Background: Anal area H.P.V. associated condylomata acuminata frequently recur after treatment. H.I.V. positive individuals are considered at greater risk of recurrence, and of carcinoma in ano when associated with some strains of H.P.V.
Objectives: Our purpose was to develop a protocol for outpatient treatment of these condylomata including the immunosuppressed.
Methods: Biopsies, CD4/CD8, H.P.V. tests, and evaluation of five therapies were done for 44 patients with anal area condylomata acuminata.
Results: H.P.V. shedding with clinical latency was common. Results included latency less than six months, more than six months, or even possible cure. Which of the categories a patient ended in was an individual matter, perhaps related to local immunity for H.P.V. rather than CD/4/CD/8, H.I.V. negativity or treatment modality. None of our patients had dysplasia or carcinoma in ano.
Conclusion: Based on these findings, we present a protocol for outpatient treatment of condylomata acuminata, including H.I.V. positives.
In considering treatment for anal condylomata, several facets of the problem need addressing.
Recurrences are common and the risk of recurrence is believed even greater in the immunosuppressed. for this reason, many trials of therapeutic modalities reported exclude H.I.V. positives. What modalities would be suitable to include H.I.V. patients? Are any patients cured, and are there indicators for predicting recurrences? It is also believed that with certain strains of the H.P.V. virus, and in the immunosuppressed, there may be more risk of carcinoma. Is there a need for routine H.I.V. and H.P.V. testing in condylomata patients? How should the possibility of carcinoma in ano be handled? (1,2,3,4)
With these considerations, the purpose of this study was to develop a protocol suitable for outpatient treatment of anal condylomata patients as they presented without exclusions.
Our patients were a narrowly defined group, since all were members of the Kaiser Permanente Health Maintenance Organization. They were referred for treatment of anal condylomata, and were entered into our study consecutively as they presented. There were 44 individuals. H.I.V. positive males accounted for 29; nonimmune suppressed males were 13 in number, and 2 were nonimmunosuppressed females. None of our patients had untreated lues. We kept records of age and sex and obtained a CD4/CD8 ratio and/or an H.I.V. test for each patient, as a measure of immunity.
Patients were positioned on a suitable table and the perianal and anal areas were inspected using an 8 cm anal speculum. This procedure will be described in detail under surgical procedures. The location and number of condylomata were noted, H.P.V. testing done and a biopsy obtained. In this investigation, presence or absence of condylomata was assessed clinically. The acetoacid whitening test was not used since its applicability to this area has not been reported on. Also its value for the penis has been questioned,(5)and similar problems might be found for the anus.
We used a hybridization test with swabs (Virapap TM).(a) This test detects H.P.V. virus in surface cells indicating viral shedding. Patients were advised not to have enema preceding, since this might wash away surface cells this test relies on. (b) A dacron swab from the test kit was stroked firmly into the perianal crevices, then inserted about 2 cm into the anal canal, rotated gently and withdrawn. Blood on the swab had to be avoided since it lessened or negated the results of this test. The swab was placed in the transport medium tube provided. The tube was stored in the freezing compartment of a refrigerator until transported on ice to our virus lab for processing. H.P.V. types 6 and 11 were reported together as were also types 16 and 18, and types 31, 33, 35. These 7 types were the only ones tested for. For some patients, biopsies were taken from sites of condylomata that had been treated by us and were no longer present clinically at the time. Paraffin block sections from these biopsies were used for in situ hybridization studies (Omniprob TM) (c) in our virus lab and for polymerase chain reaction (P.C.R.) for H.P.V. detection.
---------------------------------------
(a) Virapap TM and Omniprob TM were obtained from
Digene Diagnostics Inc.
2301-B Broadbirch Drive
Silver Springs, MD 20904
(b) Personal communication
Palefsky J.M., M.D.
Department of Laboratory Medicine and Stomatology
University of California San Francisco
San Francisco, California
(c) P.C.R. was done in the laboratories of N.S. Penney, M.D.
School of Medicine, Dept. of Dermatology, University of Miami
Miami, FL 33136
and is much appreciated
For perianal condylomata, nonsurgical therapies were used initially much of the time, and surgical methods where nonsurgical therapies were not tried or were no longer effective. Recurrences also were handled with nonsurgical and surgical methods as above. In the anal canal, surgical procedures were used both initially and for recurrences.
