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Webber J, Fromm D. Photodynamic Therapy for Carcinoma In Situ of the Anus. Arch Surg. 2004;139(3):259–261. doi:10.1001/archsurg.139.3.259
Photodynamic therapy (PDT) for carcinoma in situ of the anus is an alternative to surgical excision in patients who are seropositive for human immunodeficiency virus (HIV).
Tertiary referral center.
Twelve HIV-seropositive patients who were actively being treated for AIDS with high-grade dysplasia on anal Papanicolaou test results had site-directed biopsies of acetowhitening foci immediately after application of dilute acetic acid. Biopsy results showed that 5 patients had anal carcinoma in situ. These patients were given the photosensitizer δ-aminolevulinic acid orally. Four to 4.25 hours later, the entire anal circumference was treated with PDT. All 5 patients, after being treated with PDT, had repeated Papanicolaou tests at monthly intervals. If acetowhitening occurred at the fifth month, site-directed biopsy was done.
Main Outcome Measures
Anal cytologic examination by Papanicolaou test and site-directed biopsy if acetowhitening was found at 5 months in order to determine effectiveness of PDT in downstaging cytologic findings.
All patients had a consistent downgrading of cytologic findings during the 5 months of follow-up. Papanicolaou test results showed 2 patients had no dysplasia, 2 had mild dysplasia, and 1 had moderate dysplasia. Moderate dysplasia was confirmed by site-directed biopsy results. No complications of PDT occurred, but all 5 patients developed various abnormalities in liver function test results that returned to baseline values within 2 weeks; this also has been noted in patients ingesting δ-aminolevulinic acid who are presumably HIV seronegative.
In a group of patients who are at high risk for recurrence irrespective of initial treatment, PDT can be used as a successful alternative to surgical excision for anal carcinoma in situ.
It is currently believed that the cytologic finding of high-grade squamous intraepithelial lesions (HSIL) in the anus is a precursor of cancer. Now that anal Papanicolaou (Pap) tests are being done more routinely in patients who are positive for human immunodeficiency virus (HIV), HSIL are more frequently found. The prevalence of HSIL is increased in HIV-positive individuals.1 Another important risk factor for anal cytologic abnormalities is human papilloma virus (HPV) infection. Immunosuppression caused by HIV infection increases the likelihood of HPV infection and subsequent anal intraepithelial neoplasia. These observations presumably account for the increasing incidence of anal cancer recognized in patients with AIDS.2,3
There appears to be little argument that high-grade dysplastic lesions of the anus require treatment. The standard approach involves surgical excision, but the problem is that such lesions may be multifocal, requiring removal of large areas of anal epithelium. Furthermore, eradication of HPV infection by excision is unlikely and the chance of recurrent HSIL is estimated to be at least 30% across 5 years.4 There are no known medical therapies at present that effectively treat HSIL. An alternative to surgical excision or gross destruction is photodynamic therapy (PDT), which is associated with a low incidence of complications and can be used for sequential treatments. Photodynamic therapy has been variably successful in eradicating high-grade dysplastic lesions of the lower female genital tract and esophagus.
The purpose of this study was to determine the effectiveness and safety of PDT using the photosensitizing agent δ-aminolevulinic acid (ALA) as an alternative to surgical excision for carcinoma in situ of the anus occurring in patients who were also receiving treatment for HIV infection. Clinically, PDT is based on 2 steps. The first involves the selective accumulation of a photosensitizer in the target tissue. The second involves activation of the photosensitizer with an appropriate wavelength of light. This results in selective tissue destruction via a photochemical reaction. In itself, ALA is not photoreactive but is converted, especially by premalignant and malignant tissues, to its photosensitive end product, protoporphyrin IX.5
Twelve HIV-positive patients who had Pap test results indicating high-grade dysplasia were referred to us (J. W. and D. F.) with the understanding that if biopsy results confirmed the Pap test findings, the patients did not want to undergo surgery. Site-directed anal biopsies were done after a swab soaked in 3% acetic acid was placed in the anus for 1 minute.6 Immediately after removal of the swab, the anus was examined for so-called acetowhitening, which generally indicates the presence of abnormal squamous epithelium, using either an operating microscope or magnifying loupes. Biopsies were only directed at site(s) of whitish-appearing epithelium. High-grade dysplasia was confirmed on the biopsy results of 5 patients (3 white and 2 African American men), each of whom gave informed consent to enter the study, which was approved by the Food and Drug Administration, Rockville, Md, and Wayne State University Human Investigation Committee, Detroit, Mich. Patient characteristics relative to HIV are shown in Table 1. In addition, each of the patients had normal levels of serum electrolytes, white blood cell count, prothrombin time, and creatinine. All had a hemoglobin level of at least 10 g/dL, a platelet count greater than 165 × 103/µL, and a partial thromboplastin time that did not exceed 10% of the normal range. None met National Cancer Institute/National Institutes of Health Hepatic Toxicity Criteria greater than grade 1. All were less than American Society of Anesthesiologists class IV. None had a history of cutaneous photosensitization or received an investigational drug within 1 month of study enrollment.
