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Granuloma pyogenicum
GRANULOMA
PYOGENICUM
DONALD A. KEKR, D.D.S., M.S., Ass
ARBOR, MICH.
T
HE lesion designated granuloma pyogenicum occurs commonly in the skin and the mucous membranes and is well recognized by the dermatologist. It has not received equal attention by all pathologists, dentists, and clinicians. To the patient and the clinician who are not familiar with the lesion, it is frequently viewed with alarm because it appears rapidly and tends to recur following partial removal. The lesion therefore frequently is thought to be malignant. tissue or more often Histologically, it is misinterpreted as granulation as an infected hemangioma. Because the lesion frequently is misinterpreted clinically and histologically and since the lesions of the mucous membrane have not been appreciated fully in the field of dentistry, the literature was reviewed and the available information was correlated in this review of 289 cases.
Historical In 1870 Bollinger,” and in 1884 Rivolta,” 4 described botryomycosis in horses following castration. In 1897 Yoncet and Do?’ described a lesion in man which was comparable to that described by Rivolta, and designated it botryomycosis hominis. Following the original description of Poncet and Dor in the French literature, several reports appeared in the German literature,““, 34,3jt 52 some of which questioned the etiology and terminology. The first report in the American literature was that of Hartzell in 1904.‘8 A second report‘of cases with a review of the literature was rnade by Wile in 1910.fi” For a period of time only case reports were found in the literature. In 1925 Michelson4j reported a series of cases and reviewed the literature. In 1932 Montgomery and Cu1ver4” added another series of cases and suggested a relationship to high blood pressure. In 1936 Berger and associatesF questioned the etiology of the disease and suggested that there was a human counterpart to animal botryomycosis, but that it should not be confused with granuloma pyogenicum. The only attempt to produce the lesion experimentally was made by Kimmelstiel and Easley? Series reports by Lenorrnant”” in 1910, Michelson in 1925,45 and Montgomery and Culver in 1932,46 in addition to numerous case reports, account for the most important significant contributions in the literature.
Terminology When Poncet and Dar”’ described the lesion in man, they designated it botryornycosis hominis, assuming that the lesion was the same as that described by @voltas in horses. The work of Sabraz& and Laubies5 and Bodin* indicated that the streptococcus was the etiologic agent of the lesion of granuloma 158
pyogenicum. The &xman authors introduced a descriptive terminology ; Kiittner”” suggested the term granuloma telangiretodes hecaausc it describes the histologic appearance of the lesion. F’rederic &lit%used the term granuloma pcdiculatum benignum to describe the histologic ~h~~ngcs as well as some of tht clinical characteristics of the tumor. Several authors used the term granuloma trlangiectaticum pediculat~ml for the same reasnns. In 1903 tllc term granuloma pyogenicum appeared in Crockcr’s” test on skin diseases. although Hartzell, whose paper’ was ~~ul~lishr~d in 1901, is credited lry FVile and others with sug‘Ycsting the term granuloma pyogenicum, which is generally accepted at the Gresent time except by the Frcncli, who designate the lesion ~~seudol~otryorr~ycosis.
Material The 289 cases in this study were collected from the routine surgical diagnostic material subrnitt,ed to the I)epartment, 0C Pathology of the lTniversity of Michigan over a twenty-five-year period, so that the distribution of lesions is representative of a large populat,ion group. There may have been a high proportion of oral lesions since the surgical material from the School of Dentistry The material was of the University of Michigan is included in this material. received frorn outside hospitals and clinics, or from private practitioners and, thercforc, only the cases from our own dental clinic and [University Hospital This incompleteness in recording is a disadvantage in have complete histories. the correlation of trauma with the appearance of the lesion and the assembly of other statistical data.
Etiology The earl). writers, as the tcrminolopy intlicates, incorrectly interpreted the lesion as myc*otic. llowever, \vitll study of this and other infections, it was show11 that st rcptocdoeci liiight l)rodurc eoloiiies with cliarac+35stics of fungi. Kitt”” suggested that stal)ll?-loc.oc~c~i mighi protluce this lesion, but accepted Sal~rnz~s ant1 I i:nll)iez” cliscusse~l I he nonI)ot ryomycosis as a clisease entity. I-Gxlin,’ sl)rc*ific char;rc*tcr of’ the lesion ant1 associatrtl it bvith staphylococci. in bacteriologic and inoculation expcrimcnts. itlentificd t,he bodies found in the lesions as staph>-lococci. DIagrou”O also tlcmonst,rated that the myeotic-like c*olonies were staphylococci and the lesions cwuld IW protlu~ecl h,v the injection of an appropriate number of organisl~is. IIis work could not. he duplica,ted. liimmclstiel and Easley:~” iIttcml,trd t 0 l~r~otl~~~ethe lcsiou c~spet’imentall? in to 1lie gasl rointt3l inill t ritc*t 1)) llsiug Ml l)ot1(, ilS il I’orcig.lr l)otly in atltlition itill?hvli:coc.c.i. ‘i’hr\- !llc~!l~!.tlt tllilt il fot,c>iglr llotl>. \v;Is t,c*c[lrir(*(l to ltr~c~~llleetllc lesion. Tlirrc sernithtl to l)c aprc~t~nic‘nt 1)) t*~~(7~ilt\vrilc~rs 1Ital tire gixtlttlolttil ~)~‘ib genicuni resllltrtl f1.0111 SOltIC minor Irauma whic*ll I)t~c)vitlrd il ])ilill\YCl?- for in\-asion ot’ lui~roor’ganistlrs. to whic~l~ th(~l \VilS ;I c*lmIxc~lrCs1 ic* I issue rtq3onsc due to the low virulence of the organisms. (.‘LlI.Iis” suggcstcct that the vascular prolifei*at.ion rrsultcd from lvcaliziitioii of the int’cc*tion ill tlrc wall of a blood WlN~ltccl tl1l.W of fi\-c CiiStY-Gin which high vessel. Montgomery and (‘uIvcP blood pressure was associated and suggested that “there might be some eti-
160
DONALD
A. KERR
They noted that “hisological connection between the two phenomena.” tologically the tumor is nothing more than granulation tissue, particularI.! rich in capillary blood vessels, and that, therefore, anything, that may give They also suggested t,hat rise to csilherant ~~ilDlll~tiO~1 tissue may cause it.” it was l)rohable that the st~~l~hyl~~~~~~cci arltl strel)tocotci were inciclental ant1 not etiologiral fartom. The findings in the present material apprar to agree wit,h the suggestions OF Montgomery and Culver.4” E’ifty-seven typical cases from various anatomical locations were selected and the sections were stained with Gram’s stain. The characteristic mycotic granules could not be demonstrated in any of the cases, but in the lesions with an ulcerated surface, typical colonies of saprophytic organisms often were present in the exudate. In the nonulcerated lesions the usual flora of the skin or mucous membrane was present. and few if any organisms could be demonstrated in the granulation tissue. In the lesions with an ulcerated surface, organisms could be demonstrated in the superficial granulation tissue. At the surface the organisms sometimes grew in colonies, but beneath the surface were distributed uniformly throughout the granulation tissue. Gram-positive and gram-negative cocci and rods were demIn the oral lesions the variety of organisms was characteristic of onstrated. the oral flora. Only scattered organisms were folmd in t,he deeper parts of the lesions. In a Sew cases phagocytized organisms were demonstrated in the deeper parts of the lesions, and in one they appeared in the wall of a capillary. In sections of t,he base of the lesions organisms could not be demonstrated. The response of the tissue appeared to be an overzea,lous healing process in response to trauma rather than specific infection, and t,he organisms present in the lesions were thought to be contaminants from the skin or mucous membrane. While no specific etiologic agent has been detected, the lesion has a somewhat characteristic histologic picture. Excessive granulation tissue is produced, characterized by marked endothelial cell proliferation and results in numerous vascular channels and spaces of variable size. Similar morphologic changes characterize the so-called pregnancy tumor or granuloma gravidarum which occurs on the gingiva in about 1 per ,cent of the patients having gingivitis gravidarum. The gingivitis of pregnancy also is characterized by vascular proliferation and the formation of many new vessels. The increased vascularity is attributed to endocrine stimulation. In granuloma gravidarum the changes are more intense and localized to a smaller area, but indistinguishable from granuloma pyogenicum elsewhere in the body. It may be possible that with injury there is an innate tendency for overzealous repair, which is characterized by vascular proliferation. Endocrine stimulation might be effective in an area where minor trauma occurred. Montgomery and Culver 46 drew an analogy between granuloma pvogenicum and keloid, pointing out that both are tissue responses to injury which occur spontaneously, grow to a certain size, and when removed recur to the previous size. Granuloma pyogenicum does not recur if adequately removed, while keloid, even though completely removed, frequently recurs and attains greater
GKlNULOWA
PPOGENCUM
161
size. The tendency of keloid to rewr is an indication of its inherent charat>ter. These investigators indicated that there was no tendency for keloid to develop in an area from which a granulonra yyogenicum had been removed. They concluded that “the analogies are altogether too striking to be lightly cast asi(Ie.” We do not have in our material keloids forwing in areas from which a granuloma I)yogonicum has Ixen tw~ovcd, but we found evidence of healing of the lesions which r*es~:ltetl ill the forwation of small fibr~:~c~~ithclial papillomata, histoIn this sc*rirs of cases varying degrees of healing logic*ally similar to krloids. were noted. Bloc;t of tlrc lesions lwcarne ulcerated and cwntinued irritation and infection delayed the healing. that ~ranuloma pyogenicum was a r’esponse of a partiwrlar It ilppWl"Cd t.q)c to injury x:itlr 111~prodnction of a small ulrer* which, d\ir to infection arrd irhritaticn. did not heal. The abundant granulaticn tissue produc~ed by the attempted healing produced the ~haractwistic lesion. This response was s3 nnI’OIm that, it established the condition as an entity which might be produced 01‘ The, appearance of two lesions simulinfluenced by some intrinsic factor. taneously on the finger and lip in one patient supported the suggestion of an intrinsic factor.
