The Immunotherapy of Anal Condyloma Acuminatum* HERAND ABCARIAN, M.D.,]` DURAND SMITH, M.D.,]" NEHAMA SHARON, PH.D.++
CONDYLOMA ACUMINATUM is a common lesion of the anorectal and urogenital regions. Various methods have been utilized for treatment of anal condylolna acumina, tum, bu,t none has been uniformly and consistently curative; therefore, the recurrence ra,te is extremely high. This report describes the use of immunotherapy in the treatment of anal condyloma acuminatum with excellent results and a low recurrence rate. Material and Method During a two-year period, immunotherapy was used in the treatmen, t of 39 consecutive patients who had extensive anal condyloma acuminatum. T h e r e were 36 men and three women in this group. Most patients were in the third and fourth decades of life, wi,th an average age of 27 years. All but three of the men were either overt homosexuals or had histories of occasional anal intercourse. T h e r e was no such previous history in any of the cases of the female patients. Durations of the disease ranged from four weeks to ten years, with an average of 6.8 months. Eight of the patients either had warts on other body sites at the time * Read at the meeting of the American Society of Colon and Rectal Surgeons, San Francisco, California, May 4 to 8, 1975. This paper won the New York Society of Colon and Rectal Surgeons award. ]-Section of Colon and Rectal Surgery, Cook County Hospital, 1825 West Harrison Street, Chicago, Illinois 606]2. S Department of Pathology, Evanston Hospital, Evanston, Illinois. Address reprint requests to Dr. Abcarian.
of initial examination or had histories of having had fadal, truncal or e~tremity wa~rts that had either spontaneously disappeared or been removed by chemical or surgical means. Twen,ty-four patients had had no previous therapy for their condylomas, and 15 patients had had a total of 36 sessions of treatment hy chemicals, fulguration or formal surgical removal of the condylomas, with p r o m p t recurrence and persistence of their disease. Some of the patients had had various combinations of treatment or had been treated more than once by the same method (Table i). There were histories of syphilis in one case, gonococcal proctitis in four, and gonococcal urethritis in eight. One of the women, who also had severe vulvovaginal condylomas, had a history of pelvic inflanlmatol"y disease. Most of the patAents (37 of 39) complained of appearance or recurrence of warts in the perianal region. Pruritus ani and bleeding secondary to trauma were seen frequently; however, severe anal pain was rare even in the presence of extensive disease. Symptoms are summarized in Table 2. Anorectal examination revealed condylomata acuminata in a variety of sizes and shapes, from small, single-pointed vegetation to fist-sized cauliflower-like masses. All patients in this group had ex.tensive disease as man,ifested by circumferen, tial anal a n d / o r perianal involvenlent (Fig. 1). Assooiated clinical findings are listed in Table 3. Proctosigmoidoscopy was routinely performed preoperatively, and be-
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TABLE 1. Prior Therapy of Anal Condyloma Acuminatum Treated by Immunotherapy 24 Patients with no previous treatment 15 Patients previously treated (recurrent disease) Podophyllin 18 Fulguration 8 Surgical excision 8 Acid compounds 2 Total prior therapeutic sessions
36
TABLE 2. Distribution o[ Symptoms Number of Patients Visible perianal warts Pruritus ani Bleeding Anal discomfort, and wetness Protrusion Vaginal discharge Perineal pain and drainage
37 24 17 7 2 2 1
TABLE 3. Clinical Findings Number of Patients Condyloma acuminatum Anal and perineal Anal canal only Perianal only Internal hemorrhoids Severe perianal dermatitis Anal fissure Perianal hidradenitis suppurativa Vulvovaginal condylomas
39 35 2 2 5 2 1 1 1
n i g n a d e n o m a t o u s p o l y p s were f o u n d in two p a f i e m s . T h e s e were t r e a t e d by excision b i o p s y a n d f u l g u r a t i o n . Collection of Condyloma Tissue for V a c c i n e P r e p a r a t i o n : T h e m a j o r i t y of p a t i e n t s (31 of 39) were a d m i t t e d to the h o s p i t a l a n d g i v e n g e n e r a l or s p i n a l anesthesia. L a r g e a n d e x o p h y t i c warts were t h e n excised a n d collected in sterile virus-
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h o i d i n g m e d i u m . A l l these p a t i e n t s h a d uneven, tful recoveries a n d w e r e d i s c h a r g e d from the h o s p i t a l on the s e c o n d o r t h i r d postopera,tive clays. O f the r e m a i n i n g e i g h t p a t i e n t s , three h a d a few large easily accessible p e r i a n a l c o n d y l o m a s , a n d five o t h e r s refused to be a d m i t t e d to the hospital. T h e s e patien, ts were given local anesthesia in the office a n d some of the p e r i a n a l c o n d y l o m a s were excised and collected in virus-holding medi urn. M i c r o s c o p i c sl,ides were p r e p a r e d in all cases for histologic c o n f i r m a l i o u of the tliagnosis. I n b o t h g r o u p s of p a t i e n t s , an at, t e m p t was n l a d e to s u b n t i t at least 5 g of c o n d y l o m a tissue for the p r c p a r a . t i o n of 7 vaccine a n d cell cultuJ'es. P r e p a r a t i o n o f C e l l C u l t u r e s : Fresh c o n d y l o m a tissue collected in v i r u s - h o l d i n g t n e d i u m was c u t i n t o l-ruth ~ pieces and w a s h e d twice in H a n k ' s basic salt solution. T h e pieces were i m m e r s e d in chicken p l a s m a a n d p l a c e d in clean tissue-culture bottles a n d tubes. T h e tissue was left at r o o m t e m p e r a t u r e for 2() to 30 m i n u t e s for the p l a s m a to gel. N u t r i e n t m e d i u m c o n t a i n i n g M e d i u m 199 s u p p l e m e n t e d w i t h p e n i c i l l i n a n d s t r e p