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. Immunocytochemical studies for the localization o f S-100 protein in the blue nevus cells were performed. A comprehensive review 6 f 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 clinically or colposcopically. However, it appears in most instances as a blue-black lesion in the posterior 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 ultrastructural observations, s u p p o r t s c o m b i n e d m e l a n o c y t i c and schwannian differenti~ltion of the blue nevus cell. Huxt PATilOL 1 6 : 7 9 - 8 6 , 1985.

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

Immunocytochemlcal Studies for S-100 protein

Formalin-fixed p a r a f f i n - e m b e d d e d sections from two cases were studied for localization of S-100 protein by a modification of the peroxidase-antiperoxidase (PAP) lnethod of Sternberger. 21 Sections were d e p a r a f f i n i z e d , h y d r a t e d , and sequentially treated with rabbit anti-S- 100 protein antibody (Dako Corporatiola, Santa Barbara, California), stleep antirabbit 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-dilnethylforlnalnide rather than in diaminobenzidine. The visible 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-fixed p a r a f f i n - e m b e d d e d sections from five cervices obtained from ltysterectomy specinaens that did not contain blue nevi served as additional 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 lnicroscope; a didyxniuln filter was used to enlmnce the contrast between the red reaction product and the brown lnelanin pigntent.

Bhxe nevi of the endocervix, like other extracutaneous bhle nevi, are rare, benign, pigmented, melanin-containing lesions. Only 47 cases ltave been reported in the literature, l-'-'0 Most of these clitfically unsuspected lesions have been incidental findings dnring gross and microscopic examination of hysterectolny or cervical biopsy specilnens. D n r i n g the seven-year period from 1977 to 1983, we saw tltree blue nevi of the endocervix. Tlle present paper reports on gross pathologic, light microscopic, ilnnmnocytochentical, 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,ltnres.

MATERIALS AND METHODS

Tlte surgical pathology files of Sinai Hospital were reviewed for the period front 1977 to 1983, revealing 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 obtained fi'om the patients' medical records. In two cases tire hysterectolny specintens were available for gross patllologic review as well as for exaxnination under a dissecting nncroscope.
4 . .

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-buffered gluteraldehyde and postfixed in osmium tetroxide. Approl)riate thit~ sections were stained with uranyl acetate and lead citl-ate for ultrastructnr,tl exalnination.

Light Microscopic Examination

Appropriate sections of the cervix from tlte pigmented areas were fixed in 10 per cent neutral buffered forlnalin, entbedded in paraffin, cut at 6 p.m,

Received from tile Department of Pathology,Sinai Hospital RESULTS of l~ahimoreand 1"heJohus Hopkins UniversitySchool of Medicine, Bahimore, Maryhmd. Accepted for publication March 7, GrossPathologic Findings 1984. Address correspondence and reprint requests to Dr. BhaThe blue to blue-black, flat, 2- to 3-111111 ill-degavan: Sinai llospital of Bahimore, Bahimore. MD 21215. fined lesions were located ill the endocervix and ex79

HUMAN PATHOLOGY

Volume16, No. I [January '1985]

tein. In general, tile red reaction product was visualized in inverse proportion, to the amount of intracytoplasmic melanin. In addition, S-100 protein-containing nerve cells were distributed througlaout the cervix. Negative control specimens showed no reaction product. The sections of granular cell myoblastomas stained for S-100 protein. The five additional control cervices that were examined showed numerous stained nerve and sheath cells distributed t h r o u g h o u t 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 M i c r o s c o p i c Findings

FI@UREi. 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 intraoperatively.
Light Microscopic Findings

T h e light microscopic findings were similar in the three cases. Collections of spindle cells, the majority of which had bipolar or dendritic processes, were observed in the superficial endocervical stroma, in the vicinity of the squamocolumnar junction, beneath the overlying mucosa and between the endocervical glands (fig. 2). T h e 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 a n d black with Grimelius and Fontana-Masson stains (fig. 3). However, the granules failed to react with the Prussian blue, periodic acidSchiff, and colloidal iron stains. T h e cytoplasm of these cellg a p p e a r e d blue with Masson's trichrome stain. In no specimen did the overlying colunmar or squamous epithelium show the presence of pigmentcontaining cells. In case 3 similar cells were found s'cattered in the stroma o f the small endocervical polyp.
Immunocytochemical S-100 Protein Localization of

Ultrastructurally, the pigment-bearing cells had spindled, e l o n g a t e d appearances, with modest a m o u n t s o f cytoplasm. Intricate elongated cytoplasmic processes extended into dense collagenous stroma. The cytoplasm was richly packed with fidly melaninized, discrete, m e m b r a n e - b o u n d electrondense 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 microfilaments were sparse. An occasional tight jtmction could be seen between the adjoining nevus cells (fig. 5). The plasma membrane was surrounded by a tmiform, occasionally interrupted basal lamina that separated the cell body fi'ont the surrounding dense collagenous matrix (fig. 5). Plasmalemmal interdigitations or mesaxon-like structures 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