Clinical Findings Granuloma p,vogenicum was usually an elevated lesion. Many were att;r(+hed by a small pedicle but others were s(>:-xde. The character of the lesion varied with age and anatorniral location. The lesions, especially when young, were soft but, not Criable in wnsistenc;v. The older lesions were firrn and suggested fibromas or keloids. The surface was usually smooth. hlrt lobulations wcrc pwsrnt clue to 111~supurfieial, tlilatctl vascular s~inccs which prc~luccd a l'iI~l)l~C?i'l')~ il~~l~~‘~Ll’allCJ~‘. The ttiwjority of the lcsioris were irlccrxte~l an(1 soln( CXU(!Nl l)rrrulent L~~tCl’iill. AlOSt were (*l’LlStt+l alltl some llil(l il \Wl't?il~~~~~~ll3ll~~.
162
DONALD
A.
KERR
c.
clinil CUIT’ mont marl ing with
g. l.-(Magnification, X30; hematoxylin and eosin stain.) Four cases shoa and pathologic forms of granuloma pyogenicum. Slightly elevated sessile lesion from the lip of a 57-year-old woman. Th ‘two weeks following injury during extraction of a tooth and was preset Lobulated appearance in submucosa is evident. Somewhat elevated but broad. flat lesion from the hand of a 35-year-old epithelial proliferation at the border tends to produce a papillomatous char Lesion from the dorsum of the tongue of a 62-year-old man, present&yc;r; sillomatous configuration and resembling a circumvalate papilla. avy inflammatory infiltrations.
ril
‘SI
e lesi 1t for
Oil
OCt
hree
The at ster. Feeks, Sl lOW.tt :d s UT ,face
GRilXULOMA
PYOGENICUM
1%
I.) If inadequately removed, the lesions rapidly grew to the original size and hecame static. The lesions were insensitive to manipulation. In some cases thera was associated adenitis and lymphangitis. (b‘ig. 1.)
Fig. l.--1)., Lesion dilated vascular the ulcerated surface. ency to henlorrhage.
111C~Ous
from forearm of a man. Papillomatous lesion with slender stalk. NUspaces engorged with blood are present, both deep in the lesion and at This produced stippled rrd character ami was responsible for the tend-
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280 cases and 16!) involved mucous mcmbranc while 111 affected the skin. The highest incidence was in the oral region in which there were 143 eases involving gingiva, lip, tongue, and bnccal inucosa. The nasal mucous membrane was the site of the lesion in 21 cases, probably associated w&h the habit of “picking the nose. ” The gingiva was the most common oral lorat,ion wit,h 64. (Table III.) TABLE II. ~.-____~~. AGE 0.5
AGE DISTRIBUTION-* .___
INCIDENCE
AGE
4
41-45 46-50 51-55 56-00 61-65 66-70 71-75 76-80
____-
6 9 19
6-10 11-15
16-20 21-25 26-30 31-35 36-40 .____-.__
15 21 12 15
~~-~ -___
INCIDENCE
18
14 9
12 8 2 1 4 169
Total *Age distribution
in l(i9 cltses
in which
the age was
known.
In 53 instances lesions occurred on the hands and 44 of them were on the Of the other 58 lesions of the skin in the series, 22 were on the face fingers. and 36 were distributed over the trunk and extremities. The location of the lesions suggested trauma as an etiologic factor. The hands and the oral mucosa are traumatized frequently and the majority of lesions occurred in these areas. Tnsr>e III. Mucous Membrane Oral cavity (;;ingiva Lips Tongue Buccal mucosa Alveolar socket Angle mouth Naris Conjunctiva Tonsil
*Anatomical
distribution
ANATOMICAL
169
143 64 40 20 11 4 4 21 3 2
of
ZSO cas?s
in which
DISTRIBUTiON*
Skin, Hand Finger Palm Face (no location) Nose Chin Ear Trunk Back Abdomen Chest Breast Shoulder Extremities Leg Arm Foot S&l, Total the
location
of the
lesion
111
5 44 4
14 F2 6
11 1 2 4 !? ‘1 I9 i 4 5
3 280 was
known.
The nasal mucosa also is traumatized frequently. In this series a history of trauma was obtained in 36 per cent of the 280 eases. This is lower than reported by Michelson, but may be attributable to the method of collecting the material. Michelson’s cases were collected clinically, while, with the exception of the material from the Dental School, our cases were collected from the pathologic diagnostic material, and a complete history was not available.
GRANULOMA
PYOGENICUJI
165
Histologic Changes (7ranuloma pyogrnicum is characterized by granulation tissue similar to that found il; any healing wound, but in this instance it is more exuberant and confined to a localized area. The most constant and characteristic feature of the lesion is extreme endothelial proliferation and formation of numerous vascular spaces (Fig. 2). E’ibroblastic proliferation is associated, but usually- plays a minor role in the development of the lesion. The cellular infiltrations var; greatly in number as well as in kind: dependin g upon the locat,ion of t,he lesion and degree of ulceration. Usually granuloma pyogenicum is a papillomatous or l)edunculated nodule of small size arisin g in the submucosa or corium (Fig. 3 ) I The epithelium covering the surface is thin and atrophic, while at the border there is hgperplasia and often hyperkeratosis. The epithelium at the immediate border of the lesion proliferates and partially encapsulates the granulation tissue. In many of the lesions the epithelium at the summit of the lesion is ulcerated and the surface is covered by inflammatory exudate. (Fig. 4.) Vascular spaces are seen at the ulcerated margin and produce a hemorrhagic* character in the exudate as well as being responsible for bleeding.
I&~llr~ath ihc epithelial surface in the submucosa or corium tl~erc arts wiat i\-rly quell-circ.unlsc~ribetl areas of connective tissue and endothelial 1)roliferation. 111 some instwnccs this has a lobulated appearance with the lobules extending (F’ig. 5.) Fasciculi of connective tissue illto the snbmucosa and pannirulus. radiate ~IWU the base or site of origin of the lesion into t,he granulomatous mass. Between t tlese fasciculi are masses of endothelial cells which show proliferative and in some instances numerous vessels of capillary character are activity, productd and many become dila.ted cndothelial-lined spaces. (Fig. 6.) In
Fig. 3.-(Magnification, X30 ; hematoxylin and eosin staid) Papillomatous lesion the right temporal region of a woman aged 26 years. Lesion present about six weeks epithelial proliferation at the border of the lesion is shown. The epithelial-lined space center of the mass is a dilated sebaceous gland orifice. Higher magnification ( X 100) a solid area with marked proliferation of endothelial cells without the formation of vessels. Connective tissue septa and area of vascularization.
Fig. 4.- (Magnification, X 20 : hematoxylin from Anger of woman, aged 42 years. Marked is ulcerated :ml covered with a crust.
and eosin stain. ) epithelial proliferation
Sessile ulcerated at border. The
1 from 1. The in the shows blood
lesion surface
GRANULOMA
PYOGENICUM
16’;
IIIC lesions lhe endothelial cells tlo not organize in a specific pattern but are ‘und in solid masses, giving the appearance of a very cellular, relatively ~~:ular endothelial neoplasm. (Fig. 7.) These characteristics ma)- be seen Fig.
3.
I’edunrulatril lt+i~ill Fig. 2, -( ~lagnification, X:30 ; lr layer Itf ~~nilothelial rells forming their \vxlls. _ large. irregular.
a single lesion. The ticcpcr and ulder portion of the lesion is character r nests of prolifcrating cndothelial ~11s. Yascular spaces of varying ;ving some connective tissue in their wall, are surrounded by mature
168
DONALD
A.