t o m y c i n , 100 /~/ml, w i t h 10 p e r cent i n a c t i w t t e d calf s e r u m was a d d e d . T h e n m d i u t n was c h a n g e d once a week u n t i l g r o w t h of cells was o b s e r v e d (Fig. 2); then it was c h a n g e d twice a week. Cells d e v e l o p e d after two to three weeks of i n c u b a t i o n (Fig. 3). T h e cells were s t a i n e d for v i r a l i n c l u s i o n bodies a n d an,tfigens, b u t were f o u n d to be negative for both. P r e p a r a t i o n o f Vaccine: C o n d y l o m a tissue was collected in v i r u s - h o l d i n g m e d i u m t h a t c o n t a i n e d basic salt s o l u t i o n , a l b u m i n a n d antibiotics. T h e tissue was k e p t frozen u n t i l p r e p a r e d . A f t e r t h a w i n g , the tissue was washed twice in H a n k ' s basic s a k solution, cut i n t o small pieces, a n d 10 p e r cent suspension, by weight, was p r e p a r e d in M e d i u m 199 s u p p l e m e n t e d w i t h p e n i c i l l i n
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and streptomycin, 100 t~/ml. T h e suspension was homogenized in a Sorvall electric Omni-mixer and the homogenate was frozen in a dry-ice alcohol bath and thawed four times. T h e homogenate was then centrifuged at 5,000 r p m for 10 minutes in an IEC refrigerated centrifuge and the supernatant was collected and heated for 60 minutes at 56C. After this inactiwtion process, the homogenate was centrifuged again at 10,000 rpm for 10 minutes in a refrigerated Sorvall cen,trifuge and the supernatant was collected into a Vacutainer tu,be to be used as the vaccination m~terial. T h e vaccine was then tested for bacterial steril&y. Vaccination of Patients: T h e vaccine is kept frozen until bacterial sterility is proven. T h e n 0.5 ml of the vaccine is injeoted subctrtaneou.sly in the deltoid area, once a week for six consecutive weeks. In the in,terim the vaccine is stored in a frozen state. No adverse reaotion has been observed in any patient receiving the vaccine. Results All patients were examined by anoscope biweekly during and immediately after termination of vaccination. Subsequently, they were examined at 4-12 week intervals. Of the 39 p~tients, three were lost to follow-up either during or right after immunotherapy. These patients are excluded from I~he study. T h e follow-up periods for the remaining 36 patien.ts ranged from 5 to 26 months, with an average of 15 months. Thirty-three patien,ts (91.7 per cent) had favorable results following immunotherapy. T h i r t y patients (83.3 per cent) had had no recurrence at the time of completion of inmmnotherapy and have remained free of disease during the follow-up periods (Fig. 4). T h r e e patients (8.3 per cent) had only one or two clusters of condylomas seen after completion of immunotherapy. These were fulgurated once with
2~()
Fro. 1. Extensive anal and perianal condyloma acuminatum in a young black man.
tile electrocoagulation unit at the office, and the patients have remained free of disease since. Three patients (8.3 per cent) manifested recurrent condylomas as early as two weeks postopera.tively and before immunotherapy could be insti,tuted. T w o of these three patients needed a.s many as six sessions of ei,ther fulguration or application of 25 per cent podophyllin in tincture of benzoin to control recurrence after completion of immunotherapy. T h e condyloma of one patien.t has remained resistant to all treatments, including three previous surgical excisions performed elsewhere. This patient has had a repeat surgical excision of his condyloma and is awai,ting a second course of immuno:therapy. T h e resul, ts of i m m u n o t h e r a p y are summarized in Table 4. Discussion Condyloma acuminatu.m is cur~ren,tly be1,ieved to be of viral etiology. Transmission by cell-free filtrate was first reported by Giuffo in 1907. 4 Lewis and Wheeler 1~ cited the autoinoculability of warts, and the inoculation of gTound suspension of warts to volun, teers has resulted in the transmission of the disease. Strauss el al. 2~ identified intranuclear inclusion in 19~9.
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FIG. 2. Photomicrograph showing growth of condyloma cells in tissue culture. Dark area at left is the original excised condyloma tissue. • 40.
Electron microscopic studies of epithelial cells from condylomas has shown indirect evidence of viral agen.ts. 14, 21 Walter et al., 24 using fluorescein-tagged anti-human wart antiserum, demonstrated the presence of viral antigen in the nuclear areas of the gxanular layer of dermal papillomas in man. Oriel and Almeida, 19 using the electron nficroscopic technique of negative staining, demonstrated intranuclear virus particles in specimens from 13 of 25 pat,ients who had anal and genital warts. In morphology and distribution, these particles resemble those previously found in h u m a n cutaneous warts. T h e virus is probably transmitted by sexual con.tact as venereal disease. Thus,
condyloma acumination is commonly referred to as "venereal warts." T h e anorectal and urogenital areas offer a warm, moist environment, which is necessary for the growth of the virus: T h e r e is a high incidence of anal condyloma acunlinatum in male homosexuals. Marino 12 reported that 25 per cent of anorectal lesions found in male homosexuals were condyloma acuminatum. In this series, 91 per cent of the men were either h,)mosexuals or had histories of anal intercourse. This incidence was reported as 46 per cent by Swerdlow and Salwtti 23 and 81.8 per c e n t by ~gaugh. 2s In Oriel's series, a7 83 per cent of tile men and 62 per cent of women with anal con-
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Fro. 3. P h o t o m i c r o g r a p h taken three weeks after incubation of c o n d y l o m a tissue in tissue culture m e d i u m , d e m o n s t r a t i n g c d l u l a r proliferation. • 100.
