. FIBROUS PAPULE OF THE NOSE 197 • WCE

Fm.4. Fibrous papule. a. Dome-shaped configuration, vascular ectasia, and melanocytes and a theque of nevus cells (arrow) at the dermoepidermal junction. H & E, A 120. b. Higher magnification of a. illustrates the theque of nevus cells at the tip of a rete ridge. Melanocytes are present along the sides of the rote ridge. H & E, A 430. granules in the epidermis and cerium representssin negative at pH 1.7 and 0.4, but reacted with ribonuclease resistant nucleic acid complexes asso- aleian blue at pH 2.5. Since iron compounds in ciated with the tyrosine-tyrosinase reaction ofthe tissue may produce a false positive colloidal melanin synthesis. Mast cells and the dermal hairiran reaction, Gomori's reaction for iron was used papillae are known sites of sulfated acid muco-as a control. Iron was absent in the corium. polysaccharides and this accounts for the resist- The vacuolated cells in the epidermis were PAS ance to hyaluronidase and ribonuclease digestion.negative, whereas some melanoeytes at the dermo- The mast cells and dermal hair papillae were posi-epidermal junction and giant cells in the cerium tive with aldehyde-fuehsin at pH 1.7 and 0.4, andcontained PAS-positive diastase-resistant material with alcian blue at pH 2.5 and 0.4. These resultsin the cytoplasm. The exact nature of this positive verify the presence of sulfated acid mueopulysac- charides in the mast cells and dermal hair papillaematerial is not known, but it may represent a re- since at low pH values (0.4) only strongly acidaction of nucleic acid complexes associated with substances such as the sulfated acid mueopoly-melanin or melanin synthesis. Variable amounts of saccharides will yield a positive reaction. ThePAS-positive diastase-lahile material (glycogen) mast cell population was increased and as high aswas present in the outer root sheath of the lanugo 25—30 per high power field in several examples ofhairs. the fibrous papule. The hyaluronic acid in the Bodian's method for nerve fibers and nerve end- interfibrillar ground substance was aldehyde-fueh-ings demonstrated a network of fine nerve fibrils ¶/4t44Ø

a .4' 71 I• 4

J1L Fia. 5. Fibrous papule. a. Multinucleated giant cells and melanin pigment in the corium. One of the giant cells has a dendritie process intimately associated with it. Fontana-Masson stain, X395.b. High power magnification showing melanin pigment free and within a giant cell. Fontana-Masson stain,>< 635.

a - 1: ; Y-Th:c;-H. - - -- :-t"' - -' a - _"W - - - wr - '- - H. - - 7 .- -- - y I • -. ------:[.--. - - -'. - —-.-- _t - - -I - - •* --- - -'n - /—------I

•Fic. 6. Fibrous papule showing melanin in the epidermis and hair follicles. Fibrous proliferation about lanugo hairs is arranged in a concentric pattern. Outlines of atrophic follicles are present. Fontana-Masson stain, X 66. 198 FIBROUS PAPULE OF THE NOSE 199