KERR
often abundant stroma. (Figs. 2 and 3.) There is a gradation from this mature tissue at the site of origin to that of young granulation tissue at the periphery. In t,he peripheral areas the vascular spaces are large and numerous and without a wall of supporting tissue. The vascular spaces are in a delicate young proliferating matrix. (Fig. 8.) The pattern of the vascular change often is included in the descriptive name of the lesions. In t,hose in which endothelial proliferation is marked with tendency to form small vessels, the term tela.ngiomatosum is added. In those showing marked format,ion of vessels and dilated vascular spaces, the term telangiectaticum is used. Cellular infiltrations are interspersed throughout the connective tissue and in some instances in the endothelial areas. The cells vary in type and quantity, depending on the condition of the surface. In the ulcerated lesions there are heavy infiltrations of inflammatory cells with polymorphonuclear leucocytes predominating. The leucocytes are concentrated in the surface and are less numerous and more disseminated in the deeper areas. Also in the deeper areas are plasma cells, large mononuclear phagorytes, and only occasional lymphocytes. (Figs. 6, 7, and 8.) Frequently areas of recent and old hemorrhage are found throughout the lesion. (Fig. 1.) There is a change in character as the lesions become older and show evidence of healing. The connective tissue elements become more pronounced and the tissue more mature. With healing there is loss of vascular proliferation SO the vessels become fewer, the small capillaries become obliterated, and the larger vascular spaces remain but show thickening of the walls. In the advanced stages of healing the residua,l mass is dense fibrous tissue with only a few residual vascular spaces. The structure resembles a fibroepithelial papilloma but is more vascular. (Fig. 9.) There is great variation in healing as some lesions that had been present for twenty years retained the characteristics of the early healing phase, while some present for a few months showed a marked tendency to heal. The differential diagnosis of the lesion depends upon the endothelial proliferation. In the lesions characterized by numerous vessels and thin-walled vascular spaces, the differential diagnosis must include hemangioma. Granuloma pyogenicum is usually circumscribed in character while hemangioma is poorly defined and involves the dermis and subcutaneous tissue. The variation in proliferation and vessel size evident from the base to the surface of granuloma pyogenicum may not be present in a hemangioma. The tendency for epithelium to surround the deeper lesions of granuloma pyogenicum is characteristic and not usually seen in hemangiomata. In those cases in which the endothelial proliferation is marked but without the formation of vessels, the lesions must be differentiated from hemangiosarcoma and Kaposi’s sarcoma. In hemangiosarcoma there is a tendency for panniculus and muscle to be invaded. The invasion is irregular and poorly circumscribed, unlike granuloma pyogenicum. In Kaposi’s sarcoma the vascular foci and the cellular det,ail may be somewhat like granuloma pyogenicum, but the histologic clue is the disposition of the
GRANULOMA
169
PYOGENICUM Fig.
7.
Fig.
8.
-(Magnification. Xl00 hwiatoxylin and eosin stain. ) Higher magnifkati< (1 nngioblastic proliferation with slight tendency to form vascular spaces. -(Magnification, X 100 : hematoxylin and eosin stain. ) Surface area uf ?ictnn from fowlwall of a man, aged 24 years. Surface shows loss of ncl the accumulation of exudate. Heneath the epithelium is young vaacul; This illustrates tilrx characteristics of the peripheral portion of the lesi
of p-r dth ar
DONALD
A.
KERR
B. Lesion from tongue of a 9.-(Magnification, X30 : hematoxylin and cosin stain.) man, present for twenty years. The central portion is dense conA, Papillomatous character of a nearly healed lesion. nective tissue containing dilated vascular spaces. Higher magnification of Fig. R, (Magnification. Xl00 ; hematoxylin and eosin stain.) d Shows the hyaiinisation of the connective tissue, the obliteration of the vascular spaces mith residual endothelixl cells, and the thin-m-allell vascular spaces. Fig.
GRANTJLOMA
171
PYOGENICUM
vascular foci near the cpiclermis and also isolated about appendages in the deeper layers of the dcrinis. The presence of vascanlar foci at a distance Cr01n the surface of the skin is runlike thr ordinary pattern of the response of skin to inflanimalion and serves to diffcrentiwtc Kaposi ‘s sarcoma from gr+anuloma pyogenicum and hemangioma, The usual comparison js between this lesion and ulcerated and secondarily infected hemangioma and simple granulation tissue.
Relationship Between Granuloma Pyogenicum and So-Called ‘ ‘ Pregnancy Tumor ’ ’ The I)regnanq- tunror is a lesion of the gingiva which occurs during pregnancy. ( Fig. 10.) It usually appears about, the third month and gradually increases in size urilil the trr*mination of gestation. Following parturition, the lesion subsides and may disappear ~omplctcly. I’sually regression is not complete and the lesion persists in the involuted state until the next pregnancy, when it, is again stimulated to growth. It may achieve its previous size rapid13 and remain in that state for the entire period of pregnancy or it may, in rare instances, grow during the entire state of pregnancy. The behavior of the lesion is believed to be the result of excessive hormonal stimulation and occurs in about 1 per cent of patients with gingivitis of pregnancy.
Fig 10. -~:ranuloma gravidarum nlly increase,t in size until parturition. t.\\‘b rrronths post-partum.
occurred during the Herluced one-third
sixth month of pregnancy. (:lwluPhotograph in size post-partum.
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DONALD
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Relationship Between Granuloma Pyogenicum and Epulis -The term epulis does not denote a specific lesion, simply a tumor of the gingiva. The two lesions most commonly found in this group are the peripheral giant cell tumor and the so-called fibroid epulis. Both lesions, like granuloma
Fig. Il.-(Magnification, Xl00 ; hematoxylin of two months’ duration in a woman. aged 26 years. occasions with two previous pregnancies. Patient
and eosin stain.) Granuloma graviclarum The lesion h&s been removed on two other six months’ pregnant at time lesion was
rmlove~l.
Fig. lZ.-(Magnification, Xl00 ; hematoxylin and eosin stain.) Characteristic f’$arrloma pyogenicum with numeroup gianti cells of the type seen in peripheral . This lesion came from the gmgiva of a woman.
changes of giant cell
pyogenicum, are responses to injury. The peripheral giant cell tumor arises from the periosteum or periodontal membrane as the result of injury. It is a proliferat,ive renarative rwpons~ characterized by fibroblastic proliferation, the
presence of ndmerous hound cells, and varying numbers of giant cells of osteoelastic type. The number and type of inflammatory cellular infiltrations vary These lesions, with the degree of ulceration and amount, of secondary infection. like granuloma pyogenicum, show limitation of growth, t.endency to recur unless the site of origin is removed completely, and occasionally the lesions heal spontaneously with a residual fibrous maw like a fibroepithelial papilloma. The fibroid epulis is the result of excessive healing that results in t,be formation of an excess amount of mat,uw wnnecative tissue. Tfte lesion is a hypertrophic scar and usually is designated a fibroepithelial papilloma. It occurs in some instances as the healed phase of rither a granuloma pyogenicum or a peripheral giant cell tumor. Mixed lesions ma>- be present in which the c*harartcristics of both l-he peripheral giant ~4~11 tumor and granuloma pyogenicum are present in the same lesion. (Fig. 12.) Also, granuloma pyogenicum and fibroid epulis arc seen in the same lesion. It is, in all cases, difficult to determine The simultaneous which was the initial lesion and which was superimposed. occurrence of these lesions suggests a common etiology.
Discussion and Comment (~iranuloma pyogenicum arises as the result of minor t,rauma. The response is that of healing of tissue but is exaggerated in proportion to the degree of injury so that a localized overgrowth of granulat,ion tissue results. The phase There of the healing process most exaggerated is the endothelial proliferation. does not appear to he cvidence that this lesion is a specific reaction to any partissue are of ticular infectious agent. (~fY.g-anismspresent in the granulation little significance as is tlrc isolation of various organisms from the lesions. Their preserwe ma)- give c~redcrrw to the tranccpt that grnnuloma pyogenicum does 1lOt ll:lVe iA specific etiology. The pathologic changes are so c*haracteristic and constant Ihat the lesion is dewribed as at1 tantii\-. There must bc some irrfluential fac>tor which (*auses this parti4ar req~)nsr in wrtwiu individuals as has been suggest,ed by Montgomery in drawing an analogy with keloids. The governing factor could be a general or systemic factor. This factor ~nay be an innate one or, as is suggested by tlic relation between gwir ulorna l)yogenicmn and granuloma graridarum, the lesion ma\- appear as the rwult of an acquired physiologic state swh as hormonal stiniulalion of lhc ginyival n~nw)iis 11IClIII)L’illlC durirr~ prw nancy. l’irt*
ttitltlellq~
for
1 litwl
it%ii)lis
lo
il t?l,l!L!i.