d y l o m a a c u m i n a t u m h a d histories o[ a n a l intercourse. T o prove the venereal transmission of a n a l c o n d y l o m a a c u m i n a t u m , O r i e l 17 a t t e m p t e d to e x a m i n e all sexual contaQts or p a r t n e r s of the p a t i e n t s b e f o r e a n d at~ter a p p e a r a n c e of a n a l warts. N o n e of the e x a m i n e d contacts, however, h a d p e n i l e warts. It m u s t be n o t e d also that not all patients w h o have a n a l warts h a v e h a d a n a l coitus. T h e presence of c u t a n e o u s warts has b e e n i m p l i c a t e d as an e t i o l o g i c factor in such cases. A b o u t 25 p e r c e n t of o u r p a t i e n t s h a d h a d cuLaneous warts prev~iously or h a d t h e m at the time of e x a m i n a t i o n . T h i s i n c i d e n c e was r e p o r t e d as 15 p e r cent by Oriel, I8 b u t he also f o u n d tha.t c u t a n e o u s
warts w e r e c o m m o n in a c o n t r o l g r o u p . Y o u n g 26 has suggested t h a t the w a r t virus m a y be a n o r m a l i n h a b i t a n t of the anor e c t u m in some p e o p l e , a n d t h a t a n a l coitus m a y a l l o w its en,try i n t o the a n o d e r m because of r e p e a t e d t r a u m a . H o w e v e r , if one accepts this t.heory, one w o u l d e x p e c t to see a n a l warts as a c o m p l i c a t i o n of c h r o n i c a n a l ctisorders such as a n a l fissure. T h e r e f o r e , al.though the v e n e r e a l e t i o l o g y of a n a l c o n d y l o m a a c u m i n a t u m is q u i t e p r o b a b l e , the lack of cul, ture t e c h n i q u e s for c o n d y l o m a virus p r e c l u d e s an u n e q u i v o c a l conclusion. N u m e r o u s m e t h o d s h a v e b e e n used for the t r e a t m e n t of c o n d y l o m a a c u m i n a t u m ( T a b l e 5), b u t n o n e has been u n i v e r s a l l y
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FIG. 4. Same patient as in Figure 1, six weeks after completion of immunotherapy. Note the normal anal appearance except for a right posterior skin tag. No condyloma tissue is present.
successful. Forty consecutive patien,ts t r e a t e d by us p r i o r to u t i l i z a t i o n of i m m u n o t h e r a p y were s t u d i e d r e t r o s p e c t i v e l y . T h e m a j o r m e t h o d s of t h e r a p y used were podop h y l l i n , b i c h l o r a c e t i c acid, excision, a n d fulgur~t.ion. I n 18 cases o n l y one mod a l i t y of t r e a t m e n t was used; however, in 22 o t h e r s c o m b i n a t i o n s of these m e t h o d s were utilized. I n o n l y 10 cases (25 p e r cent) were these t r e a t m e n t s successful in e l i m i n a t i n g all c o n d y l o m a s in one o r two sessions. I n 30 o t h e r s (75 peqc cent) the patien, ts n e e d e d p e r i o d i c a p p l i c a t i o n of o n e o r m o r e m e t h o d s of t r e a t m e n t for prol o n g e d periods, r a n g i n g f r o m [our m o n t h s to m o r e t h a n two years. I n a s i m i l a r series of p~tients there were 11 failures in 48 cases. 23 Even w h e n the tre~mnent is event u a l l y successful, it is difficult to p r e d i c t h o w m a n y sessions of t r e a t m e n t will be necessary to e r a d i c a t e the c o n d y l o m a . T h e possible reasons for the h i g h recurrence r a t e are: 1) T h e disease is p r o b a b l y the result of sexual contact, a n d m a n y patients r e s u m e sexual activity before comp l e t i o n of t h e i r t r e a t m e n t . 2) T h e incubat i o n p e r i o d of the v i r u s is u n k n o w n , a n d if this p e r i o d were m a n y m o n t h s , a new
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c o n d y l o m a m i g h t a p p e a r a f t e r the comp l e t i o n of an a p p a r e n t l y successful course of t h e r a p y ; b y r e i n f e c t i n g the sexual partners of the p a t i e n t it c o u l d easily start a n e w cycle. 3) T h e t r e a t e d p a t i e n t s m a y c h a n g e sexual p a r t n e r s a n d a c q u i r e new i n f e c t i o n s (same o r d i f f e r e n t strains of virus?). T h e use of i m m u n o t h e r a p y , therefore, b e c o m e s qudte a t t r a c t i v e in the t r e a t m e n t of entensive o r r e c u r r e n t c o n d y l o n a a acum i n a t u m . I n 1944, B i b e r s t e i n 2 p u b l i s h e d a lengthy report, "Immunization Therapy of W a r t s . " H e used a vaccine on a v a r i e t y of watts, a n d also r e p o r t e d t h a t beneficial results were seen in 90 p e r cen.t of the patients who had condyloma acuminatum. H o w e v e r , u n t i l the recent r e p o r t of Powell et al.2o in 1970, i m m u n o t h e r a p y h a d app a r e n d y f a l l e n i n t o disuse, I n this study, 24 p a t i e n t s w h o h a d p e r s i s t e n t or r e c u r r e n t
TABLE 4. Results of Imrnunotherapy Total number of patients Lost to follow-up Total number of patients available for follow-up Excellent results Good results Poor results
39 3 36 30 (83.3 per cent) 3 ( 8.3 per cent) 3 ( 8.3 per cent)
TABLE 5. Methods o[ Treating Condyloma .4cuminatum Surgical excision Electrodesiccation Podophyllin,~ Bichloracetic acid~-z Cryotherapy Carbon dioxide snows, 11 Liquid air7 Liquid nitrogenal, 1~ Antitumor preparations Thiotepaa, o 5-FluorouracilG, 1~ BleomycinlZ Immunotherapy~6. z0
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anorectal or urogeni.tal c o n d y l o m a s were treated with a u t o g e n o u s vaccine, with excellent results i n 20, good results i n three, a n d poor results in one. Nel a n d F o u r i e ~6 r e p o r t e d 70 per cent complete regression, 10 per cent p a r t i a l regression, a n d 20 per cent n o regression in 10 cases in which condylornas were treated by i m m u n o t h e r apy. T h e y also suggest the ini.tial topical a p p l i c a t i o n of 5 per cent 5-fluorouracil ointm e n t to decrease the size of g i a n t condylomas p r i o r to i m m u n o t h e r a p y to achieve better results. A b l i n a n d C u r t i s ~ also reported excellent results a n d n o recurrence f o l l o w i n g the i m m u n o t h e r a p y of a p a t i e n t with large g e n i t a l warts. I n o u r series, 91.7 per cent of the patients had excellent or good resul.ts, a n d 8.3 per cent showed early recurrence with no regression despite immunc~therapy, h n m u n o t h e r a p y had no adverse systemic effect a n d d i d n o t alter the course of the disease u n f a v o r a b l y . T h e m e c h a n i s m by which i m m u n o t h e r apy causes regression of c o n d y l o m a s remain,s speculative. It has b e e n sttggested -~v that the relative isola,tion of p o t e n t i a l antigen (virus?) in the superficial layers of c o n d y l o m a precludes its contact with the c i r c u l a t i n g lymphocytes. I n j e c t i o n of atttogenous vaccine s u b c u t a n e o u s l y may provide more direct exposure of the a n t i g e n to the a n t i b o d y - f o r m i n g cell,s, thereby augm e n t i n g the i m m u n e m e c h a n i s m s of the host. However, Nel a n d Fou,rie 16 believe that regression p r o b a b l y d e p e n d s on "killer lymphocytes" destroying "foreign t u m o r cells" rather t h a n on a n t i v i r a l antibodies. T h e y also a,t t r i b u t e the c o n c o m i t a n t increase i n an,tiviral an,tibodies to the des t r u c t i o n of t u m o r cells a n d the l i b e r a t i o n of i n t r a c e l l u l a r viral antigens. F a i l u r e of i m m u n o t h e r a p y is also a t t r i b u t e d to the presence of p r e f o r m e d c i r c u l a t i n g antibodies, which could conceivably have a b l o c k i n g effect a n d thus prevenit contact wi,th the "killer lymphocytes," a n d perhaps even result in e n h a n c e m e n t .
