Blue Nevus of the Uterine Cervix

DEVBALA S. PATEL, MD, AND BELUR S. BHAGAVAN, MD

The clinical, gross pathologlc, and light and electron microscopic features o f three blue nevi of the endocervix were studied. Im- munocytochemical studies for the localization o f S-100 protein in the blue nevus cells were performed. A comprehensive review 6f 47 previously published cases is also presented. Blue nevi of the endocervix appear to be rare incidental lesions; they are often f6und in hysterectomy specimens from middle-aged women. The lesion is seldom detected cl inically or colposcopically. However, it appears in most instances as a b lue-black lesion in the pos- terior wall of the endocervix on gross pathologic examination. The demonstration of S-100 protein in the blue nevus cells before and after bleaching in the present study, along with the ultra- s tructural observat ions , supports combined me lanocy t i c and schwannian differenti~ltion of the blue nevus cell. Huxt PATilOL 16:79-86 , 1985.

Bhxe nevi of the endocervix, like other extracu- taneous bhle nevi, are rare, benign, pigmented, mel- anin-containing lesions. Only 47 cases ltave been re- ported in the literature, l-'-'0 Most of these clitfically unsuspected lesions have been incidental findings dnring gross and microscopic examination of hyster- ectolny or cervical biopsy specilnens. Dnring the seven-year period from 1977 to 1983, we saw tltree blue nevi of the endocervix. Tlle present paper re- ports on gross pathologic, light microscopic, ilnnm- nocytochentical, and ultrastrnctural features of tltese three cases and discusses the differential diagnoses of pigmented lesions of the cervix. We also present a comprehensive review of the previously published cases to elncidate the clinical and epidenaiologic fe,l- tnres.

MATERIALS AND METHODS

Tlte surgical pathology files of Sinai Hospital were reviewed for the period front 1977 to 1983, re- vealing three cases of bhle nevi of the cervix among 2,500 hysterectomy specimens. No blne nevi were identified in cervicaJ cone or biopsy specimens. The pertinent clinical and gross pathologic data were ob- tained fi'om the patients' medical records. In two cases tire hysterectolny specintens were available for gross patllologic review as well as for exaxnination

4 . .

under a dissecting nncroscope.

Light Microscopic Examination

Appropriate sections of the cervix from tlte pig- mented areas were fixed in 10 per cent neutral buff- ered forlnalin, entbedded in paraffin, cut at 6 p.m,

and stained with Lillie's melanin, Prussian blue, Gri- melius, Fontana-Masson, periodic acid-Schiff with and withont diastase digestion, colloidal iron, *las- son's trichrome, and Itematoxylin-eosin stains.

Immunocytochemlcal Studies for S-100 protein

Formalin-f ixed paraf f in-embedded sections from two cases were studied for localization of S-100 protein by a modification of the peroxidase-antipe- roxidase (PAP) lnethod of Sternberger. 21 Sections were deparaf f in ized , hydrated, and sequentially treated with rabbit anti-S- 100 protein antibody (Dako Corporatiola, Santa Barbara, California), stleep anti- rabbit gamlna globulila, and the PAP reagent. The site of S-100 protein was visualized by developing the slides in 3-amino-9-ethylcarbazol in N,N-dilnethyl- forlnalnide rather than in diaminobenzidine. The vis- ible reaction product appeared red and could easily be distinguished from the brown lnelanin pigntent. Endogenous peroxidases and nonspecific binding of collagen were blocked by pretreattnent of the slides with 3 per cent hydrogen peroxide and norlnal sheep serum. Nerve bundles in the adjoining cervical tissne and sections from granular cell ntyoblastomas served as positive control specimens. Parallel sections served as negative contol specintens; in these sections the specific anti-S- 100 protein antiserum was omitted and replaced by plmsplmte-buffered saline solution. This procedure was repeated after a Iwdrogen peroxide bleach was used to remove the melanin piglnent. 22

Formalin-f ixed para f f in -embedded sections from five cervices obtained from ltysterectomy spec- inaens that did not contain blue nevi served as addi- tional negative control specintens. These sections were treated in a manner identical to that nsed for the sections of the cervices containing bhte nevi.