T h e S-100 protein a p p e a r e d as a diffuse 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 pro80

The most distinctive featnre of blue nevi of tile cervix is the presence of elongated, slender, somewhat wavy and dendritic melanin-containiug cells, in irregular clusters or scattered deep in the subepithelial stroma and between tile endocervical glands and tunnels. These cells lie parallel and close to the endocervical mucosal el)ithelium, which remains uninvolved by the nevus cells. The finely granular, intracytoplasmic argyrophil and argentaffin melanin pigment is usually abundant. Melanophages and mast cells are frequently observed. These features are similar to tbose of the common cutaneous blue nevus. The common blue nevus of the skin, first described by Ti6che in 1906, 23 is a widely recognized cutaneous pigmented lesion. Babes 24 was the th'st to

BLUE NEVUS OF UTERINECERVIX (Patel & Bhagavan]

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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. [FontanaMasson stain, x 56.] Inset, elongated, spindled and dendritic features of the nevus cells. [ x 400.]

HUMAN PATHOLOGY
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Volume '16,No. '1 (January 1985]

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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 recognized until 1959, when Cid I described the lesion in uteri removed from two patients for myomas. Subsequently, 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 reasons otheq than the presence of the pigmented lesion itself. 4-2~ Our finding of three blue nevi of the cervix a m o n g 2,500 hysterectomy specimens fi~rther supports the relative rarity of the lesion. E x t r a c u t a n e o u s blue nevi have also been reported 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
82

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 b l u e gray p i g m e n t e d macules and a p p e a r e d 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). T h e 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 o f two or more ill-defined p i g m e n t e d 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 o f cervical biopsy specimens, 7,'~ an endocervical polypY cervical biopsy cone specimens, 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, dysflmctional uterine bleeding, and other similar reasons. T h e 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 sections, supports the observation that blue nevi of the cervix occur predonfinantly in middle aged and elderly women. Celhflar blue nevi are generall)' considered benign 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. Extracutaneous 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 ,15month follow-up period, the vaginal tumor was described 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, h e m o r r h a g e within nabothian cysts, foci of hemosiderin deposits due to obstetric and surgical trauma, and malignant melanoma. Ahnost all cases of superficial ectocervical endometriosis are ap-

BLUE NEVUS OF UTERINE CERVIX [Patel & B h a g a v a n ]

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FIGUI~E 5 [top]. S p i n d ! e - s h a p e d blue nevus cells c o n t a i n i n g m e l a n o s o m e s in various stages o f m a t u r a t i o n [ u p p e r insels]. L o w e r inset, a continuous basal l a m i n a e n v e l o p s the nevus cell [thin arrows]. Rare tight junctions a r e also present [thick arrow]. A fibroblast {fJ is visible a t t h e lower right9 [Uranyl a c e t a t e a n d l e a d citrate stain9 x 6,300. U p p e r inset, x 40,400; l o w e r inset, x 16,800.] FIGURE 6 [ b o t t o m ] . Interstitium o f blue nevus containing, in a d d i t i o n to the typical striated c o l l a g e n fibrils, fibrous l o n g . s p a c i n g c o l l a g e n Luse b o d i e s [lu]. The p i g m e n t - b e a r i n g processes o f the nevus cells show a basal l a m i n a [arrows]. A fibroblast [0 is visible [top right o f field]. [Uranyl a c e t a t e a n d l e a d citrate stain9 x 43,600.) 83

HUMAN PATHOLOGY

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

25

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TABLE t.

Blue Nevus of the Cervix: Location in the Endocervix

No. o f Cases* 5 22 1 24 52

as siderosis o f the cervix. 4 Histologically, tile coarseland m o r e retractile hemosiderin granules stain for iron and are n o n a r g e n t a f f i n . Epithelial pigmentation, junctional actMty, and cytologic features o f malignancy are clmracteristics o f m e l a n o m a o f tile cervix and are absent fl'om blue nevi. O u r electron microscopic d e m o n s t r a t i o n o f mel a n o g e n i c o r g a n e l l e s a n d m e l a n i n g r a n u l e s in the nevus cells is similar to the uhrastructnral observations o f previous a u t h o r s who studied cervical blue nevi. 8,9.11.12,17,~~ O u r f i n d i n g o f p r o m i n e n t basal lamina investing the nevus cells is similar to the findings o f Diaz De M o l n a r et al., II O s a m u r a et al. 17 and K u d o et al. 2~ but is not in a g r e e m e n t with the findings o f H e r n a n d e z , s W a x m a n and Vuletin, 9 and U f f and Hall. l" We were not able to d e m o n s t r a t e the pinocytotic vesicles in the cytoplasm o f tile blue nevus cells that were described by Diaz De M o l n a r et al. II and K u d o et al. 2~ Fibrous long-spacing collagen or the Luse b o d i e s o b s e r v e d in o u r cases h a v e b e e n described 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 i n t e r d i g i t a t i o n s a n d m e s a x o n - l i k e s t r u c t u r e s have been identified only by K u d o et al. 2~ T h e uhrastructural featurhs o f the blue nevus cell, as r e p o r t e d by various authors, are presented in table "t. Notwithstanding these differences, it is clear that the blue nevus cells o f the cervix have overlapping features o f m e l a n o c y t i c a n d S c h w a n n cell d i f f e r e n t i a t i o n . T i l e presence o f a melanogenic apl)aratus in these cells is s u f f i c i e n t e v i d e n c e f o r melanocytic d i f f e r e n t i a t i o n . T h e p r o m i n e n t basal lalnina a r o u n d cell bodies, elong a t e d c y t o p l a s m i c p r o c e s s e s e n v e l o p e d in basal lamina, cell junctions, myelin figures, lysosomes, and