243
I n a_n a t t e m p t to answer some of these questions, we are presently s t u d y i n g the cellular a n d h u m o r a l responses of p a t i e n t s with c o n d y l o m a a c c m n i n a t u m before a n d after i m m u n o t h e r a p y . Conclusion T h e i m m u n o t h e r a p y of c o n d y l o m a acum i n a t u m offers a h i g h success rate. Specific i n d i c a t i o n s for i m m u n o t h e r a p y are: 1) extensive anal a n d p e r i a n a l c o n d y l o m a acum i n a t u m ; 2) resistance to other convent i o n a l m e t h o d s of therapy; 3) r e c u r r e n c e following other forms of t r e a t m e n t . References 1. Ablin RJ, Curtis WW: Immunotherapeutic treatment of condyloma acuminata. Gynecol Oncol 2: 446, 1974 2. Biberstein H: Immunization therapy of warts. Arch Dermatol 50: 12, 1944 3. Cheng SF, Veenema RJ: Topical application of thio-tepa to penile and urethral tumors. J Urol 94: 259, 1965 4. ciuffo G: Inesto positivo con filtrato di verruca volgare. Gior Ital Mal Ven Pelle 48: 12, 1907 5. Culp OS, Kaplan IW: Condylomata acuminata: Two hundred cases treated with podophyllin. Ann Surg 120: 251, 1944 6. Farber S, McMillan L: Treatment of condyloma acuminata (letter to editor). S Afr Med J 46: 522, 1972 7. Gold JD: Liquid air and carbonic acid snow: Therapeutic results obtained by the dermatologist. NY Med J 92: 1276, 1910 8. Hall AF: Advantages and limitations of liquid nitrogen in the therapy of skin lesions. Arch Dermatol 82: 9, 1960 9. Halverstadt DB, Parry WL: Thiotepa in the management of intraurethral condylomata acuminata. J Urol 101: 729, 1969 10. Lewis GM, Wheeler CE Jr: Practical Dermatology. Third edition. Philadelphia, "vg. B. Saunders, 1967, 679 pp 11. Lyell A: Management of warts. Br Med J 2: 1576, 1966 12. Marino AW Jr: Proctologic lesions observed in male homosexuals. Dis Colon Rectum 7: 121, 1964 13. Mishima Y, Masahiro M: Effect of bleomycin on benign and malignant cutaneous tumours. Acta Derma Venereol 52: 211, 1972 14. Morgan HR, Balduzzi PC: Propagation of an intranuclear inclusion-forming agent from human condyloma acuminatum. Proc Natl Acad Sci USA 52: 1561, I964
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15. Nahra KS, Moschella SL, Swinton NW Sr: Condyloma acuminatum treated with liquid nitrogen: Report of five cases. Dis Colon Rectum 12: 125, 1969 16. Nels WS, Fourie ED: Immunotherapy and 5 per cent topical 5-fluoro-uracil ointment in the treatment of condylomata acuminata. S Afr Med J 47: 45, 1973 17. Oriel JD: Anal warts and anal coitus. Br J Vener Dis 47: 373, 1971 18. Oriel JD: Natural history of genital warts. Br J Vener Dis 47: I, 1971 19. Oriel JD, Almeida JD: Demonstration of virus particles in h u m a n genital warts. Br J Vener Dis 46: 37, 1970 20. Powell LC Jr, Pollard M, Jinkins JL Sr: Treatment of cond'yloma acuminata by autogenous vaccble. South Med J 63: 202, 1970
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21. Smith KO, Dougherty E, Melnick JL, et al: Fine structure of unassembled viral subunits from human warts. J Bacteriol 90: 278, 1965 22. Strauss MJ, Shaw EW, Bunting H, et al: "Crystalline" virus-like particles from skin papillomas characterized by intranuclear inclusion bodies. Proc Soc Exp Biol Med 72: 46, 1949 " 23. Swerdlow DB, Salvati EP: Condyloma acuminaturn. Dis Colon Rectum 14: 226, 1971 24. Walter EL Jr, Walker DL, Cooper GA: Localization of specific antigen in h u m a n warts. Arch Pathol 79: 419, 1965 25. Waugh M: Condyloma acuminata. Br Meal J 2: 527, 1972 26. Young HM: Viral warts in the anorectum possibly precluding rectal cancer. Surgery 55: 367, 1964
Memoir REEDER, FRANK E., Paducah, Kentucky; b o r n J a n u a r y 2, 1931, F r a n k l i n , Kentucky; University of Louisville School of M e d i c i n e 1957; i n t e r n s h i p University o[ T e n n e s s e e Hospitals; colon a n d rectal residency, Ferguson Clinic. Dr. R e e d e r was elected to Associate Fellowship in the A m e r i c a n Society of Colon a n d Rectal Surgeons in 1975. H e was a D i p l o m a t e of the A m e r i c a n Board of Colon a n d Rectal Surgery a n d of the A m e r i c a n Board of Surgery, a n d a Fellow, A m e r i c a n College o[ Surgeons. H e was a m e m b e r of the A m e r i c a n Medical Association, K e n t u c k y Medical Association, McCracken C o u n t y Medical Society a n d Kentucky Surgical Society; o n the staff at W e s t e r n Baptist a n d Lourdes Hospitals. Dr. R e e d e r died D e c e m b e r 23, 1975.