(A) Podophyllin (6)
This was used as a 25% standardized solution (Podoben TM) until podophyllotoxin (Condylox TM) reached market. Podophyllotoxin was used from then on.
Podophyllin in one of these forms was used as initial therapy for many of our patients. The patients whose condylomata seemed to fibrous to respond to podophyllin were treated initially with surgery. Cases where there was doubt as to whether the condylomata were or were not too fibrous were also treated with podophyllin. Patients were instructed to apply this with a Q-tip all around the perianal area until soreness occurred. At this point, the treatment was stopped, then resumed when soreness subsided. Treatment was continued in this intermittent fashion until no more clinical improvement was achieved. Then surgical procedure was undertaken.
Podophyllotoxin, when it became available, was used as initial therapy for nonfibrous condylomata, as discussed in the preceding. the recommended protocol, twice a day applications on 3 successive days, once a week for 4 weeks, was followed (7). Repeated 4-week treatments were prescribed until no more clinical improvement occurred, then surgical procedure undertaken as for podophyllin.
We also tried podophyllin and later on podophyllotoxin immediately after surgical treatment of the perianal area in an attempt to prevent recurrence and stop viral shedding.
In all, podophyllin or podophyllotoxin was used in 26 of our 44 patients. As initial therapy, it caused reduction in number and size of condylomata in many, but only in one did it bring about complete absence of condylomata (latency). When used after surgery, it did not prevent recurrence in about 3 months nor stop viral shedding. Podophyllotoxin was found more effective and less irritating than extract of podophyllin, but with the same results.
(B) Fluorouracil (8)
5 Fluorouracil cream 5% was used in some of our patients, who were instructed to apply it perianally once daily until soreness ensued, then to stop and resume when better. It was quite erosive, not as effective as podophyllin in initial treatment of condylomata, and did not bring about complete latency even in one case. We also tried it immediately after surgical intervention where it did not prevent recurrences nor stop viral shedding.
5 Fluorouracil cream 1% was less irritating and was well-tolerated by most patients immediately after surgery perianally and even in the anal canal. Because it might be of value in prolonging clinical latency, we eventually prescribed its use this way routinely after surgery, even though we did not do a controlled study. In all, we tried 5 Fluorouracil cream on 20 of our patients.
(C) Interferon (9)
Interferon alpha-2a (Roferron TM), 5 million units in 1 ml of solution, was injected into the anal area, 1/4 ml at each of 4 sites - 12, 3, 6 and 9 o'clock. The 1/4 ml was distributed evenly along the needle tract, starting about 1 cm inferior and proceeding to about 1 cm superior to the anal sphincter at each injection site, using a 30 gauge 1" needle.
Interferon was not used as initial therapy. 33 of our patients, 24 H.I.V. positive and 9 H.I.V. negative, were treated post surgery at two- to three- week intervals. This treatment did not prevent clinical recurrences within about 3 months nor stop viral shedding.
Ten of these 33 patients experienced several months of clinical latency after their surgical treatment, but with viral shedding coincident with this latency. During this latent period, we treated six of these 10 (CD4/CD8 ratios ranging from .08 to .5) with interferon as described previously, once a week for 8 weeks. the other four (CD4/CD8 .02, .26, .3 and one H.I.V. negative) were treated with interferon twice a week for 8 weeks.
In none of these 10 cases was viral shedding eliminated, and in all of them, condylomata reappeared within about 3 months after interferon injections stopped. In the H.I.V. negative patient, condylomata reappeared at 7 weeks while the patient was still receiving interferon injections.
With our patients, and used as described above, interferon was ineffective and was dropped from our protocol. In one published report, interferon was used adjuvant with cryotherapy for condylomata and results were judged not better than use of cryotherapy alone. (10)
Patients were postured on an adjustable table, and the anal area positioned at operator eye level. An intense spot light mounted high overhead provided illumination without interference from the head of the operator. An 8 cm polished metal speculum was used, and light bouncing off its polished surfaces gave adequate visibility. Several insertions of the speculum were needed to make accessible the entire perimeter of the anal canal.
The perianal area and the anal canal immediately superior to the sphincter required anesthesia. The rest of the anal canal is insensitive and was operated on without anesthesia.