l.ocation Anterior wall Posterior wall Anterior and posterior wall Not stated Total

TABLE 2.

Blue Nevus of the Cervix: Method of Diagnosis

Type of Tissue
Uterus Cervical biopsy specimen Cervical cone biopsy sl)ecimen Cervical polyp Enttometrial a n d endocervical curettage specimen Total

No. of Cases
,t2 5 l l 1 50

* In two cases two blue nevi are described, one on the anterior a n d one on the posterior wall o f the endocervix.

p a r e n t o n speculum o r colposcopic exmination o f the cervix, a p p e a r i n g e i t h e r as small, r o u n d , slightly elevated r e d , t o d a r k blue spots or as m o r e extensive m a c u l a r lesions. 38 P r i m a r y superficial e n d o c e r v i c a l endometriosis is e x t r e m e l y uncomnaon and is likely to be c o n f u s e d on gross e x a m i n a t i o n with tile e n d o cervical blue nevus, ss H e m a n g i o m a o f the cervix appears as a diffuse red o r purple, somewhat raised 16siofi, with a t e n d e n c y to blanch on pressure. 39 H e m m o r r h a g i c n a b o t h i a n follicles a r e s h a r p l y dexnarcfited, elevated,, blue o r d a r k lesions. Histologically, n o n e o f these lesions should pose diagnostic probldms. However, grossly and nficroscopically evident pigmentatioil d u e to hemosiderin deposits is not unc o m m o n in the cervix and may resemble the blue nevus. Blue nevi lmve occasionally been misclassified 84

TABLE 3.

Blue Nevus of the Endocervix: Number of Lesions

No. of Lesions
Single Muhiple 2 3 5 6 >6 Not stated Total

No. of Cases
36 -t I I 1 1 6 50

BLUENEVUSOF UTERINECERVIX(Patel & Bhagavan] TABLE 4.

.Melalmgeuic Basal Lamiml Al)paratus + ~+
+

Blue Nevus of the Cervix: Ultrastructural Observations

Mesaxon-like Structures _
-

Author I iernandez s Waxman and : Vuletin 9 Diaz De Molnar et al. n U. f f and flail 1'-' Osamura et al. 17 Kudo et al. -'20 Present study

i'lasmalemlnal lnterdigitations

Fibrous l.ong-spacing Collagen NS NS

Tight Junctions NS NS + NS NS +
+

I'inocytotic Vesicles NS NS + NS NS +
-

Golgi Apparatus NS NS + NS NS + (Rare) + (Rare)

NS NS +

+ + + +

+ + +

NS + -

NS NS NS
+

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

Luse bodies, as a constellation o f 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 melanocytes 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 schwannian differentiation of these cells. T h e 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 c o n t a i n i n g tlm blue nevus) control cervices is intriguing. Whether this represents schwannian proliferation related to obstetric tl'auma or is a normal histologic feature of cervices remains to be elncidated. T h e literature is replete with arguntents concerning the histogenesis of blue nevus cells. T h e me" lanocyte, Schwann cell, endocervical stromal cells, and perineural cells have all been proposed as possible progenitor cells of the blue nevus. 1-20 Out" observations, 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 considered tire progenitor cell of both tnelanocytes and Schwann cells. T h e combined melanocytic and schwannian properties are also expressed by cells of tuntors r e g a r d e d as n e u r o e c t o d e r m a l neol)lastns, suclt as pigntented epithelioid schwannoma, 42 neur,ofibroma,43 clear cell sarcoma, 44,45 and experinten-, . ,I

sian f o r a s s i s t a n c e with t h e e l e c t r o n m i c r o s c o p i c e x a m i n a tion. T h e y also a c k n o w l e d g e t h e h e l p f u l criticisnts o f T i m Triche.

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tall)' 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 r0sustentactdar, or schwannian and fibrocytic prope r t i e s o f n e u r o c r i s t i c c e l l s s h o u l d b e r e g a r d e d as a mutable continuum..

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 and staff for l)hotography, Toby Merrenblutn for perf o r m i n g t h e i m t n u n o c y t o c h e m i c a l stu(lies, a n d S t e v e K e o 85

HUMAN PATHOLOGY

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