CONDYLOMA ACUMINATUM is a common lesion of the anorectal and urogenital regions. Various methods have been utilized for treatment of anal condylolna acumina, tum, bu,t none has been uniformly and consistently curative; therefore, the recurrence ra,te is extremely high. This report describes the use of immunotherapy in the treatment of anal condyloma acuminatum with excellent results and a low recurrence rate. Material and Method During a two-year period, immunotherapy was used in the treatmen, t of 39 consecutive patients who had extensive anal condyloma acuminatum. T h e r e were 36 men and three women in this group. Most patients were in the third and fourth decades of life, wi,th an average age of 27 years. All but three of the men were either overt homosexuals or had histories of occasional anal intercourse. T h e r e was no such previous history in any of the cases of the female patients. Durations of the disease ranged from four weeks to ten years, with an average of 6.8 months. Eight of the patients either had warts on other body sites at the time * Read at the meeting of the American Society of Colon and Rectal Surgeons, San Francisco, California, May 4 to 8, 1975. This paper won the New York Society of Colon and Rectal Surgeons award. ]-Section of Colon and Rectal Surgery, Cook County Hospital, 1825 West Harrison Street, Chicago, Illinois 606]2. S Department of Pathology, Evanston Hospital, Evanston, Illinois. Address reprint requests to Dr. Abcarian.
of initial examination or had histories of having had fadal, truncal or e~tremity wa~rts that had either spontaneously disappeared or been removed by chemical or surgical means. Twen,ty-four patients had had no previous therapy for their condylomas, and 15 patients had had a total of 36 sessions of treatment hy chemicals, fulguration or formal surgical removal of the condylomas, with p r o m p t recurrence and persistence of their disease. Some of the patients had had various combinations of treatment or had been treated more than once by the same method (Table i). There were histories of syphilis in one case, gonococcal proctitis in four, and gonococcal urethritis in eight. One of the women, who also had severe vulvovaginal condylomas, had a history of pelvic inflanlmatol"y disease. Most of the patAents (37 of 39) complained of appearance or recurrence of warts in the perianal region. Pruritus ani and bleeding secondary to trauma were seen frequently; however, severe anal pain was rare even in the presence of extensive disease. Symptoms are summarized in Table 2. Anorectal examination revealed condylomata acuminata in a variety of sizes and shapes, from small, single-pointed vegetation to fist-sized cauliflower-like masses. All patients in this group had ex.tensive disease as man,ifested by circumferen, tial anal a n d / o r perianal involvenlent (Fig. 1). Assooiated clinical findings are listed in Table 3. Proctosigmoidoscopy was routinely performed preoperatively, and be-
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TABLE 1. Prior Therapy of Anal Condyloma Acuminatum Treated by Immunotherapy 24 Patients with no previous treatment 15 Patients previously treated (recurrent disease) Podophyllin 18 Fulguration 8 Surgical excision 8 Acid compounds 2 Total prior therapeutic sessions
36
TABLE 2. Distribution o[ Symptoms Number of Patients Visible perianal warts Pruritus ani Bleeding Anal discomfort, and wetness Protrusion Vaginal discharge Perineal pain and drainage
37 24 17 7 2 2 1
TABLE 3. Clinical Findings Number of Patients Condyloma acuminatum Anal and perineal Anal canal only Perianal only Internal hemorrhoids Severe perianal dermatitis Anal fissure Perianal hidradenitis suppurativa Vulvovaginal condylomas
39 35 2 2 5 2 1 1 1
n i g n a d e n o m a t o u s p o l y p s were f o u n d in two p a f i e m s . T h e s e were t r e a t e d by excision b i o p s y a n d f u l g u r a t i o n . Collection of Condyloma Tissue for V a c c i n e P r e p a r a t i o n : T h e m a j o r i t y of p a t i e n t s (31 of 39) were a d m i t t e d to the h o s p i t a l a n d g i v e n g e n e r a l or s p i n a l anesthesia. L a r g e a n d e x o p h y t i c warts were t h e n excised a n d collected in sterile virus-
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h o i d i n g m e d i u m . A l l these p a t i e n t s h a d uneven, tful recoveries a n d w e r e d i s c h a r g e d from the h o s p i t a l on the s e c o n d o r t h i r d postopera,tive clays. O f the r e m a i n i n g e i g h t p a t i e n t s , three h a d a few large easily accessible p e r i a n a l c o n d y l o m a s , a n d five o t h e r s refused to be a d m i t t e d to the hospital. T h e s e patien, ts were given local anesthesia in the office a n d some of the p e r i a n a l c o n d y l o m a s were excised and collected in virus-holding medi urn. M i c r o s c o p i c sl,ides were p r e p a r e d in all cases for histologic c o n f i r m a l i o u of the tliagnosis. I n b o t h g r o u p s of p a t i e n t s , an at, t e m p t was n l a d e to s u b n t i t at least 5 g of c o n d y l o m a tissue for the p r c p a r a . t i o n of 7 vaccine a n d cell cultuJ'es. P r e p a r a t i o n o f C e l l C u l t u r e s : Fresh c o n d y l o m a tissue collected in v i r u s - h o l d i n g t n e d i u m was c u t i n t o l-ruth ~ pieces and w a s h e d twice in H a n k ' s basic salt solution. T h e pieces were i m m e r s e d in chicken p l a s m a a n d p l a c e d in clean tissue-culture bottles a n d tubes. T h e tissue was left at r o o m t e m p e r a t u r e for 2() to 30 m i n u t e s for the p l a s m a to gel. N u t r i e n t m e d i u m c o n t a i n i n g M e d i u m 199 s u p p l e m e n t e d w i t h p e n i c i l l i n a n d s t r e p t o m y c i n , 100 /~/ml, w i t h 10 p e r cent i n a c t