The sections were examined with a' light lnicro- scope; a didyxniuln filter was used to enlmnce the contrast between the red reaction product and the brown lnelanin pigntent.

Electron Microscopic Examination

Small blocks of formalin-fixed tissne fl-om the pigmented areas of tire cervices fi'Oln cases 2 and 3 were diced and refixed in 2 per cent pllosphate-buff- ered gluteraldehyde and postfixed in osmium te- troxide. Approl)riate thit~ sections were stained with uranyl acetate and lead citl-ate for ultrastructnr,tl ex- alnination.

Received from tile Department of Pathology, Sinai Hospital RESULTS of l~ahimore and 1"he Johus Hopkins University School of Medi- cine, Bahimore, Maryhmd. Accepted for publication March 7, Gross Pathologic Findings 1984.

Address correspondence and reprint requests to Dr. Bha- The blue to blue-black, flat, 2- to 3-111111 ill-de- gavan: Sinai llospital of Bahimore, Bahimore. MD 21215. fined lesions were located ill the endocervix and ex-

7 9

HUMAN PATHOLOGY Volume 16, No. I [January '1985]

FI@URE i. Blue nevus of the endocervL~ Submucosal linear exten-- sion and poor circumscription of the blue-black pigmented lesion are evident. {x 6.}

tended along the superficial submucosal region of the lower endocervical canal (fig. 1). No tumefaction or distortion of the canal had been caused by the lesion. In case 3 there was a small endocervical polyp that did not appear to be pigmented. In none of the cases had the lesion been suspected clinically or intraop- eratively.

Light Microscopic Findings

The light microscopic findings were similar in the three cases. Collections of spindle cells, the ma- jority of which had bipolar or dendritic processes, were observed in the superficial endocervical stroma, in the vicinity of the squamocolumnar junction, be- neath the overlying mucosa and between the endo- cervical glands (fig. 2). The cytoplasm of the cells, including that of the dentritic processes, was filled with fine, brownish, nonrefractile 1)igment granules. These granules appeared green when stained with Lillie's melaniu and black with Grimelius and Fon- tana-Masson stains (fig. 3). However, the granules failed to react with the Prussian blue, periodic acid- Schiff, and colloidal iron stains. The cytoplasm of these cellg appeared blue with Masson's tr ichrome stain. In no specimen did the overlying colunmar or squamous epithelium show the presence of pigment- containing cells. In case 3 similar cells were found s'cattered in the s t roma o f the small endocervical polyp.

I m m u n o c y t o c h e m i c a l Loca l iza t ion of S-100 Protein

The S-100 protein appea red as a d i f fuse red reaction product within the cytoplasm of cells. The blue nevus cells, in addition to the brown melanin granules, contained variable amounts of S-100 pro-

tein. In general, tile red reaction product was visu- alized in inverse proportion, to the amount of intra- cytoplasmic melanin. In addition, S-100 protein-con- taining nerve cells were distributed througlaout the cervix. Negative control specimens showed no reac- tion product. The sections of granular cell myoblas- tomas stained for S-100 protein. The five additional control cervices that were examined showed nu- merous stained nerve and sheath cells distributed throughout the cervix but no melanin-containing cells. S-100 protein could still be localized in the blue nevus cells after the melanin had been bleached with hydrogen peroxide (fig. ,t).