.~j!!~!lilill!.tl!:s
1>- ;ttrtf
tltrts
!)t’ti~tllt’t~
fi~)rOPpitholiirl papillomas, while othf~r3 wttraitr t’or ,vw~*s wilhoul vharrpt:, iliso indicates that some factors otl~rr tllarl 10~~~1irritation arid foral infection ill’t’ of significance. The tendency i’or t Ire lesions to ~c’ur dess the site of s)rigitl is I.(WI~IW~ c~*ompletely might seem t I) contradict t 1~ sJ.stemir etiologic factor=. HOWWW, after complete removal, local conditions affected by systemic: factors are no longer present, so that the lesions do not wcur’ , grannloma gravidarum! if completely removed during the period of gestation, does not, recur, but reports indicate that incomplete surgical removal of t,hc lesions during gestation stimu-
174.
DONALD
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KERR
lates endothelial proliferation and hemangiosarcomas have developed. This may indicate that the site of origin is of significance in addition to the systemic stimulation. The variation of reactions favors a complex etiology for granuloma pyogenicum. The relatjionship between granuloma pyogenicum, peripheral giant cell tumor, and gingival fibroepithelial papilloma would support the hypothesis that these lesions have some systemic predisposing factor. Because of the specific clinical behavior and histologic characteristics, the granuloma pyogenirum should be described as a definite entity, thus providing a standard terminology for pathologist and clinician. The clinician is frequently alarmed by its clinical behavior while the pathologist is not impressed with the histologic picture. If the pathologist describes the lesion as sirnple granulation tissue, the proper significance is not conveyed to the clinician.
Conclusions Granuloma pyogenicum is an exaggerated response to minor trauma not related to any specific infectious agent. Stains for bacteria in the lesions do not demonstrate specific granules oi colonies of organisms. On the surface of ulcerated lesions colonies of saprophytic organisms can be demonstrated, identical with those present in many ulcers. The similarity between granuloma pyogenicum, keloid, and the so-called pregnancy tumor indicates that some syst,emie factor which stimulates vascular proliferation plays a part in the etiology of this lesion. The morphologic picture of the lesion is so constant that it is considered to be an entity a,nd is designated granuloma pyogenicum. The lesion found in the gingiva in pregnancy is identical and cannot bc diagnosed pregnancy tumor without knowledge of the physiologic state of the patient. To indicate the similarity of these lesions, the term granulorna gravidarum is preferable to pregnancy tumor. Granulomata pyogenicum heal spontaneously and produce a residual fibrous mass or fibroepithelial papillornas. In the mouth many so-called fibroepithelial papillomas and fibroid epulides are healed granulomata pyogenicum. Granuloma pyogenicum is equally common in mucous membranes as skin and is, therefore, of as much interest to the dentist and otolaryngologist as it is to the dermatologist. It is not merely a skin lesion but a blastomatoid lesion which may involve any surface of the body.
References 1. Allison, J. R.: Granulorna Pyogenicum Treated With Sulfathiazole, Arch. Dermat. 6Syph. 45: 579, 1942. 2. Armstrong, John: Granuloma Pyogenicum, Abst., Arch. Dormat. & Syph. 2: 128, 1920. 3. Aronstam, N. E.: Human Botryomycosis, J. Michigan M. Sot. 35: 315-316, 1936. 4. Aronstam, N. E.: Human Botryomycosis, TJrol. & Cutan. Rev. 40: 407-409, 1936. 5. Aynaud, M.: T>a botryomycose du mouton (ah& du mouton, maladie caseeuse), Ann. Inst. Pasteur 42: “2%281. 1928. 6. Berger, L., Vallee, A., and Vkzina, C.: Genital Staphylococcic Actinophytosis (Botrgomycosis) in Human Beings, Arch. Path. 21: 273-283, 1936. 7. Bichat, H.: De la botryomycose humaine, Arch. g6n. de med. 1: 281-301, 1904.
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PTOGENICU1\I
175
8. Bodin, E.: Sur la botryomycosr! humaine, Arth. de dermat. et syph., Paris, 4s., III: 289-302, 1902. T’irchoxs brch. f. path. Anat. 49: 3. Bollinger, 0.: Mycosis der Lunge l)eim Pferde, 583. 1870. 10. Civatte, A., and Charpy, I’.: Un cas de botryoru,vcome de la lbvre inferieure gueri par les rayons ultra-violets, Bull. Sot. frany. de dermat. & syph. 28: 324327, 1921. 11. Cracker, H. R.: Diseases of the Skin, ed. 3, Philadelphia, 1903, I’. Blakiston’s Son c Co., 1,466 pp. Denartment of Dermatolopv, ._, TTniversity of 12. Curtis. A. C.: Personal communication. Michigan School of Medicine. ou ttlmeur~ hylmrplasiques tics It‘s\ res, Rex. cle stomatc)l. 111.: Botryomycomer 13. ljerhaume, 39: 628-633, 1933. humaine, I,yon mGd. 9.1: 376-379, 1899. 14. Delnre, X. : Botryomycose Un cas de botryomycose humaine, Ahst., TAyon m&l., no. .49, Dec. 9, 1909, 1.5. Delore, 5.: 563 pp. F’issuratum, Sutton (Granuloma ‘I’elsngiectodrs Fissuratum) : 16. Diasio, F. A.: Granuloma (:ase, Arch. Dermat. & Syph. 28: 521-525, 1933. M. W.: Botryomycome ungueal, Bull. ROY. franc. (le dermat. et xyph. 28: 17. Dubreuilh, 516, 1921. 18. Eisen, D.: Granuloma Pyogenicum (Report of 4 Cases Treated by Roentgen Rays), Canad. M. A. J. 42: 528-530, 1940. 19. Falkenstein, F.: Ueber Granuloma Pediculatum, Dermat. Ztschr. 37: 209-304, 1923. 20. Fink, A. A.: Staphylococcic Artinophytotic (Botryomyrotic) Abscess of Liver With Pulmonary Involvement,, Arch. Path. 31: 103-107, 1941. 41. Finnerud, C. W.: Dermatologic Affections (Granuloma Pyogenicum) in Children, M. Clin. North America 13: i285-1298, 1930. 22. Frank, I., and Blahd, M.: Pyogenic Granuloma of Nasal Fossn, Arch. Otolaryng. 31: 919-924, 1940. H. : Telangiectatic Granuloma, Arch. f. Dermat. u. Hyph. 166: 669-698, 1932. 23. Freund, 24. Fumagalli, C. R.: La vrai botryomycose; a propos de 2 cas d’ostbom-elite ZL grains botryomycose, Ann. d’anat. path. 4: 513529, 1927. "5. Geiger, Etiology and Pathogenesis of Granuloma Pyogenicum: Case, Arch. f. R.: Dermat. u. Syph. 161: 469-475, 1930. 1904. 26. Gilchrist, T. C.: (Two cases discussed, abst.), J. Cutan. Dis., p. 524, November, 2s. Hagedoorn, A.: Telangiectatic Granuloma-Botryom~c~)sis. Brit. .T. Ophth. 18: 561570, 1934. “S. Hartzell, M. B.: Granuloma Pyogenicum (I{otr!-om?-c.osis of French Author:, , , .J. Cutan. Dis., incl. Spph., N. Y. 22: 5265%. 199-r. 29. Heuck, W.: Hotryomykosr), Ueber “ Granuloma Pediculatum ’ ’ (cog. mcnwhliche Dermat. Ztschr., Berl., 19: 221 324, 404, 1912. 30. Kelly, R. J.: Granuloma Pyogenjcum of Tongue ? Awh. Drrmat. & Syph. 31: 861-865, 1936.
?I1. Kimmelstiel, I’.. and Oden, 1’. IT.: Bat rj,cmrycosis: tirport of 2 Cases of Intraabdominal Granuloma, Arch. Path. 27: 313319. 1939. 32. Kimmelstiel, P., and Easley, C. -4.: Jr.: h:sperimental Botryomycosis, Am. J. Path. 16: 95-102, 1940. 33. Kitt, Th.: Dermicrococcus ascoformans und tlas M-kofil~rorn (ICP I’ferdrs, (‘entrall)l. f. Bakt. 3: 177, 1888. 34. 3.5. ::Ei. :i; :f. XJ. 4n. 41. 4". Marin, A.: PI. hlartinowa:
Bntrvompcosis‘bf the Mouth, I’nion 3TPd. du Canada 63: 53.;8, 1934. TTeber dir wgel~anntr Botriomykrw Swim menwhen. .ir(,h.. W. D.: Dermat. II. Syph. 161: 4294.17. 1930. P.: Plait de guerre l)otr?-orn?;co~ir~~~e, T,yon chir. 15: ?30. 1918. a. lfasson, Granuloma Pyogenicum : Clinical nrrtl Histologic Review of H. E.: .43. llichelson, Cases, Arch. Dermat. 6r S>-ph. 12: 492-505, 192.3.
f. L’S
176
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46. Montgomery, D. W.,
PYOGENICUM
DONALD A. KEKR, D.D.S., M.S., Ass
ARBOR, MICH.