i w t t e d calf s e r u m was a d d e d . T h e n m d i u t n was c h a n g e d once a week u n t i l g r o w t h of cells was o b s e r v e d (Fig. 2); then it was c h a n g e d twice a week. Cells d e v e l o p e d after two to three weeks of i n c u b a t i o n (Fig. 3). T h e cells were s t a i n e d for v i r a l i n c l u s i o n bodies a n d an,tfigens, b u t were f o u n d to be negative for both. P r e p a r a t i o n o f Vaccine: C o n d y l o m a tissue was collected in v i r u s - h o l d i n g m e d i u m t h a t c o n t a i n e d basic salt s o l u t i o n , a l b u m i n a n d antibiotics. T h e tissue was k e p t frozen u n t i l p r e p a r e d . A f t e r t h a w i n g , the tissue was washed twice in H a n k ' s basic s a k solution, cut i n t o small pieces, a n d 10 p e r cent suspension, by weight, was p r e p a r e d in M e d i u m 199 s u p p l e m e n t e d w i t h p e n i c i l l i n
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and streptomycin, 100 t~/ml. T h e suspension was homogenized in a Sorvall electric Omni-mixer and the homogenate was frozen in a dry-ice alcohol bath and thawed four times. T h e homogenate was then centrifuged at 5,000 r p m for 10 minutes in an IEC refrigerated centrifuge and the supernatant was collected and heated for 60 minutes at 56C. After this inactiwtion process, the homogenate was centrifuged again at 10,000 rpm for 10 minutes in a refrigerated Sorvall cen,trifuge and the supernatant was collected into a Vacutainer tu,be to be used as the vaccination m~terial. T h e vaccine was then tested for bacterial steril&y. Vaccination of Patients: T h e vaccine is kept frozen until bacterial sterility is proven. T h e n 0.5 ml of the vaccine is injeoted subctrtaneou.sly in the deltoid area, once a week for six consecutive weeks. In the in,terim the vaccine is stored in a frozen state. No adverse reaotion has been observed in any patient receiving the vaccine. Results All patients were examined by anoscope biweekly during and immediately after termination of vaccination. Subsequently, they were examined at 4-12 week intervals. Of the 39 p~tients, three were lost to follow-up either during or right after immunotherapy. These patients are excluded from I~he study. T h e follow-up periods for the remaining 36 patien.ts ranged from 5 to 26 months, with an average of 15 months. Thirty-three patien,ts (91.7 per cent) had favorable results following immunotherapy. T h i r t y patients (83.3 per cent) had had no recurrence at the time of completion of inmmnotherapy and have remained free of disease during the follow-up periods (Fig. 4). T h r e e patients (8.3 per cent) had only one or two clusters of condylomas seen after completion of immunotherapy. These were fulgurated once with
2~()
Fro. 1. Extensive anal and perianal condyloma acuminatum in a young black man.
tile electrocoagulation unit at the office, and the patients have remained free of disease since. Three patients (8.3 per cent) manifested recurrent condylomas as early as two weeks postopera.tively and before immunotherapy could be insti,tuted. T w o of these three patients needed a.s many as six sessions of ei,ther fulguration or application of 25 per cent podophyllin in tincture of benzoin to control recurrence after completion of immunotherapy. T h e condyloma of one patien.t has remained resistant to all treatments, including three previous surgical excisions performed elsewhere. This patient has had a repeat surgical excision of his condyloma and is awai,ting a second course of immuno:therapy. T h e resul, ts of i m m u n o t h e r a p y are summarized in Table 4. Discussion Condyloma acuminatu.m is cur~ren,tly be1,ieved to be of viral etiology. Transmission by cell-free filtrate was first reported by Giuffo in 1907. 4 Lewis and Wheeler 1~ cited the autoinoculability of warts, and the inoculation of gTound suspension of warts to volun, teers has resulted in the transmission of the disease. Strauss el al. 2~ identified intranuclear inclusion in 19~9.
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FIG. 2. Photomicrograph showing growth of condyloma cells in tissue culture. Dark area at left is the original excised condyloma tissue. • 40.
Electron microscopic studies of epithelial cells from condylomas has shown indirect evidence of viral agen.ts. 14, 21 Walter et al., 24 using fluorescein-tagged anti-human wart antiserum, demonstrated the presence of viral antigen in the nuclear areas of the gxanular layer of dermal papillomas in man. Oriel and Almeida, 19 using the electron nficroscopic technique of negative staining, demonstrated intranuclear virus particles in specimens from 13 of 25 pat,ients who had anal and genital warts. In morphology and distribution, these particles resemble those previously found in h u m a n cutaneous warts. T h e virus is probably transmitted by sexual con.tact as venereal disease. Thus,
condyloma acumination is commonly referred to as "venereal warts." T h e anorectal and urogenital areas offer a warm, moist environment, which is necessary for the growth of the virus: T h e r e is a high incidence of anal condyloma acunlinatum in male homosexuals. Marino 12 reported that 25 per cent of anorectal lesions found in male homosexuals were condyloma acuminatum. In this series, 91 per cent of the men were either h,)mosexuals or had histories of anal intercourse. This incidence was reported as 46 per cent by Swerdlow and Salwtti 23 and 81.8 per c e n t by ~gaugh. 2s In Oriel's series, a7 83 per cent of tile men and 62 per cent of women with anal con-
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Fro. 3. P h o t o m i c r o g r a p h taken three weeks after incubation of c o n d y l o m a tissue in tissue culture m e d i u m , d e m o n s t r a t i n g c d l u l a r proliferation. • 100.