About 9 ml of 2% lidocaine with 1 ml of 8.4% sodium bicarbonate solution mixed in the syringe was used, with a 30 gauge 1" needle. This buffering reduced significantly the discomfort of the above procedure. (11). Anesthetic was injected all around and about 1 cm inferior to the anal orifice, and then superiorly to reach the anal sphincter. This gave anesthesia about 2 cm inferior and 1 cm superior to the anal sphincter. Condylomata extending more inferiorly from the sphincter had to be anesthetized separately. We also used a long-acting anesthetic, bupivacaine HCI (Sensorcaine TM). It precipitated when buffered and caused considerable stinging on injecting without buffer. Therefore, buffered lidocaine was used first, followed by 10 ml to 20 ml of 0.5% bupivacaine infiltrated in the same tissue mass, giving 4 to 6 hours of anesthesia with minimal possible discomfort from injection. Lidocaine/prilocaine (Emla TM) applied for an hour or more to the perianal area did not reduce significantly the discomfort of the above procedures when tried on several of our patients. We did not continue its use. Propoxyphen was prescribed for postsurgical need.
Perianal condylomata were vaporized then with the CO2 laser and curetted down to a firm base. Pedunculated condylomata were clamped at the base, then cut off with the laser along the clamp line. Our laser had a variable spot size. We used 0.1 mm for cutting and 2.5 for ablation, and whatever power setting was useful, considering the thickness of the tissue to be treated.
Reports of the presence of H.P.V. in clinically normal skin (12) prompted our attempts to eliminate the virus by extending superficial ablation 1.5 cm beyond the clinical margins of condylomata (13), in 5 patients suitable for this trial. Prolonged morbidity resulted, but latency was not increased significantly, or viral shedding eliminated. therefore, routinely we destroyed about 5 mm of normal apearing tissue surrounding the condylomata being treated.
A smoke evacuator capable of removing H.P.V., hepatitis B and H.I.V. virus particles (0.04, .042, and 0.18 microns in size)(14) from the laser plume smoke should be used (Air Safe TM). An assistant held the inlet of the smoke evacuator close to the site of fume generation. Precautions suitable for surgical procedures with biologically hazardous materials were carefully observed. The frequent perianal recurrences were also treated as above with CO2 laser initially, or after podophyllin or podophyllotoxin where this seemed likely to reduce the condylomata in size and/or number.
Liquid N2 spray (LN2) for 60 to 90 seconds was found necessary to destroy condylomata. This amount of freezing for the perianal area resulted in significantly prolonged healing compared to CO2 lasering, which became our treatment of choice for the area.
Conversely, laser ablation of condylomata in the anal canal was found not optimal. Frequent bleeding from erosions into the highly vascular anal tissue by the laser beam occurred, and suturing in the anal canal on outpatients under local anesthesia should be avoided.
However, LN2 freezing for 60 to 90 seconds for condylomata in the anal canal did destroy them with satisfactory healing. We needed to spray the condylomata located around the perimeter of the canal, at times from 2 to 5 cm from the sphincter. We used an LN2 can (Cryop TM) which accommodated a needle with a Luer lock adapter. An 18 gauge aluminum spinal puncture needle was adapted to our use by bending about 8 mm of the needle end approximately 45 degrees. We proceeded carefully so as not to narrow the lumen, and then filed the tip off (Figure 1 [unavailable]). With this needle attached to the end of the spray can, and inserted through the speculum, LN2 could be applied directly to condylomata on the walls of the anal canal for the 60 to 90 seconds required. Smoke evacuation was necessary so that fumes from evaporation of LN2 did not obscure the operating field. For nitrogen fumes an evacuator with larger pore size (Evaculase TM) was adequate. The speculum was inserted, the anal canal wiped clear of mucus and stool, and a square of gauze inserted up against the rectum, to keep the canal clear for freezing. Frozen areas were permitted to thaw before withdrawing the speculum, so as to obtain the maximum effect from freezing. The frequent recurrences were retreated with LN2
Patients were observed after therapy at monthly intervals for the start, and at longer intervals later as determined by clinical course. All surgically treated patients were instructed to use 1% 5 fluorouracil cream as previously described, starting immediately after surgery for both anal and perianal sites.