T
HE lesion designated granuloma pyogenicum occurs commonly in the skin and the mucous membranes and is well recognized by the dermatologist. It has not received equal attention by all pathologists, dentists, and clinicians. To the patient and the clinician who are not familiar with the lesion, it is frequently viewed with alarm because it appears rapidly and tends to recur following partial removal. The lesion therefore frequently is thought to be malignant. tissue or more often Histologically, it is misinterpreted as granulation as an infected hemangioma. Because the lesion frequently is misinterpreted clinically and histologically and since the lesions of the mucous membrane have not been appreciated fully in the field of dentistry, the literature was reviewed and the available information was correlated in this review of 289 cases.
Historical In 1870 Bollinger,” and in 1884 Rivolta,” 4 described botryomycosis in horses following castration. In 1897 Yoncet and Do?’ described a lesion in man which was comparable to that described by Rivolta, and designated it botryomycosis hominis. Following the original description of Poncet and Dor in the French literature, several reports appeared in the German literature,““, 34,3jt 52 some of which questioned the etiology and terminology. The first report in the American literature was that of Hartzell in 1904.‘8 A second report‘of cases with a review of the literature was rnade by Wile in 1910.fi” For a period of time only case reports were found in the literature. In 1925 Michelson4j reported a series of cases and reviewed the literature. In 1932 Montgomery and Cu1ver4” added another series of cases and suggested a relationship to high blood pressure. In 1936 Berger and associatesF questioned the etiology of the disease and suggested that there was a human counterpart to animal botryomycosis, but that it should not be confused with granuloma pyogenicum. The only attempt to produce the lesion experimentally was made by Kimmelstiel and Easley? Series reports by Lenorrnant”” in 1910, Michelson in 1925,45 and Montgomery and Culver in 1932,46 in addition to numerous case reports, account for the most important significant contributions in the literature.
Terminology When Poncet and Dar”’ described the lesion in man, they designated it botryornycosis hominis, assuming that the lesion was the same as that described by @voltas in horses. The work of Sabraz& and Laubies5 and Bodin* indicated that the streptococcus was the etiologic agent of the lesion of granuloma 158
pyogenicum. The &xman authors introduced a descriptive terminology ; Kiittner”” suggested the term granuloma telangiretodes hecaausc it describes the histologic appearance of the lesion. F’rederic &lit%used the term granuloma pcdiculatum benignum to describe the histologic ~h~~ngcs as well as some of tht clinical characteristics of the tumor. Several authors used the term granuloma trlangiectaticum pediculat~ml for the same reasnns. In 1903 tllc term granuloma pyogenicum appeared in Crockcr’s” test on skin diseases. although Hartzell, whose paper’ was ~~ul~lishr~d in 1901, is credited lry FVile and others with sug‘Ycsting the term granuloma pyogenicum, which is generally accepted at the Gresent time except by the Frcncli, who designate the lesion ~~seudol~otryorr~ycosis.
Material The 289 cases in this study were collected from the routine surgical diagnostic material subrnitt,ed to the I)epartment, 0C Pathology of the lTniversity of Michigan over a twenty-five-year period, so that the distribution of lesions is representative of a large populat,ion group. There may have been a high proportion of oral lesions since the surgical material from the School of Dentistry The material was of the University of Michigan is included in this material. received frorn outside hospitals and clinics, or from private practitioners and, thercforc, only the cases from our own dental clinic and [University Hospital This incompleteness in recording is a disadvantage in have complete histories. the correlation of trauma with the appearance of the lesion and the assembly of other statistical data.
Etiology The earl). writers, as the tcrminolopy intlicates, incorrectly interpreted the lesion as myc*otic. llowever, \vitll study of this and other infections, it was show11 that st rcptocdoeci liiight l)rodurc eoloiiies with cliarac+35stics of fungi. Kitt”” suggested that stal)ll?-loc.oc~c~i mighi protluce this lesion, but accepted Sal~rnz~s ant1 I i:nll)iez” cliscusse~l I he nonI)ot ryomycosis as a clisease entity. I-Gxlin,’ sl)rc*ific char;rc*tcr of’ the lesion ant1 associatrtl it bvith staphylococci. in bacteriologic and inoculation expcrimcnts. itlentificd t,he bodies found in the lesions as staph>-lococci. DIagrou”O also tlcmonst,rated that the myeotic-like c*olonies were staphylococci and the lesions cwuld IW protlu~ecl h,v the injection of an appropriate number of organisl~is. IIis work could not. he duplica,ted. liimmclstiel and Easley:~” iIttcml,trd t 0 l~r~otl~~~ethe lcsiou c~spet’imentall? in to 1lie gasl rointt3l inill t ritc*t 1)) llsiug Ml l)ot1(, ilS il I’orcig.lr l)otly in atltlition itill?hvli:coc.c.i. ‘i’hr\- !llc~!l~!.tlt tllilt il fot,c>iglr llotl>. \v;Is t,c*c[lrir(*(l to ltr~c~~llleetllc lesion. Tlirrc sernithtl to l)c aprc~t~nic‘nt 1)) t*~~(7~ilt\vrilc~rs 1Ital tire gixtlttlolttil ~)~‘ib genicuni resllltrtl f1.0111 SOltIC minor Irauma whic*ll I)t~c)vitlrd il ])ilill\YCl?- for in\-asion ot’ lui~roor’ganistlrs. to whic~l~ th(~l \VilS ;I c*lmIxc~lrCs1 ic* I issue rtq3onsc due to the low virulence of the organisms. (.‘LlI.Iis” suggcstcct that the vascular prolifei*at.ion rrsultcd from lvcaliziitioii of the int’cc*tion ill tlrc wall of a blood WlN~ltccl tl1l.W of fi\-c CiiStY-Gin which high vessel. Montgomery and (‘uIvcP blood pressure was associated and suggested that “there might be some eti-
160
DONALD
A. KERR
They noted that “hisological connection between the two phenomena.” tologically the tumor is nothing more than granulation tissue, particularI.! rich in capillary blood vessels, and that, therefore, anything, that may give They also suggested t,hat rise to csilherant ~~ilDlll~tiO~1 tissue may cause it.” it was l)rohable that the st~~l~hyl~~~~~~cci arltl strel)tocotci were inciclental ant1 not etiologiral fartom. The findings in the present material apprar to agree wit,h the suggestions OF Montgomery and Culver.4” E’ifty-seven typical cases from various anatomical locations were selected and the sections were stained with Gram’s stain. The characteristic mycotic granules could not be demonstrated in any of the cases, but in the lesions with an ulcerated surface, typical colonies of saprophytic organisms often were present in the exudate. In the nonulcerated lesions the usual flora of the skin or mucous membrane was present. and few if any organisms could be demonstrated in the granulation tissue. In the lesions with an ulcerated surface, organisms could be demonstrated in the superficial granulation tissue. At the surface the organisms sometimes grew in colonies, but beneath the surface were distributed uniformly throughout the granulation tissue. Gram-positive and gram-negative cocci and rods were demIn the oral lesions the variety of organisms was characteristic of onstrated. the oral flora. Only scattered organisms were folmd in t,he deeper parts of the lesions. In a Sew cases phagocytized organisms were demonstrated in the deeper parts of the lesions, and in one they appeared in the wall of a capillary. In sections of t,he base of the lesions organisms could not be demonstrated. The response of the tissue appeared to be an overzea,lous healing process in response to trauma rather than specific infection, and t,he organisms present in the lesions were thought to be contaminants from the skin or mucous membrane. While no specific etiologic agent has been detected, the lesion has a somewhat characteristic histologic picture. Excessive granulation tissue is produced, characterized by marked endothelial cell proliferation and results in numerous vascular channels and spaces of variable size. Similar morphologic changes characterize the so-called pregnancy tumor or granuloma gravidarum which occurs on the gingiva in about 1 per ,cent of the patients having gingivitis gravidarum. The gingivitis of pregnancy also is characterized by vascular proliferation and the formation of many new vessels. The increased vascularity is attributed to endocrine stimulation. In granuloma gravidarum the changes are more intense and localized to a smaller area, but indistinguishable from granuloma pyogenicum elsewhere in the body. It may be possible that with injury there is an innate tendency for overzealous repair, which is characterized by vascular proliferation. Endocrine stimulation might be effective in an area where minor trauma occurred. Montgomery and Culver 46 drew an analogy between granuloma pvogenicum and keloid, pointing out that both are tissue responses to injury which occur spontaneously, grow to a certain size, and when removed recur to the previous size. Granuloma pyogenicum does not recur if adequately removed, while keloid, even though completely removed, frequently recurs and attains greater
GKlNULOWA
PPOGENCUM
161
size. The tendency of keloid to rewr is an indication of its inherent charat>ter. These investigators indicated that there was no tendency for keloid to develop in an area from which a granulonra yyogenicum had been removed. They concluded that “the analogies are altogether too striking to be lightly cast asi(Ie.” We do not have in our material keloids forwing in areas from which a granuloma I)yogonicum has Ixen tw~ovcd, but we found evidence of healing of the lesions which r*es~:ltetl ill the forwation of small fibr~:~c~~ithclial papillomata, histoIn this sc*rirs of cases varying degrees of healing logic*ally similar to krloids. were noted. Bloc;t of tlrc lesions lwcarne ulcerated and cwntinued irritation and infection delayed the healing. that ~ranuloma pyogenicum was a r’esponse of a partiwrlar It ilppWl"Cd t.q)c to injury x:itlr 111~prodnction of a small ulrer* which, d\ir to infection arrd irhritaticn. did not heal. The abundant granulaticn tissue produc~ed by the attempted healing produced the ~haractwistic lesion. This response was s3 nnI’OIm that, it established the condition as an entity which might be produced 01‘ The, appearance of two lesions simulinfluenced by some intrinsic factor. taneously on the finger and lip in one patient supported the suggestion of an intrinsic factor.