a a AS • FIG.7. Fibrous papule. a. Reticular fibers surround lanugo hairs and outline atrophic follicles. Snook's reticulum stain, ><115.b. A dense network of reticular fibers are located about individual giant cells and inflammatory cells. Snook's reticulum stain, ><305.e. No elastic fibers are present in the corium. Several giant cells are present. Pentachrome 1 stain, X305. ramifying the fibrous stroma and showing an in-theques of nevus cells at the dermoepidermal timate relationship to the giant cells. junction. Elastic tissue stains demonstrated a decreased Variable amounts of melanin pigment was pres- to absence of elastic fibers (Fig. 7c). The penta-ent in the basal layer of the epidermis. In many chrome stain showed thickened collagen bundlesof the lesions, the number of melanocytes was in- and an associated fibrocytic proliferation. In areascreased along the dermoepidermal junction and of inflammation, about giant cells, lanugo hairs,an occasional nevus giant cell was observed. In and blood vessels there was a prominent prolifera-general, a grenz zone of connective tissue sepa- tion of reticular fibers (Figs. 7a and 7b). rated the epidermis from nests and strands of The giant cells failed to react to the various fatnevus cells located in the eorium. Often the nevus stains. cells were arranged at right angles to the epi- Cellular ned: Of the 70 lesions studied, 42 weredermis. Nevus giant cells were common and ob- histologically classified as intradermal cellular neviserved at all levels of the corium, but were more and 28 as compound cellular nevi. Many of tbeconcentrated in the upper eorium. These giant latter group would ordinarily be classified as intra-cells were of 2 morphological types; 1 type ap- dermal cellular nevi, but multiple sections in-peared as clusters of nevus cells and the second variably demonstrated a single or only a fewtype showed a peripheral ring of nuclei arranged 200 THEJOUENAL OF INVESTIGATIVE DEEMATOLOGY

about a mass of cytoplasm. Intermediate forms ofthe cytoplasm. Mast cells were observed in in- the 2 types were observed. Dilated vessels, nervecreased numbers and scattered throughout the trunks, laougo hairs, and sebaceous glands werenests and strands of nevus cells. The substance seen in the majority of the lesions. Evidence ofdemonstrated in the nevus cells and nevus giant regression with thinning out of nevus cells wascells probably represents nucleic acid complexes observed in several oevi. The changes of regres-associated with the production of melanin. sion included fibrosis, inflammation, and fat infil- The Bodian stain showed fine argyrophilic nerve tration. The nevus giant cells showed some dis-fibers ramifying and intimately associated with tortion, but were still intact in regressing lesions.the nests and strands of nevus cells. The fibrous proliferation about nevus cells in some The pentachrome stain showed thinning or ab- areas was dense and appeared to be "choking thesence of elastic and collagen fibers in areas occu- nevus cells." Lanugo hair follicles were surrounded pied by the nevus cells. Elastic fibers appeared and compressed by connective tissue fibers ar-normal or hypertrophic beneath and lateral to the ranged in a laminated configuration (Fig. 8). Innests and strands of nevus cells. Reticular fibers one of the nevi showing changes of regression,surrounded and separated the aggregates of nevus multiple sections revealed 2 theques of nevos cellscells. at the junction of the dermis and outer root sheath Some of the nevus cells and nevus giant cells of a rudimeotary pilosebaceous follicle located incontained lipid material and this was demon- the deeper corium. strated by all the fat stains utilized. Special histochemical studies showed the following significant results: The Fontana-Masson DISCUSSION stain for melanin demonstrated an abundance of Zackheim and Pinkus (fi), in 19fi0, reported pigment in the epidermis, nevus cells, nevus giant cells, melanophages, and free in the corium. 5 patients with papular lesions of the skin The nevus cells and nevus giant cells containedunder the title of "perifollicular fibromas." cytoplasmic colloidal iron positive material whichThey (fi) described the lesion as showing was: hyaluronidase and ribonuclease resistant;pathological changes of a benign fibroma with a Feulgen negative; aldehyde-fuchsin negative; and alcian blue reactive at pH 2.5 and negative at pHstriking perifollieular arrangement of collagen 0.4. An occasional nevus cell and nevus giant cellfibers. In their (fi) review of the literature, contained PAS-positive diastase-labile material inthe report of 1 case by Burnier and Rejsek (7)