Despite our large proportion of immune depressed patients, and doing 208 surgical procedures, there were only three instances of complication. One was a recurrences of herpes coincident with the use of 5 fluorouracil cream. The other two had bacterial infections. On culture, gram negative aerobes and anaerobes were identified. Ciprofloxacin, 500 mgm bid, and metronidazole, 500 mgm qid were useful.
Figures 2, 3, 4, 5, and 6 show condylomata before, during and after treatment [not available].
We did 414 H.P.V. swab tests on our patients. On the basis of this large number of tests and prolonged observation, we divided our patients into three groups, summarized in Tables I, II and III.
The eleven patients in Table I showed positive viral shedding every time tested, and variable periods of clinical latency.
The 22 patients in Table II had negative viral shedding tests returning to positive on later testing. Latency for more than a year coincident with four consecutive viral shedding tests during that time was not found in this group. This criterion, however, permitted us to define Table III with eleven patients who did meet the test.
Many of the headings in our three tables are similar and self-explanatory. CD4/CD8 ratio was used as a measure of immune suppression, and was not determined where H.I.V. was negative. Under H.P.V. are listed the types found: A for 6 or 11, B for 16 or 18, C for 31, 33, 35. Var. under the H.P.V. heading denotes whether variation, different type of H.P.V.,was found in the same patient at different times. Under Observation, one column shows total months of treatment and the other, duration of clinical latency separated by a comma where more than one such period occurred. Table III has different headings under Observation. Treated lists the months of treatment before latency, and Latent, the duration of latency.
There is another heading in Table III, P.C.R. (polymerase chain reaction). All eleven patients in Table III were biopsied at the sites of prior condylomata. In tissue culture, it has been shown that H.P.V. requires differentiating epithelial cells, on their way from the basal cell layer to keratinization, for expression. (15) Therefore, we sent sections from the paraffin blocks of these biopsies for in situ hybridization testing. all these tests were negative, detecting no H.P.V. latent in the basal cell layers. The blocks were sent then for P.C.R. testing. Of the 9 so tested, one was positive and 8 were negative.
Many of our 44 patients had infection with multiple H.P.V. types. Twenty-three of the 44 showed variations - different types being found at different times. The cause of this variation is not known, but its occurrence is significant in amount; and for this reason, the type of H.P.V. found cannot be relied on as representative of the infection, unless many tests are taken over a prolonged period of time, as we have done.
The patients in Table I had a positive swab test every time this was done. Many had prolonged clinical latency coincident with these negative tests. After the end of our observation period, one of the patients in Table I with 14 months of latency came back with clinical condylomata. Thus a positive H.P.V. test can be taken to denote infectiousness, and probability of clinical recurrence, irrespective of duration of latency.
The 22 patients in Table II had variably negative H.P.V. swab tests that returned to positive. some of these negative tests were found even in the presence of overt condylomata. Thus a negative H.P.V. test cannot be accepted as proof positive of lack of H.P.V. shedding unless perhaps, multiple tests are taken over a prolonged period of time.
This brings us to the 11 patients in Table II with coincident clinical latency and 4 consecutive negative swab tests during one year or more. The P.C.R. is much more sensitive and probably more reliable than the hybridization tests and was positive in 1 of 9 patients tested, but negative in the other 8.
It has been reported that using P.C.R. with different blocks from the same pathologic tissue, some had negative results and some showed different H.P.V. types from the others. This was thought due to the highly focal localization of H.P.V. in clinically pathologic tissue.(4) Also, in clinically normal tissue up to 1 cm away from condylomata, H.P.V. was located.(12)
Thus a positive P.C.R. test can be accepted as proof of presence of H.P.V. However, a negative test is valid only for the site taken from at best, and cannot clear all of the anal or perianal tissue of harboring H.P.V., or the patient involved of possible infectiousness or recurrence.
Nevertheless, the 11 patients in Table III did have unique characteristics. They had a higher percentage of H.I.V. negative and no H.P.V. 16 or 18. The preceding considerations cannot negate the possibility that H.P.V. had really been eliminated. However, seven patients in Tables I and II were also H.I.V. negative with no H.P.V. 16 or 18; so we have no way of predicting from these two criteria which Table a patient would end in.