Clinical Findings Granuloma p,vogenicum was usually an elevated lesion. Many were att;r(+hed by a small pedicle but others were s(>:-xde. The character of the lesion varied with age and anatorniral location. The lesions, especially when young, were soft but, not Criable in wnsistenc;v. The older lesions were firrn and suggested fibromas or keloids. The surface was usually smooth. hlrt lobulations wcrc pwsrnt clue to 111~supurfieial, tlilatctl vascular s~inccs which prc~luccd a l'iI~l)l~C?i'l')~ il~~l~~‘~Ll’allCJ~‘. The ttiwjority of the lcsioris were irlccrxte~l an(1 soln( CXU(!Nl l)rrrulent L~~tCl’iill. AlOSt were (*l’LlStt+l alltl some llil(l il \Wl't?il~~~~~~ll3ll~~.
162
DONALD
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c.
clinil CUIT’ mont marl ing with
g. l.-(Magnification, X30; hematoxylin and eosin stain.) Four cases shoa and pathologic forms of granuloma pyogenicum. Slightly elevated sessile lesion from the lip of a 57-year-old woman. Th ‘two weeks following injury during extraction of a tooth and was preset Lobulated appearance in submucosa is evident. Somewhat elevated but broad. flat lesion from the hand of a 35-year-old epithelial proliferation at the border tends to produce a papillomatous char Lesion from the dorsum of the tongue of a 62-year-old man, present&yc;r; sillomatous configuration and resembling a circumvalate papilla. avy inflammatory infiltrations.
ril
‘SI
e lesi 1t for
Oil
OCt
hree
The at ster. Feeks, Sl lOW.tt :d s UT ,face
GRilXULOMA
PYOGENICUM
1%
I.) If inadequately removed, the lesions rapidly grew to the original size and hecame static. The lesions were insensitive to manipulation. In some cases thera was associated adenitis and lymphangitis. (b‘ig. 1.)
Fig. l.--1)., Lesion dilated vascular the ulcerated surface. ency to henlorrhage.
111C~Ous
from forearm of a man. Papillomatous lesion with slender stalk. NUspaces engorged with blood are present, both deep in the lesion and at This produced stippled rrd character ami was responsible for the tend-
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280 cases and 16!) involved mucous mcmbranc while 111 affected the skin. The highest incidence was in the oral region in which there were 143 eases involving gingiva, lip, tongue, and bnccal inucosa. The nasal mucous membrane was the site of the lesion in 21 cases, probably associated w&h the habit of “picking the nose. ” The gingiva was the most common oral lorat,ion wit,h 64. (Table III.) TABLE II. ~.-____~~. AGE 0.5
AGE DISTRIBUTION-* .___
INCIDENCE
AGE
4
41-45 46-50 51-55 56-00 61-65 66-70 71-75 76-80
____-
6 9 19
6-10 11-15
16-20 21-25 26-30 31-35 36-40 .____-.__
15 21 12 15
~~-~ -___
INCIDENCE
18
14 9
12 8 2 1 4 169
Total *Age distribution
in l(i9 cltses
in which
the age was
known.
In 53 instances lesions occurred on the hands and 44 of them were on the Of the other 58 lesions of the skin in the series, 22 were on the face fingers. and 36 were distributed over the trunk and extremities. The location of the lesions suggested trauma as an etiologic factor. The hands and the oral mucosa are traumatized frequently and the majority of lesions occurred in these areas. Tnsr>e III. Mucous Membrane Oral cavity (;;ingiva Lips Tongue Buccal mucosa Alveolar socket Angle mouth Naris Conjunctiva Tonsil
*Anatomical
distribution
ANATOMICAL
169
143 64 40 20 11 4 4 21 3 2
of
ZSO cas?s
in which
DISTRIBUTiON*
Skin, Hand Finger Palm Face (no location) Nose Chin Ear Trunk Back Abdomen Chest Breast Shoulder Extremities Leg Arm Foot S&l, Total the
location
of the
lesion
111
5 44 4
14 F2 6
11 1 2 4 !? ‘1 I9 i 4 5
3 280 was
known.
The nasal mucosa also is traumatized frequently. In this series a history of trauma was obtained in 36 per cent of the 280 eases. This is lower than reported by Michelson, but may be attributable to the method of collecting the material. Michelson’s cases were collected clinically, while, with the exception of the material from the Dental School, our cases were collected from the pathologic diagnostic material, and a complete history was not available.
GRANULOMA
PYOGENICUJI
165
Histologic Changes (7ranuloma pyogrnicum is characterized by granulation tissue similar to that found il; any healing wound, but in this instance it is more exuberant and confined to a localized area. The most constant and characteristic feature of the lesion is extreme endothelial proliferation and formation of numerous vascular spaces (Fig. 2). E’ibroblastic proliferation is associated, but usually- plays a minor role in the development of the lesion. The cellular infiltrations var; greatly in number as well as in kind: dependin g upon the locat,ion of t,he lesion and degree of ulceration. Usually granuloma pyogenicum is a papillomatous or l)edunculated nodule of small size arisin g in the submucosa or corium (Fig. 3 ) I The epithelium covering the surface is thin and atrophic, while at the border there is hgperplasia and often hyperkeratosis. The epithelium at the immediate border of the lesion proliferates and partially encapsulates the granulation tissue. In many of the lesions the epithelium at the summit of the lesion is ulcerated and the surface is covered by inflammatory exudate. (Fig. 4.) Vascular spaces are seen at the ulcerated margin and produce a hemorrhagic* character in the exudate as well as being responsible for bleeding.
I&~llr~ath ihc epithelial surface in the submucosa or corium tl~erc arts wiat i\-rly quell-circ.unlsc~ribetl areas of connective tissue and endothelial 1)roliferation. 111 some instwnccs this has a lobulated appearance with the lobules extending (F’ig. 5.) Fasciculi of connective tissue illto the snbmucosa and pannirulus. radiate ~IWU the base or site of origin of the lesion into t,he granulomatous mass. Between t tlese fasciculi are masses of endothelial cells which show proliferative and in some instances numerous vessels of capillary character are activity, productd and many become dila.ted cndothelial-lined spaces. (Fig. 6.) In
Fig. 3.-(Magnification, X30 ; hematoxylin and eosin staid) Papillomatous lesion the right temporal region of a woman aged 26 years. Lesion present about six weeks epithelial proliferation at the border of the lesion is shown. The epithelial-lined space center of the mass is a dilated sebaceous gland orifice. Higher magnification ( X 100) a solid area with marked proliferation of endothelial cells without the formation of vessels. Connective tissue septa and area of vascularization.
Fig. 4.- (Magnification, X 20 : hematoxylin from Anger of woman, aged 42 years. Marked is ulcerated :ml covered with a crust.
and eosin stain. ) epithelial proliferation
Sessile ulcerated at border. The
1 from 1. The in the shows blood
lesion surface
GRANULOMA
PYOGENICUM
16’;
IIIC lesions lhe endothelial cells tlo not organize in a specific pattern but are ‘und in solid masses, giving the appearance of a very cellular, relatively ~~:ular endothelial neoplasm. (Fig. 7.) These characteristics ma)- be seen Fig.
3.