Electron Microscopic Findings

Ultrastructurally, the pigment-bearing cells had spindled, e longated appearances , with modest amounts of cytoplasm. Intr icate e longated cyto- plasmic processes extended into dense collagenous stroma. The cytoplasm was richly packed with fidly melaninized, discrete, membrane-bound electron- dense granules, nunlerotls lamellar melanosomes, and several membrane-bound premelanosomes (fig. 5). Compound melanosomes were rarely seen. A few mitochondl~ia were dispersed among the granules. Secretory vacuoles, tonofilaments, myofilaments, and dense bodies were absent. Golgi complexes were not identified. Rough endoplasmic reticulum and micro- filaments were sparse. An occasional tight jtmction could be seen between the adjoining nevus cells (fig. 5). The plasma membrane was surrounded by a tmi- form, occasionally interrupted basal lamina that sep- arated the cell body fi'ont the surrounding dense col- lagenous matrix (fig. 5). Plasmalemmal interdigita- tions or mesaxon-l ike s tructures were not seen. Pinocytotic vesicles were absent. Mast cells and spindle-shaped fibroblasts, interspersed among the nevus cells, contained no melanin granules.

The intercellular stroma between the blue nevus cells was largely composed of typical striated collagen. Fibrous long-spacing collagen or Luse bodies were also present in the matrix, in close proximity to the blue nevus cells (fig. 6).

DISCUSSION AND REVIEW OF THE LITERATURE

The most distinctive featnre of blue nevi of tile cervix is the presence of elongated, slender, some- what wavy and dendritic melanin-containiug cells, in irregular clusters or scattered deep in the subepithe- lial stroma and between tile endocervical glands and tunnels. These cells lie parallel and close to the en- docervical mucosal el)ithelium, which remains unin- volved by the nevus cells. The finely granular, intra- cytoplasmic argyrophil and argentaffin melanin pig- ment is usually abundant. Melanophages and mast cells are frequently observed. These features are sim- ilar to tbose of the common cutaneous blue nevus.

The common blue nevus of the skin, first de- scribed by Ti6che in 1906, 23 is a widely recognized cutaneous pigmented lesion. Babes 24 was the th'st to

80

BLUE NEVUS OF UTERINE CERVIX (Patel & Bhagavan]

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~l~:~ : ~,, ' ~ ~ , FIGURE 2. [top] Pigmentecl blue nevus cells with spindle and dendritic features interspersed in the endocervical stroma and betwee~q endocervical glands. [Hematoxylin-eosin stain, x 56.] FIGURE 3 [bottom]. Pigmented lesion located in the submucosal endocenzical stroma accentuated by an argentaffin stain. [Fontana- Masson stain, x 56.] Inset, elongated, spindled and dendritic features of the nevus cells. [ x 400.]

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FIGURE 4. Immunocyfochemical localization of S-lOB protein in the blue nevus cells after application of hydrogen peroxide bleach. The stained nevus cells contrast with the nonreactive stroma as well as with the endocervical epithelium (top left of field). (Peroxidase- antiperoxidase reaction with rabbit anti-S-lO0 serum. Light green counterstain, x 140.)

describe the presence of melanin-containing cells in the uterine mucosa and in the stroma of a uterine polyp. However, the cervical blue nevus was not rec- ognized until 1959, when Cid I described the lesion in uteri removed from two patients for myomas. Sub- sequently, Cid ]-3 systematically reviewed ,t66 cervices and found nine blue nevi of the cervix, including the two previously described--an incidence of 1.9 per cent. Since that time, 38 cases have been reported in the literature, with most authors regarding the lesion as a rare incidental finding in uteri removed tbr rea- sons otheq than the presence of the pigmented lesion itself. 4-2~ Our finding of three blue nevi of the cervix among 2,500 hysterectomy specimens fi~rther sup- ports the relative rarity of the lesion.

Extracutaneous blue nevi have also been re- ported in other genital and extragenital areas, such ,as the vagina, 25 prostate gland, z~ oral mucosa, ss,-st and lymph nodes.SS, 30 The cervix appears to be the most comnton site for extracutaneous blue nevi: ,t7 of a total of 109 reported extracutaneous blue nevi were located in the cervix.