Fm. 8. Intradermal cellular nevus of the nose showing regression changes. Fibrotic connective tissue is "choking" the nevus cells and is arranged about a lanugo hair in a concentric pattern. H & E, >< 103. FIBROUS PAPULE OF THE NOSE 201 was considered as showing the pathologichad their lesions diagnosed as cellular nevi, and changes of a fihroma with a perifollicular pat-6 patients had histological evidence of nevi tern. Zackheim and Pinkus (6) considered pen-involving the head and neck region. Compari- follicular fibromas as a relatively rare condi-son of clinical data from patients with fibrous tion, and described the lesions clinically aspapules and cellular nevi of the nose show a small firm papules, either flesh-colored or pink,striking similarity. and located on the face and neck. They (6) Histologic evidence supporting origin of the mentioned the clinical appearance was not dis-fibrous papule from a cellular nevus include: tinctive, but suggested a nevus, triehoepitheliomaconfiguration of the lesion; abundance of or related condition. Zackheim and Pinkus (6)melanin pigment; 5 lesions with theques of concluded that perifollicular flbromas eitherncvus cells at the dermoepidermal junction; constituted a true nevoid condition, falling inincreased numbers of melanocytes at the the broad category of adnexal tumors, or simplydermoepidermal junction; 1 lesion with epi- represented a fibroblastic response to previousdermal changes resembling senilelentigo; follicular inflammation. Nickel and Reed (8),vacuolated cells in the epidermis; fibrosis with in 1962, reviewed 74 biopsies from the skin ofa tendency for the fibers to run at right 38 patients with tuberous sclerosis and stressedangles to the epidermis; vascular ectasia; the fibrous and vascular changes in the cutane-lanugo hairs; giant cells resembling nevus ous hamartomas of this disease. Percival,giant cells; colloidal iron positive material in Montgomery and Dodds (9), in 1962, illustratedthe giant cells; melanin pigment in the giant the histopathology of a soft fibroma in figure 377.cells; intimate relationship of nerve fibers to They stated, "Numerous hair follicles may bethe giant cells; thinning or absence of elastic present in those which develop and enlarge onfibers; and a proliferation of reticular fibers the face in middle-aged females." The grossabout the giant cells. morphology of the fibrous papule is not en- The natural regression of cellular nevi bas tirely distinctive, but there is a good possibilitybeen reported in detail by Unna (11), Lund that the clinical photograph illustrated inand Stobbe (12), and Stegmaier (13, 14). figure 32 by Conway (10) represents an ex-Stegmaier (13, 14) lists inflammation (halo ample. Conway (10) referred to a dome-shapednevus phenomenon), development of skin tags, lesion of the tip of the nose as representativefibrosis, and fat degeneration as changes in- of fibroma durum. Microscopically, there is avolved in the pathogenesis of regression and resemblance between the facial angiofibromasdisappearance of cellular nevi. Stegmaier (13) (8) of adenoma sebaceum, perifollicular fi-states that all regressing nevi show evidence of bromas (6), soft fihromas (9), and what wefibrosis, except for the very superficial, imma- have reported as fibrous papules of the nose.ture nevi with junctional proliferation. The microscopic changes of a lesion from the Our histopathologic observations in cellular face of a 34 year old woman illustrated innevi of the nose indicate a general sparsity of figure 6 in the report by Nickel and Reed (8)collagen in areas of the corium occupied by shows features identical with those seen innests and strands of nevus cells. As the nevus fibrous papules of the nose. The soft fibromacells disappear, the void is replaced by fibrous illustrated by Percival et al. (9) also appears identical with the lesion we are reporting. Itproliferation and this change appears to play a role in the involution of the nevus cells. The would appear that at least 4 of the cases with perifollieular fibromas (6) are identical to thereason for a persistent fibrous papule as a lesions from our patients with fibrous papules ofresidual of a regressed cellular nevus is difficult the nose. Cases 2 and 5 had perifollicular fibro-to answer, but anatomical