I’edunrulatril lt+i~ill Fig. 2, -( ~lagnification, X:30 ; lr
a single lesion. The ticcpcr and ulder portion of the lesion is character r nests of prolifcrating cndothelial ~11s. Yascular spaces of varying ;ving some connective tissue in their wall, are surrounded by mature
168
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KERR
often abundant stroma. (Figs. 2 and 3.) There is a gradation from this mature tissue at the site of origin to that of young granulation tissue at the periphery. In t,he peripheral areas the vascular spaces are large and numerous and without a wall of supporting tissue. The vascular spaces are in a delicate young proliferating matrix. (Fig. 8.) The pattern of the vascular change often is included in the descriptive name of the lesions. In t,hose in which endothelial proliferation is marked with tendency to form small vessels, the term tela.ngiomatosum is added. In those showing marked format,ion of vessels and dilated vascular spaces, the term telangiectaticum is used. Cellular infiltrations are interspersed throughout the connective tissue and in some instances in the endothelial areas. The cells vary in type and quantity, depending on the condition of the surface. In the ulcerated lesions there are heavy infiltrations of inflammatory cells with polymorphonuclear leucocytes predominating. The leucocytes are concentrated in the surface and are less numerous and more disseminated in the deeper areas. Also in the deeper areas are plasma cells, large mononuclear phagorytes, and only occasional lymphocytes. (Figs. 6, 7, and 8.) Frequently areas of recent and old hemorrhage are found throughout the lesion. (Fig. 1.) There is a change in character as the lesions become older and show evidence of healing. The connective tissue elements become more pronounced and the tissue more mature. With healing there is loss of vascular proliferation SO the vessels become fewer, the small capillaries become obliterated, and the larger vascular spaces remain but show thickening of the walls. In the advanced stages of healing the residua,l mass is dense fibrous tissue with only a few residual vascular spaces. The structure resembles a fibroepithelial papilloma but is more vascular. (Fig. 9.) There is great variation in healing as some lesions that had been present for twenty years retained the characteristics of the early healing phase, while some present for a few months showed a marked tendency to heal. The differential diagnosis of the lesion depends upon the endothelial proliferation. In the lesions characterized by numerous vessels and thin-walled vascular spaces, the differential diagnosis must include hemangioma. Granuloma pyogenicum is usually circumscribed in character while hemangioma is poorly defined and involves the dermis and subcutaneous tissue. The variation in proliferation and vessel size evident from the base to the surface of granuloma pyogenicum may not be present in a hemangioma. The tendency for epithelium to surround the deeper lesions of granuloma pyogenicum is characteristic and not usually seen in hemangiomata. In those cases in which the endothelial proliferation is marked but without the formation of vessels, the lesions must be differentiated from hemangiosarcoma and Kaposi’s sarcoma. In hemangiosarcoma there is a tendency for panniculus and muscle to be invaded. The invasion is irregular and poorly circumscribed, unlike granuloma pyogenicum. In Kaposi’s sarcoma the vascular foci and the cellular det,ail may be somewhat like granuloma pyogenicum, but the histologic clue is the disposition of the
GRANULOMA
169
PYOGENICUM Fig.
7.
Fig.
8.
-(Magnification. Xl00 hwiatoxylin and eosin stain. ) Higher magnifkati< (1 nngioblastic proliferation with slight tendency to form vascular spaces. -(Magnification, X 100 : hematoxylin and eosin stain. ) Surface area uf ?ictnn from fowlwall of a man, aged 24 years. Surface shows loss of ncl the accumulation of exudate. Heneath the epithelium is young vaacul; This illustrates tilrx characteristics of the peripheral portion of the lesi
of p-r dth ar
DONALD
A.
KERR
B. Lesion from tongue of a 9.-(Magnification, X30 : hematoxylin and cosin stain.) man, present for twenty years. The central portion is dense conA, Papillomatous character of a nearly healed lesion. nective tissue containing dilated vascular spaces. Higher magnification of Fig. R, (Magnification. Xl00 ; hematoxylin and eosin stain.) d Shows the hyaiinisation of the connective tissue, the obliteration of the vascular spaces mith residual endothelixl cells, and the thin-m-allell vascular spaces. Fig.
GRANTJLOMA
171
PYOGENICUM
vascular foci near the cpiclermis and also isolated about appendages in the deeper layers of the dcrinis. The presence of vascanlar foci at a distance Cr01n the surface of the skin is runlike thr ordinary pattern of the response of skin to inflanimalion and serves to diffcrentiwtc Kaposi ‘s sarcoma from gr+anuloma pyogenicum and hemangioma, The usual comparison js between this lesion and ulcerated and secondarily infected hemangioma and simple granulation tissue.
Relationship Between Granuloma Pyogenicum and So-Called ‘ ‘ Pregnancy Tumor ’ ’ The I)regnanq- tunror is a lesion of the gingiva which occurs during pregnancy. ( Fig. 10.) It usually appears about, the third month and gradually increases in size urilil the trr*mination of gestation. Following parturition, the lesion subsides and may disappear ~omplctcly. I’sually regression is not complete and the lesion persists in the involuted state until the next pregnancy, when it, is again stimulated to growth. It may achieve its previous size rapid13 and remain in that state for the entire period of pregnancy or it may, in rare instances, grow during the entire state of pregnancy. The behavior of the lesion is believed to be the result of excessive hormonal stimulation and occurs in about 1 per cent of patients with gingivitis of pregnancy.
Fig 10. -~:ranuloma gravidarum nlly increase,t in size until parturition. t.\\‘b rrronths post-partum.
occurred during the Herluced one-third
sixth month of pregnancy. (:lwluPhotograph in size post-partum.
172
DONALD
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Relationship Between Granuloma Pyogenicum and Epulis -The term epulis does not denote a specific lesion, simply a tumor of the gingiva. The two lesions most commonly found in this group are the peripheral giant cell tumor and the so-called fibroid epulis. Both lesions, like granuloma
Fig. Il.-(Magnification, Xl00 ; hematoxylin of two months’ duration in a woman. aged 26 years. occasions with two previous pregnancies. Patient
and eosin stain.) Granuloma graviclarum The lesion h&s been removed on two other six months’ pregnant at time lesion was
rmlove~l.
Fig. lZ.-(Magnification, Xl00 ; hematoxylin and eosin stain.) Characteristic f’$arrloma pyogenicum with numeroup gianti cells of the type seen in peripheral . This lesion came from the gmgiva of a woman.
changes of giant cell
pyogenicum, are responses to injury. The peripheral giant cell tumor arises from the periosteum or periodontal membrane as the result of injury. It is a proliferat,ive renarative rwpons~ characterized by fibroblastic proliferation, the
presence of ndmerous hound cells, and varying numbers of giant cells of osteoelastic type. The number and type of inflammatory cellular infiltrations vary These lesions, with the degree of ulceration and amount, of secondary infection. like granuloma pyogenicum, show limitation of growth, t.endency to recur unless the site of origin is removed completely, and occasionally the lesions heal spontaneously with a residual fibrous maw like a fibroepithelial papilloma. The fibroid epulis is the result of excessive healing that results in t,be formation of an excess amount of mat,uw wnnecative tissue. Tfte lesion is a hypertrophic scar and usually is designated a fibroepithelial papilloma. It occurs in some instances as the healed phase of rither a granuloma pyogenicum or a peripheral giant cell tumor. Mixed lesions ma>- be present in which the c*harartcristics of both l-he peripheral giant ~4~11 tumor and granuloma pyogenicum are present in the same lesion. (Fig. 12.) Also, granuloma pyogenicum and fibroid epulis arc seen in the same lesion. It is, in all cases, difficult to determine The simultaneous which was the initial lesion and which was superimposed. occurrence of these lesions suggests a common etiology.
Discussion and Comment (~iranuloma pyogenicum arises as the result of minor t,rauma. The response is that of healing of tissue but is exaggerated in proportion to the degree of injury so that a localized overgrowth of granulat,ion tissue results. The phase There of the healing process most exaggerated is the endothelial proliferation. does not appear to he cvidence that this lesion is a specific reaction to any partissue are of ticular infectious agent. (~fY.g-anismspresent in the granulation little significance as is tlrc isolation of various organisms from the lesions. Their preserwe ma)- give c~redcrrw to the tranccpt that grnnuloma pyogenicum does 1lOt ll:lVe iA specific etiology. The pathologic changes are so c*haracteristic and constant Ihat the lesion is dewribed as at1 tantii\-. There must bc some irrfluential fac>tor which (*auses this parti4ar req~)nsr in wrtwiu individuals as has been suggest,ed by Montgomery in drawing an analogy with keloids. The governing factor could be a general or systemic factor. This factor ~nay be an innate one or, as is suggested by tlic relation between gwir ulorna l)yogenicmn and granuloma graridarum, the lesion ma\- appear as the rwult of an acquired physiologic state swh as hormonal stiniulalion of lhc ginyival n~nw)iis 11IClIII)L’illlC durirr~ prw nancy. l’irt*
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fi~)rOPpitholiirl papillomas, while othf~r3 wttraitr t’or ,vw~*s wilhoul vharrpt:, iliso indicates that some factors otl~rr tllarl 10~~~1irritation arid foral infection ill’t’ of significance. The tendency i’or t Ire lesions to ~c’ur dess the site of s)rigitl is I.(WI~IW~ c~*ompletely might seem t I) contradict t 1~ sJ.stemir etiologic factor=. HOWWW, after complete removal, local conditions affected by systemic: factors are no longer present, so that the lesions do not wcur’ , grannloma gravidarum! if completely removed during the period of gestation, does not, recur, but reports indicate that incomplete surgical removal of t,hc lesions during gestation stimu-
174.