d y l o m a a c u m i n a t u m h a d histories o[ a n a l intercourse. T o prove the venereal transmission of a n a l c o n d y l o m a a c u m i n a t u m , O r i e l 17 a t t e m p t e d to e x a m i n e all sexual contaQts or p a r t n e r s of the p a t i e n t s b e f o r e a n d at~ter a p p e a r a n c e of a n a l warts. N o n e of the e x a m i n e d contacts, however, h a d p e n i l e warts. It m u s t be n o t e d also that not all patients w h o have a n a l warts h a v e h a d a n a l coitus. T h e presence of c u t a n e o u s warts has b e e n i m p l i c a t e d as an e t i o l o g i c factor in such cases. A b o u t 25 p e r c e n t of o u r p a t i e n t s h a d h a d cuLaneous warts prev~iously or h a d t h e m at the time of e x a m i n a t i o n . T h i s i n c i d e n c e was r e p o r t e d as 15 p e r cent by Oriel, I8 b u t he also f o u n d tha.t c u t a n e o u s
warts w e r e c o m m o n in a c o n t r o l g r o u p . Y o u n g 26 has suggested t h a t the w a r t virus m a y be a n o r m a l i n h a b i t a n t of the anor e c t u m in some p e o p l e , a n d t h a t a n a l coitus m a y a l l o w its en,try i n t o the a n o d e r m because of r e p e a t e d t r a u m a . H o w e v e r , if one accepts this t.heory, one w o u l d e x p e c t to see a n a l warts as a c o m p l i c a t i o n of c h r o n i c a n a l ctisorders such as a n a l fissure. T h e r e f o r e , al.though the v e n e r e a l e t i o l o g y of a n a l c o n d y l o m a a c u m i n a t u m is q u i t e p r o b a b l e , the lack of cul, ture t e c h n i q u e s for c o n d y l o m a virus p r e c l u d e s an u n e q u i v o c a l conclusion. N u m e r o u s m e t h o d s h a v e b e e n used for the t r e a t m e n t of c o n d y l o m a a c u m i n a t u m ( T a b l e 5), b u t n o n e has been u n i v e r s a l l y
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FIG. 4. Same patient as in Figure 1, six weeks after completion of immunotherapy. Note the normal anal appearance except for a right posterior skin tag. No condyloma tissue is present.
successful. Forty consecutive patien,ts t r e a t e d by us p r i o r to u t i l i z a t i o n of i m m u n o t h e r a p y were s t u d i e d r e t r o s p e c t i v e l y . T h e m a j o r m e t h o d s of t h e r a p y used were podop h y l l i n , b i c h l o r a c e t i c acid, excision, a n d fulgur~t.ion. I n 18 cases o n l y one mod a l i t y of t r e a t m e n t was used; however, in 22 o t h e r s c o m b i n a t i o n s of these m e t h o d s were utilized. I n o n l y 10 cases (25 p e r cent) were these t r e a t m e n t s successful in e l i m i n a t i n g all c o n d y l o m a s in one o r two sessions. I n 30 o t h e r s (75 peqc cent) the patien, ts n e e d e d p e r i o d i c a p p l i c a t i o n of o n e o r m o r e m e t h o d s of t r e a t m e n t for prol o n g e d periods, r a n g i n g f r o m [our m o n t h s to m o r e t h a n two years. I n a s i m i l a r series of p~tients there were 11 failures in 48 cases. 23 Even w h e n the tre~mnent is event u a l l y successful, it is difficult to p r e d i c t h o w m a n y sessions of t r e a t m e n t will be necessary to e r a d i c a t e the c o n d y l o m a . T h e possible reasons for the h i g h recurrence r a t e are: 1) T h e disease is p r o b a b l y the result of sexual contact, a n d m a n y patients r e s u m e sexual activity before comp l e t i o n of t h e i r t r e a t m e n t . 2) T h e incubat i o n p e r i o d of the v i r u s is u n k n o w n , a n d if this p e r i o d were m a n y m o n t h s , a new
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c o n d y l o m a m i g h t a p p e a r a f t e r the comp l e t i o n of an a p p a r e n t l y successful course of t h e r a p y ; b y r e i n f e c t i n g the sexual partners of the p a t i e n t it c o u l d easily start a n e w cycle. 3) T h e t r e a t e d p a t i e n t s m a y c h a n g e sexual p a r t n e r s a n d a c q u i r e new i n f e c t i o n s (same o r d i f f e r e n t strains of virus?). T h e use of i m m u n o t h e r a p y , therefore, b e c o m e s qudte a t t r a c t i v e in the t r e a t m e n t of entensive o r r e c u r r e n t c o n d y l o n a a acum i n a t u m . I n 1944, B i b e r s t e i n 2 p u b l i s h e d a lengthy report, "Immunization Therapy of W a r t s . " H e used a vaccine on a v a r i e t y of watts, a n d also r e p o r t e d t h a t beneficial results were seen in 90 p e r cen.t of the patients who had condyloma acuminatum. H o w e v e r , u n t i l the recent r e p o r t of Powell et al.2o in 1970, i m m u n o t h e r a p y h a d app a r e n d y f a l l e n i n t o disuse, I n this study, 24 p a t i e n t s w h o h a d p e r s i s t e n t or r e c u r r e n t
TABLE 4. Results of Imrnunotherapy Total number of patients Lost to follow-up Total number of patients available for follow-up Excellent results Good results Poor results
39 3 36 30 (83.3 per cent) 3 ( 8.3 per cent) 3 ( 8.3 per cent)
TABLE 5. Methods o[ Treating Condyloma .4cuminatum Surgical excision Electrodesiccation Podophyllin,~ Bichloracetic acid~-z Cryotherapy Carbon dioxide snows, 11 Liquid air7 Liquid nitrogenal, 1~ Antitumor preparations Thiotepaa, o 5-FluorouracilG, 1~ BleomycinlZ Immunotherapy~6. z0
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anorectal or urogeni.tal c o n d y l o m a s were treated with a u t o g e n o u s vaccine, with excellent results i n 20, good results i n three, a n d poor results in one. Nel a n d F o u r i e ~6 r e p o r t e d 70 per cent complete regression, 10 per cent p a r t i a l regression, a n d 20 per cent n o regression in 10 cases in which condylornas were treated by i m m u n o t h e r apy. T h e y also suggest the ini.tial topical a p p l i c a t i o n of 5 per cent 5-fluorouracil ointm e n t to decrease the size of g i a n t condylomas p r i o r to i m m u n o t h e r a p y to achieve better results. A b l i n a n d C u r t i s ~ also reported excellent results a n d n o recurrence f o l l o w i n g the i m m u n o t h e r a p y of a p a t i e n t with large g e n i t a l warts. I n o u r series, 91.7 per cent of the patients had excellent or good resul.ts, a n d 8.3 per cent showed early recurrence with no regression despite immunc~therapy, h n m u n o t h e r a p y had no adverse systemic effect a n d d i d n o t alter the course of the disease u n f a v o r a b l y . T h e m e c h a n i s m by which i m m u n o t h e r apy causes regression of c o n d y l o m a s remain,s speculative. It has b e e n sttggested -~v that the relative isola,tion of p o t e n t i a l antigen (virus?) in the superficial layers of c o n d y l o m a precludes its contact with the c i r c u l a t i n g lymphocytes. I n j e c t i o n of atttogenous vaccine s u b c u t a n e o u s l y may provide more direct exposure of the a n t i g e n to the a n t i b o d y - f o r m i n g cell,s, thereby augm e n t i n g the i m m u n e m e c h a n i s m s of the host. However, Nel a n d Fou,rie 16 believe that regression p r o b a b l y d e p e n d s on "killer lymphocytes" destroying "foreign t u m o r cells" rather t h a n on a n t i v i r a l antibodies. T h e y also a,t t r i b u t e the c o n c o m i t a n t increase i n an,tiviral an,tibodies to the des t r u c t i o n of t u m o r cells a n d the l i b e r a t i o n of i n t r a c e l l u l a r viral antigens. F a i l u r e of i m m u n o t h e r a p y is also a t t r i b u t e d to the presence of p r e f o r m e d c i r c u l a t i n g antibodies, which could conceivably have a b l o c k i n g effect a n d thus prevenit contact wi,th the "killer lymphocytes," a n d perhaps even result in e n h a n c e m e n t .