What we have left, considering the 8 negative P.C.R. patients also, is that most of the Table III group, perhaps about 20% of our total, might be free of H.P.V. virus after treatment. This is not certain because swab tests covering the entire area cannot be relied on and the P.C.R. test is valid only for the site biopsied. Other than this 20% estimate - already established here - there seems to be not much value in routine H.P.V. testing in the treatment of anal condylomata.
None of our patients showed dysplasia or carcinoma in ano. However, routine H.P.V. testing does not seem to offer much in handling of this possibility either. The diagnosis of anal carcinoma is based on clinical grounds and biopsy - irrespective of which H.P.V. may be present. Dysplasia - a possible precursor of carcinoma - is important to diagnose and eliminate. This diagnosis also must be based on clinical grounds and biopsy, irrespective of H.P.V. Dysplasia is said to resemble condylomata clinically and be curable with the same surgical procedures as for condylomata. Irregularities in topography of the anal canal are also suspect.(3) After treatment, if condylomata repeatedly recur in the same site or if irregularities persist, a repeat biopsy and treatment accordingly is indicated. Therefore, not for this purpose either do we do routine H.P.V. testing for patients with condylomata.
The last two patients in Table III and one patient in Table II had prolonged latency, greater than 6 months, following use of laser as the only treatment. Also one patient in Table II had the same result with podophyllin only. Thirty-three of our 44 patients - about 77% - did achieve prolonged latency (greater than 6 months). We compared latency with therapies in Table IV. Five patients with latency less than 6 months are shown in the upper group, and five similar patients but with prolonged latency are in the lower group. Under treatment modalities are listed C - CO2 laser, N - liquid N2 spray, I - interferon, P - podophyllin or podophyllotoxin, and F - 5 fluorouracil.
There is no consistent difference between these groups in any of the parameters listed, including general immunity status (CD4/CD8) or therapies used. Prolonged latency seems an individual characteristic, perhaps related to local immunity to H.P.V. for this area, that does not have to be parallel to general immunity and hence, is not possible to predict.
Seventy-seven percent of our patients treated long enough did enter prolonged latency. In Table III, patient A.S. was treated for 14 months and K.K. for 32 months before entering prolonged latency. Thus it would seem best that all patients, irrespective of general immunity, be treated continuously and with hope. This is in accord with the suggestions of Felman(16). There can be expectation for about 77% of prolonged latency including 20% possible, but not provable, cure with freedom from H.P.V.
Finally our present treatment protocol, yielding results as in this report is as follows: A CD4/CD8 or H.I.V. testing is necessary since some of our patients are unaware of their H.I.V. positivity and have to be informed and handled accordingly. Status relative to lues should be ascertained, since infection with more than one S.T.D. is not unlikely. We no longer use H.P.V. testing as routine. Then the number and location of condylomata are noted and a biopsy taken, to confirm the diagnosis of condyloma and ascertain whether dysplasia or carcinoma is present.
Following this, podophyllotoxin is used on perianal condylomata until latency sets in or no further improvement occurs. At this point, and as initial therapy if the condylomata seem too fibrous for podophyllotoxin, CO2 laser is used. The frequent recurrences are treated with podophyllotoxin and/or CO2 laser as above.
For anal canal condylomata, LN2 is used as initial therapy and for recurrences. After either surgical procedure, and for both anal and perianal areas, 1% 5 fluorouracil cream is prescribed.
Patients are observed at monthly intervals at the start and at longer intervals as indicated clinically. Treatment is continued until prolonged latency is achieved and is not stopped, even with persistent periods of short latency. Long continued observation is necessary.
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In situ hybridization tests (Omniprob TM) courtesy of H.K. Ziel, M.D., M. O'Connell, M.D. and R. Scruggs, H.T., A.S.C.P., Kaiser Permanente Los Angeles. We wish to thank A. Cantwell, Jr., M.D. and M.H. Klapman, M.D. (Chief) of our Kaiser Permanente Dermatology Department for their help in editing.
Palefsky J.M., M.D. Department of Laboratory Medicine and Stomatology University of California, San Francisco San Francisco, California Felman Y.M., M.D., FACP Clinical Professor of Dermatology Downstate Medical School Address is: 8100 Bay Parkway, Brooklyn, New York 11214
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