Blue nevi of the cervix have been found in adult women 22 to 73 years of age (fig. 7). The majority of the reported cases were in women in the fifth to the

sixth decades of life. Congenital blue nevi and blue nevi in pediatric patients have not been reported in this site. The patient's race was mentioned in only nine cases; five of these patients were black, and four were white.

The nevi were single, nonelevated, blue or blue- gray p igmented macules and appeared brown or black on cut surfaces. Most of the lesions were small and measured 1.0 to 't.0 mm in greatest diameter. Only two lesions were larger than 1.0 cm, measuring 1.5 and 2.0 cm, respectively (fig. 8). The most common location in the cervix was the posterior wall of the endocervical canal (table 1). In five cases the diagnosis was made from cervical biopsy specimens (table 2). 7,0,1"t- 16 In no instance did the lesion appear grossly to involve the external as, the ectocervix, or the adjoining endometritun. In eight cases the lesions consisted of two or more ill-defined pigmented patches along the endocervical canal (table 3).

Blue nevi of the cervix were seldom diagnosed or suspected prior to or during surgery. This is not surprising in view of the exclusive endocervical 1o: cation of these lesions. Except for a total of eight patients in whom the microscopic diagnosis was made on the basis of cervical biopsy specimens, 7,'~ an endocervical polypY cervical biopsy cone speci- mens, 15 and endocervical curettage specimens, l0 the remaining lesions were detected in patients 39 to 73 years of age as incidental findings in hysterectomy specimens removed for myomas, adenomyosis, dys- flmctional uterine bleeding, and other similar rea- sons. The higher incidence of this lesion in women in the fifth and sixth decades of life may reflect the large proportion of hysterectomies performed in this age group. However, the relative scarcity of reports of blue nevi diagnosed on the basis of cone biopsy of the cervix, a procedure done mostly in young women and examined by total blocking, often by serial sec- tions, supports the observation that blue nevi of the cervix occur predonfinantly in middle aged and el- derly women.

Celhflar blue nevi are generall)' considered be- nign variants of blue nevi, but the exact relation is unclear. Celhflar blue nevi, like blue nevi] are most conmtonly located in the skin and sul)cutis. Extracu- taneous celhflar blue nevi are extraordinarily rare. The only reported case of cellular blue nevus of the cervix, that reported by Rodriguez and Ackerman, 37 is unique in that the lesion was extensive, involving the cervix, wlgina, and hymenal ring. After a ,15- month follow-up period, the vaginal tumor was de- scribed as hard and nodular, whereas the cervical and vuh'ar components remained unchanged.

The differential diagnosis of blue nevus of the cervix includes assorted rare, as well as relatively common pigntented lesions of the cervix detected on colposcopic, gross, and histologic examination of the cervix. These lesions include cervical endolnetriosis, hemangiomas, hemorrhage within nabothian cysts, foci of hemosiderin deposits due to obstetric and sur- gical trauma, and malignant melanoma. Ahnost all cases of superficial ectocervical endometriosis are ap-

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FIGUI~E 5 [ top] . Spind !e -shaped b lue nevus cells con ta in ing me lanosomes in var ious stages o f matu ra t ion [ u p p e r insels]. L o w e r inset, a cont inuous basal l amina enve lops the nevus cel l [ th in arrows]. Rare tight junct ions a re a lso present [ th ick arrow]. A f ibroblast {fJ is visible a t the lower right�9 [Uranyl a c e t a t e a n d lead c i t rate stain�9 x 6,300. U p p e r inset, x 40,400; l o w e r inset, x 16,800.]

FIGURE 6 [ bo t tom] . Interstitium o f b lue nevus conta in ing, in add i t ion to the typical str iated c o l l a g e n fibrils, f ibrous l ong .spac ing c o l l a g e n - Luse bod ies [lu]. The p i gmen t -bea r i ng processes o f the nevus cells show a basal l amina [arrows]. A f ibroblast [0 is visible [ top right o f field]. [Uranyl a c e t a t e a n d l ead c i t rate stain�9 x 43,600.) 8 3

HUMAN PATHOLOGY Volume '16, No. 't [January 1985)

25

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AGE in YEARS

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FIGURE 7 (top}. Ages of patients with blue nevi of the cervix.