243
I n a_n a t t e m p t to answer some of these questions, we are presently s t u d y i n g the cellular a n d h u m o r a l responses of p a t i e n t s with c o n d y l o m a a c c m n i n a t u m before a n d after i m m u n o t h e r a p y . Conclusion T h e i m m u n o t h e r a p y of c o n d y l o m a acum i n a t u m offers a h i g h success rate. Specific i n d i c a t i o n s for i m m u n o t h e r a p y are: 1) extensive anal a n d p e r i a n a l c o n d y l o m a acum i n a t u m ; 2) resistance to other convent i o n a l m e t h o d s of therapy; 3) r e c u r r e n c e following other forms of t r e a t m e n t . References 1. Ablin RJ, Curtis WW: Immunotherapeutic treatment of condyloma acuminata. Gynecol Oncol 2: 446, 1974 2. Biberstein H: Immunization therapy of warts. Arch Dermatol 50: 12, 1944 3. Cheng SF, Veenema RJ: Topical application of thio-tepa to penile and urethral tumors. J Urol 94: 259, 1965 4. ciuffo G: Inesto positivo con filtrato di verruca volgare. Gior Ital Mal Ven Pelle 48: 12, 1907 5. Culp OS, Kaplan IW: Condylomata acuminata: Two hundred cases treated with podophyllin. Ann Surg 120: 251, 1944 6. Farber S, McMillan L: Treatment of condyloma acuminata (letter to editor). S Afr Med J 46: 522, 1972 7. Gold JD: Liquid air and carbonic acid snow: Therapeutic results obtained by the dermatologist. NY Med J 92: 1276, 1910 8. Hall AF: Advantages and limitations of liquid nitrogen in the therapy of skin lesions. Arch Dermatol 82: 9, 1960 9. Halverstadt DB, Parry WL: Thiotepa in the management of intraurethral condylomata acuminata. J Urol 101: 729, 1969 10. Lewis GM, Wheeler CE Jr: Practical Dermatology. Third edition. Philadelphia, "vg. B. Saunders, 1967, 679 pp 11. Lyell A: Management of warts. Br Med J 2: 1576, 1966 12. Marino AW Jr: Proctologic lesions observed in male homosexuals. Dis Colon Rectum 7: 121, 1964 13. Mishima Y, Masahiro M: Effect of bleomycin on benign and malignant cutaneous tumours. Acta Derma Venereol 52: 211, 1972 14. Morgan HR, Balduzzi PC: Propagation of an intranuclear inclusion-forming agent from human condyloma acuminatum. Proc Natl Acad Sci USA 52: 1561, I964
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15. Nahra KS, Moschella SL, Swinton NW Sr: Condyloma acuminatum treated with liquid nitrogen: Report of five cases. Dis Colon Rectum 12: 125, 1969 16. Nels WS, Fourie ED: Immunotherapy and 5 per cent topical 5-fluoro-uracil ointment in the treatment of condylomata acuminata. S Afr Med J 47: 45, 1973 17. Oriel JD: Anal warts and anal coitus. Br J Vener Dis 47: 373, 1971 18. Oriel JD: Natural history of genital warts. Br J Vener Dis 47: I, 1971 19. Oriel JD, Almeida JD: Demonstration of virus particles in h u m a n genital warts. Br J Vener Dis 46: 37, 1970 20. Powell LC Jr, Pollard M, Jinkins JL Sr: Treatment of cond'yloma acuminata by autogenous vaccble. South Med J 63: 202, 1970
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21. Smith KO, Dougherty E, Melnick JL, et al: Fine structure of unassembled viral subunits from human warts. J Bacteriol 90: 278, 1965 22. Strauss MJ, Shaw EW, Bunting H, et al: "Crystalline" virus-like particles from skin papillomas characterized by intranuclear inclusion bodies. Proc Soc Exp Biol Med 72: 46, 1949 " 23. Swerdlow DB, Salvati EP: Condyloma acuminaturn. Dis Colon Rectum 14: 226, 1971 24. Walter EL Jr, Walker DL, Cooper GA: Localization of specific antigen in h u m a n warts. Arch Pathol 79: 419, 1965 25. Waugh M: Condyloma acuminata. Br Meal J 2: 527, 1972 26. Young HM: Viral warts in the anorectum possibly precluding rectal cancer. Surgery 55: 367, 1964
Memoir REEDER, FRANK E., Paducah, Kentucky; b o r n J a n u a r y 2, 1931, F r a n k l i n , Kentucky; University of Louisville School of M e d i c i n e 1957; i n t e r n s h i p University o[ T e n n e s s e e Hospitals; colon a n d rectal residency, Ferguson Clinic. Dr. R e e d e r was elected to Associate Fellowship in the A m e r i c a n Society of Colon a n d Rectal Surgeons in 1975. H e was a D i p l o m a t e of the A m e r i c a n Board of Colon a n d Rectal Surgery a n d of the A m e r i c a n Board of Surgery, a n d a Fellow, A m e r i c a n College o[ Surgeons. H e was a m e m b e r of the A m e r i c a n Medical Association, K e n t u c k y Medical Association, McCracken C o u n t y Medical Society a n d Kentucky Surgical Society; o n the staff at W e s t e r n Baptist a n d Lourdes Hospitals. Dr. R e e d e r died D e c e m b e r 23, 1975.