location may be an mas (6) located on the nose, and case 3 hadimportant factor. Replacement of the nevus papules on the cheeks, chin and nose, but thecells in the corium by dense fibrosis could exact location of the lesion removed for biopsymaintain and accentuate the dome-shaped was not recorded. contour initially present in a cellular nevus There is considerable evidence supportinglocated on the nose. origin of the fibrous papule from a pre-existing Absence or thinning of elastic tissue in the cellular nevus. Clinically, 18 of the 40 patientsfibrous papules and cellular nevi that we studied 202 THEJOURNAL OF INVESTIGATIVE DEEMATOLOGY is supported by the observations of Unna (11),possible that only a minority of patients seek and Mehregan and Staricco (15). Unna (11)medical attention. observed that wherever nevus cells are numerous, all the elastic tissue between them 5UMMAEY perisbes, but close to the margin of the nevus A clinicopathological study of 40 patients the elastic tissue remains unaffected. Mehreganwith a distinct isolated fibrous papule of the and Staricco (15) studied intradermal nevi andnose is reported. The histogenesis and patho- observed that the elastic fibers in the uppergenesis of this unique tumor indicates the lesion portions of the tumor showed a tendency toprobably represents the residual of a cellular become gradually finer and thinner. nevus in which stromal elements persist because The network of nerve fibers demonstratedof the anatomical location. There is a micro- in fibrous papules and cellular nevi of ourscopic similarity of the fibrous papule to facial study are supported by the observations oflesions of adenoma sebaceum and solitary Shelley and Arthur (16). They (16) reportedhamartomas. For this reason the possibility that intradermal cellular nevi regularly possessthat the lesion could represent a hamartoma or an extremely dense network of fine nerve fibers,unusual type of neural end organ tumor can and these filaments arise from large mixednot definitely be ruled out. We propose the nerve trunks and penetrate virtually betweenname of fibrous papule for this benign dome- every nevus cell. shaped tumor of the nose. Fibrous papule Fibrous papule appears to be a commonshould be included in the differential diagnosis lesion of the nose, although they undoubtedlyof lesions involving the nose, and particularly occur on other areas of the head and neckif the clinical characteristics are suggestive of a region. In reviewing lesions coded as fibrosis,cellular nevus. Excision of the lesion flush with fibroma, fibrous polyps, and fibroepithelialthe surrounding skin is adequate treatment polyps, in over 20,000 accessions, we accepted 5and allows for excellent cosmetic results. lesions as clinically and microscopically similar to the fibrous papule of the nose. These 5 REFERENCES lesions were located on the lower eyelid near 1. McManus, J. F. A. and Mowry, R. MT.: Stain- the inner canthus, preauricular region, chin, ing Methods: Histologic and Histochemical, nasolabial fold, and forehead. Only the lesion pp. 133—135. New York, Paul B. Hoeber, Inc., Medical Book Dept., Harper and Row, from the chin showed completely characteristic 1960 changes of the fibrous papule of the nose. This 2. Movat, H. Z.: Demonstration of all connective was a 3 mm papule from a 44 year old Negro tissue elements in a single section. Arch. Path. (Chicago), 60:289,1955. man who stated the lesion had been present 3. 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10. Conway, II.: Tumors of the Skin, p. 46.13. Stegmaier, 0. C.: Natural regression of the Springfield, Ill.,CharlesC Thomas, 1956. melanocytic novus. J. Invest. Derm., 32: 11. Tjona, P. G.: The Histopathology of the Dis- 413,1959. eases of the Skin, pp. 1129—1140 (Translated 14. Stegmaier, 0. C.: Life cycle of the nevus. by Norman Walker.) New York, Macmillan Mod. Med., 31:79,1963. and Co., 1896. 15. Mehregari, A. H. and Starieco, It. C.: Elastic 12. Lund, H. Z. and Stobbe, G. D.: The natural fibers in pigmented nevi. J. Invest. Derm., 38:271,1962. history of the pigmented nevus; factors of16. Shelly, W. B. and Arthur, H. P.: Nerve fibers, age and anatomic location. Amer. J. Path., a neglected component of intradermal cellu- 25:1117,1949. lar nevi. J. Invest. Derm., 34:59,1960.