FIGURE g [bo#om). Sizes of b lue nevi of the cervix.

TABLE t. Blue Nevus of the Cervix: Location in the Endocervix

l.ocation No. o f Cases*

Anter ior wall 5 Posterior wall 22 Anter ior and poster ior wall 1 Not stated 24

Total 52

* In two cases two blue nevi are described, one on the anter ior and one on the poster ior wall o f the endocervix.

parent on speculum or colposcopic exminat ion o f the cervix, appear ing e i ther as small, round , slightly ele- vated r e d , t o dark blue spots or as more extensive macu la r lesions. 38 P r imary superf ic ia l endocerv ica l endometr ios is is ex t remely uncomnaon and is likely to be con f use d on gross examina t ion with tile endo- cervical blue nevus, ss Hemang ioma o f the cervix ap- pears as a diffuse red or purple, somewhat raised 16siofi, with a t endency to blanch on pressure. 39 Hem- m o r r h a g i c n a b o t h i a n follicles a re sha rp ly dexnar- cfited, elevated,, blue or dark lesions. Histologically, none o f these lesions should pose diagnostic prob- ldms. However , grossly and nficroscopically evident pigmentat ioi l due to hemosider in deposits is not un- c o m m o n in the cervix and may resemble the blue nevus. Blue nevi lmve occasionally been misclassified

as siderosis o f the cervix. 4 Histologically, tile coarsel- and more re t ract i le hemosider in granules stain for iron and are nonargenta f f in . Epithelial pigmentat ion, junct ional actMty, and cytologic features o f malig- nancy are clmracteristics o f melanoma of tile cervix and are absent fl'om blue nevi.

O u r electron microscopic demons t ra t ion of me- l anogenic o rgane l l es and melanin g ranu les in the nevus cells is similar to the uhras t ructnral observa- tions o f previous au thors who studied cervical blue nevi. 8,9.11.12,17,~~ O u r f i nd ing o f p r o m i n e n t basal lamina investing the nevus cells is similar to the find- ings o f Diaz De Molnar et al., II Osamura et al. 17 and Kudo et al. 2~ but is not in ag reement with the findings o f Hernandez , s Waxman and Vuletin, 9 and Uf f and Hall. l" We were not able to demons t ra te the pino- cytotic vesicles in the cytoplasm of tile blue nevus cells that were descr ibed by Diaz De Molnar et al. II and Kudo et al. 2~ Fibrous long-spacing collagen or the Luse bodies o b s e r v e d in o u r cases have b een de- scribed in association with cells o f celhdar blue nevi a~ but not in tile c o m m o n cutaneous blue nevus or tile" blue nevus o f tile cervix. Pronfinent plasmalemmal in te rd ig i ta t ions and mesaxon- l ike s t ruc tu res have been identif ied only by Kudo et al. 2~ T h e uhrastruc- tural featurhs o f the blue nevus cell, as repor ted by various authors , are presented in table "t. Notwith- s tanding these differences, it is clear that the blue nevus cells o f the cervix have over lapping features o f melanocyt ic an d Schwann cell d i f f e ren t i a t ion . T i le presence o f a melanogenic apl)aratus in these cells is suf f ic ient ev idence fo r melanocyt ic d i f f e ren t i a t ion . T h e p rominen t basal lalnina a round cell bodies, elon- ga t ed cy top l a smic processes e n v e l o p e d in basal lamina, cell junct ions , myelin figures, lysosomes, and

TABLE 2. Blue Nevus of the Cervix: Method of Diagnosis

Type of Tissue No. of Cases

Uterus ,t2 Cervical biopsy specimen 5 Cervical cone biopsy sl)ecimen l Cervical polyp l Enttometrial and endocervical

curet tage specimen 1

Total 50

TABLE 3. Blue Nevus of the Endocervix: Number of Lesions

No. of Lesions No. of Cases

Single 36 Muhiple

2 -t 3 I 5 I 6 1 > 6 1

Not stated 6

Total 50

84

BLUE NEVUS OF UTERINE CERVIX (Patel & Bhagavan]