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lates endothelial proliferation and hemangiosarcomas have developed. This may indicate that the site of origin is of significance in addition to the systemic stimulation. The variation of reactions favors a complex etiology for granuloma pyogenicum. The relatjionship between granuloma pyogenicum, peripheral giant cell tumor, and gingival fibroepithelial papilloma would support the hypothesis that these lesions have some systemic predisposing factor. Because of the specific clinical behavior and histologic characteristics, the granuloma pyogenirum should be described as a definite entity, thus providing a standard terminology for pathologist and clinician. The clinician is frequently alarmed by its clinical behavior while the pathologist is not impressed with the histologic picture. If the pathologist describes the lesion as sirnple granulation tissue, the proper significance is not conveyed to the clinician.
Conclusions Granuloma pyogenicum is an exaggerated response to minor trauma not related to any specific infectious agent. Stains for bacteria in the lesions do not demonstrate specific granules oi colonies of organisms. On the surface of ulcerated lesions colonies of saprophytic organisms can be demonstrated, identical with those present in many ulcers. The similarity between granuloma pyogenicum, keloid, and the so-called pregnancy tumor indicates that some syst,emie factor which stimulates vascular proliferation plays a part in the etiology of this lesion. The morphologic picture of the lesion is so constant that it is considered to be an entity a,nd is designated granuloma pyogenicum. The lesion found in the gingiva in pregnancy is identical and cannot bc diagnosed pregnancy tumor without knowledge of the physiologic state of the patient. To indicate the similarity of these lesions, the term granulorna gravidarum is preferable to pregnancy tumor. Granulomata pyogenicum heal spontaneously and produce a residual fibrous mass or fibroepithelial papillornas. In the mouth many so-called fibroepithelial papillomas and fibroid epulides are healed granulomata pyogenicum. Granuloma pyogenicum is equally common in mucous membranes as skin and is, therefore, of as much interest to the dentist and otolaryngologist as it is to the dermatologist. It is not merely a skin lesion but a blastomatoid lesion which may involve any surface of the body.
References 1. Allison, J. R.: Granulorna Pyogenicum Treated With Sulfathiazole, Arch. Dermat. 6Syph. 45: 579, 1942. 2. Armstrong, John: Granuloma Pyogenicum, Abst., Arch. Dormat. & Syph. 2: 128, 1920. 3. Aronstam, N. E.: Human Botryomycosis, J. Michigan M. Sot. 35: 315-316, 1936. 4. Aronstam, N. E.: Human Botryomycosis, TJrol. & Cutan. Rev. 40: 407-409, 1936. 5. Aynaud, M.: T>a botryomycose du mouton (ah& du mouton, maladie caseeuse), Ann. Inst. Pasteur 42: “2%281. 1928. 6. Berger, L., Vallee, A., and Vkzina, C.: Genital Staphylococcic Actinophytosis (Botrgomycosis) in Human Beings, Arch. Path. 21: 273-283, 1936. 7. Bichat, H.: De la botryomycose humaine, Arch. g6n. de med. 1: 281-301, 1904.
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8. Bodin, E.: Sur la botryomycosr! humaine, Arth. de dermat. et syph., Paris, 4s., III: 289-302, 1902. T’irchoxs brch. f. path. Anat. 49: 3. Bollinger, 0.: Mycosis der Lunge l)eim Pferde, 583. 1870. 10. Civatte, A., and Charpy, I’.: Un cas de botryoru,vcome de la lbvre inferieure gueri par les rayons ultra-violets, Bull. Sot. frany. de dermat. & syph. 28: 324327, 1921. 11. Cracker, H. R.: Diseases of the Skin, ed. 3, Philadelphia, 1903, I’. Blakiston’s Son c Co., 1,466 pp. Denartment of Dermatolopv, ._, TTniversity of 12. Curtis. A. C.: Personal communication. Michigan School of Medicine. ou ttlmeur~ hylmrplasiques tics It‘s\ res, Rex. cle stomatc)l. 111.: Botryomycomer 13. ljerhaume, 39: 628-633, 1933. humaine, I,yon mGd. 9.1: 376-379, 1899. 14. Delnre, X. : Botryomycose Un cas de botryomycose humaine, Ahst., TAyon m&l., no. .49, Dec. 9, 1909, 1.5. Delore, 5.: 563 pp. F’issuratum, Sutton (Granuloma ‘I’elsngiectodrs Fissuratum) : 16. Diasio, F. A.: Granuloma (:ase, Arch. Dermat. & Syph. 28: 521-525, 1933. M. W.: Botryomycome ungueal, Bull. ROY. franc. (le dermat. et xyph. 28: 17. Dubreuilh, 516, 1921. 18. Eisen, D.: Granuloma Pyogenicum (Report of 4 Cases Treated by Roentgen Rays), Canad. M. A. J. 42: 528-530, 1940. 19. Falkenstein, F.: Ueber Granuloma Pediculatum, Dermat. Ztschr. 37: 209-304, 1923. 20. Fink, A. A.: Staphylococcic Artinophytotic (Botryomyrotic) Abscess of Liver With Pulmonary Involvement,, Arch. Path. 31: 103-107, 1941. 41. Finnerud, C. W.: Dermatologic Affections (Granuloma Pyogenicum) in Children, M. Clin. North America 13: i285-1298, 1930. 22. Frank, I., and Blahd, M.: Pyogenic Granuloma of Nasal Fossn, Arch. Otolaryng. 31: 919-924, 1940. H. : Telangiectatic Granuloma, Arch. f. Dermat. u. Hyph. 166: 669-698, 1932. 23. Freund, 24. Fumagalli, C. R.: La vrai botryomycose; a propos de 2 cas d’ostbom-elite ZL grains botryomycose, Ann. d’anat. path. 4: 513529, 1927. "5. Geiger, Etiology and Pathogenesis of Granuloma Pyogenicum: Case, Arch. f. R.: Dermat. u. Syph. 161: 469-475, 1930. 1904. 26. Gilchrist, T. C.: (Two cases discussed, abst.), J. Cutan. Dis., p. 524, November, 2s. Hagedoorn, A.: Telangiectatic Granuloma-Botryom~c~)sis. Brit. .T. Ophth. 18: 561570, 1934. “S. Hartzell, M. B.: Granuloma Pyogenicum (I{otr!-om?-c.osis of French Author:, , , .J. Cutan. Dis., incl. Spph., N. Y. 22: 5265%. 199-r. 29. Heuck, W.: Hotryomykosr), Ueber “ Granuloma Pediculatum ’ ’ (cog. mcnwhliche Dermat. Ztschr., Berl., 19: 221 324, 404, 1912. 30. Kelly, R. J.: Granuloma Pyogenjcum of Tongue ? Awh. Drrmat. & Syph. 31: 861-865, 1936.
?I1. Kimmelstiel, I’.. and Oden, 1’. IT.: Bat rj,cmrycosis: tirport of 2 Cases of Intraabdominal Granuloma, Arch. Path. 27: 313319. 1939. 32. Kimmelstiel, P., and Easley, C. -4.: Jr.: h:sperimental Botryomycosis, Am. J. Path. 16: 95-102, 1940. 33. Kitt, Th.: Dermicrococcus ascoformans und tlas M-kofil~rorn (ICP I’ferdrs, (‘entrall)l. f. Bakt. 3: 177, 1888. 34. 3.5. ::Ei. :i; :f. XJ. 4n. 41. 4". Marin, A.: PI. hlartinowa:
Bntrvompcosis‘bf the Mouth, I’nion 3TPd. du Canada 63: 53.;8, 1934. TTeber dir wgel~anntr Botriomykrw Swim menwhen. .ir(,h.. W. D.: Dermat. II. Syph. 161: 4294.17. 1930. P.: Plait de guerre l)otr?-orn?;co~ir~~~e, T,yon chir. 15: ?30. 1918. a. lfasson, Granuloma Pyogenicum : Clinical nrrtl Histologic Review of H. E.: .43. llichelson, Cases, Arch. Dermat. 6r S>-ph. 12: 492-505, 192.3.
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46. Montgomery, D. W.,