TABLE 4. Blue Nevus of the Cervix: Ultrastructural Observations

.Melalmgeuic Author Al)paratus

Fibrous Basal Mesaxon-like i'lasmalemlnal l.ong-spacing Tight

Lamiml Structures lnterdigitations Collagen Junctions I'inocytotic Golgi

Vesicles Apparatus

I iernandez s + - - Waxman and ~-

: Vuletin 9 + - _ Diaz De Molnar

et al. n + + -

U. f f and flail 1'-' + - - Osamura et al. 17 + + NS Kudo et al. -'20 + + + Present study + + -

NS

NS +

NS NS NS NS

NS NS NS NS

NS + + + NS NS NS NS NS NS NS NS - + + + (Rare) + + - + (Rare)

ABI',REVIA'IIONS: NS, not stated; - , negative; + , positive.

Luse bodies, as a constellation of findings, stt'ongly indicate schwannian, differentiation.

S-100 protein, one o f the most extensively studied neural proteins, is found predominatltly in tim elements of the central and peripheral nervous systems and in the diffuse neuroendocrine system. 41 In addition, its presence has been reported in mela- nocytes and sotne nonnettral cells. 41 The presence of S-100 protein in the blue nevus cells fltrther supports our belief of the combined melanocytic and schwan- nian differentiation of these cells. The presence of numerous nontnelanized, S-100 protein-containing, bipolar dendritic cells in the stroma of the cervix in two of the present cases and in five nornml (i.e., not containing tlm blue nevus) control cervices is in- triguing. Whether this represents schwannian prolif- eration related to obstetric tl'auma or is a normal his- tologic feature of cervices remains to be elncidated.

The literature is replete with arguntents con- cerning the histogenesis of blue nevus cells. The me-

" lanocyte, Schwann cell, endocervical stromal cells, and perineural cells have all been proposed as pos- sible progenitor cells of the blue nevus. 1-20 Out" ob- servations, like those of others, contribute little to the resolution of the seenfingly etadless controversies and speculations as to the specific cell of origin of the blue nevus cell. However, tim combined melanocytic and schwannian features of blue nevus cells that we luwe dentonstrated suggest biphasic differentiation of the muhipotential neural crest cell, which is widely con- sidered tire progenitor cell of both tnelanocytes and Schwann cells. The combined melanocytic and

- , . , I

schwannian properties are also expressed by cells of tuntors regarded as neuroec todermal neol)lastns, suclt as pigntented epithelioid schwannoma, 42 neu- r,ofibroma, 43 clear cell sarcoma, 44,45 and experinten- ta l l ) ' i n d u c e d b l u e n e v i . "16 T h e s e o b s e r v a t i o n s s u p p o r t t i m a r g u n t e n t o f R e e d 47 t h a t t l t e m e l a n o c ) ' t i c , n e u - r 0 s u s t e n t a c t d a r , o r s c h w a n n i a n a n d f i b r o c y t i c p r o p - e r t i e s o f n e u r o c r i s t i c ce l l s s h o u l d b e r e g a r d e d as a m u t a b l e c o n t i n u u m . .

Acknowledgments T h e a u t h o r s t h a n k I ) o n a l d Y e a g c r a n d s t a f f fo r l ) h o t o g r a p h y , T o b y M e r r e n b l u t n f o r pe r - f o r m i n g the i m t n u n o c y t o c h e m i c a l stu(lies, a n d Steve K e o -

s ian for ass i s tance with t he e l ec t ron mic roscop ic e x a m i n a - t ion. T h e y also a c k n o w l e d g e t he he lp fu l cri t icisnts o f T i m T r i c h e .

85

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