Each patient received intravenous fluids at 100 mL per hour prior to the ingestion of ALA (Dusa Pharmaceuticals, Tarrytown, NY) and for at least 24 hours thereafter. Four to 4.25 hours after the oral ingestion of ALA (60 mg/kg), PDT of the anus was done under conscious sedation. A Pratt rectal speculum was inserted into the anus and opened to expose 2 quadrants of unfolded mucosa. A 2.5-cm light diffuser was then placed in the center of the speculum and connected to a pumped dye laser (Laserscope, San Jose, Calif) that delivered a 630-nm wavelength of light. The fluence rate was 200 mW/cm2, and fluence was 100 J/cm2. The anal speculum was rotated to expose the remaining 2 anal quadrants, which were treated in an identical fashion. Systemic absorption of ALA was confirmed by measuring the relative fluorescence of protoporphyrin IX in the palm of the hand using a noninvasive spectrophotofluorometric method previously described.7
The patients were kept in subdued light just prior to the ingestion of ALA and for 48 hours thereafter. Hematologic parameters (complete blood cell count and platelet count), chemistries (levels of serum bilirubin, serum glutamic-pyruvic transaminase, serum glutamic-oxaloacetic transaminase, alkaline phosphatase activity, electrolytes, serum urea nitrogen, creatinine, and blood sugar; partial thromboplastin time; and prothrombin time), and urinalysis were obtained for each patient just prior to PDT; 12, 24, and 48 hours after PDT; and at least biweekly thereafter until the levels returned to baseline values. Vital signs were monitored before ingestion of ALA and at least every 4 hours for 48 hours thereafter.
The patients were prospectively followed up as outpatients at least biweekly and had anal Pap tests done monthly. At the fifth month of follow-up, the anus was swabbed with acetic acid (as described earlier) and a site-directed biopsy was done only if acetowhitening was present.
No patient developed a systolic blood pressure less than that observed prior to ingestion of ALA, a photosensitive reaction, or more than mild anal discomfort following PDT. No patient experienced nausea or vomiting. Liver function test results were normal for 1 patient, and the remaining 4 patients had at least 1 transaminase abnormality immediately prior to ALA ingestion. All developed an increase in serum glutamic-oxaloacetic transaminase and serum glutamic-pyruvic transaminase levels after ALA ingestion, and these values peaked 48 hours after ALA ingestion, ranging from 1.2 to 6.4 (median, 2.3) times the upper limit of the normal range. One patient had an increase in total bilirubin level, peaking at 1.2 times that of the upper limit of the normal range at 48 hours after ALA ingestion, and another developed an abnormal alkaline phosphatase level, peaking at 1.2 times the upper limit of the normal range at 1 week. All abnormal levels returned to baseline values by 2 weeks. All other laboratory test results remained at baseline values or within normal limits.
All patients had a consistent downgrading of cytologic findings on Pap test results at each of the 5 monthly visits. Pap test results showed 2 patients had no dysplasia, 2 had mild dysplasia, and 1 had moderate dysplasia. Application of acetic acid (as described earlier) at 5 months showed acetowhitening only in the patient with moderate dysplasia seen on the Pap test results, and this was confirmed by site-directed biopsy. The anal mucosa was uniformly smooth in all cases during follow-up in contrast to 2 patients prior to PDT who had subtle mucosal irregularities. No patient developed a stricture.
Treatment decisions about cytologic abnormalities of the anus can be difficult because of the classification used, the multifocal nature of anal lesions, and the potential for recurrence. Most anal cytologic abnormalities are classified according to the Bethesda system.8 Benign lesions associated with HPV such as anal condyloma, HPV-related cellular changes (for example, koilocytosis), mild dysplasia, and anal intraepithelial neoplasia (AIN I) are included in the category of low-grade squamous intraepithelial lesions. In contrast, HSIL encompass moderate and severe dysplasia, AIN II or III, and carcinoma in situ. While data are still limited, it is currently believed that HSIL of the anus are a precursor of invasive malignancy.9
Individuals with HIV infection are at an increased risk of anal cancer and its precursor lesions, AIN. Patients who HIV positive are 2 to 7 times as likely as HIV-negative patients to have HPV infection, regardless of their sexual practices.10 Moreover, HIV-infected patients who have low-grade AIN are twice as likely as HIV-negative patients to have progression to high-grade AIN within 2 years. This risk is inversely related to the CD4 lymphocyte count.10
It is presently believed that the malignant potential of mild and moderately dysplastic (AIN I or AIN II) lesions is likely to be low and thus can be followed. However, use of HSIL for classification includes AIN II. There is little argument that high-grade dysplastic lesions, or carcinoma in situ (AIN III), should be treated. The rationale for using PDT in the treatment of anal carcinoma in situ was based on the use of PDT as an alternative treatment for dysplasia involving the esophagus11 and lower female genital tract.12 However, the effectiveness of PDT for these situations (especially the latter) has been met with variable success, which may be related to differences in photosensitizing drug, drug dose, timing of PDT, light dose, variable extents of treated sites, and sampling errors.
The major adverse effect of administering a photosensitizing drug is cutaneous photosensitization, which can result in a significant burn. The photosensitive by-product of ALA, protoporphyrin IX, is virtually gone 48 hours after taking ALA orally.13 By keeping patients in subdued light during this period, we have not observed any cutaneous photosensitive reactions. δ-aminolevulinic acid causes a variable incidence of hypotension as a result of a decrease in peripheral vascular resistance.14 This is avoided by administering an adequate amount of fluid intravenously. Nausea or vomiting occurs in about 21% of patients ingesting ALA, but this is mild and did not occur in the present study. Thirty percent of patients who are presumably HIV seronegative and not receiving potentially hepatotoxic medications will develop transient and variable abnormalities in liver evaluation test results after ingesting ALA. This was of concern in the present study because of the effects of ALA on such test results in patients receiving potentially hepatotoxic drugs used to treat HIV and the relatively high incidence of viral hepatitis in this population. However, all patients despite developing abnormalities in liver evaluation test results subsequent to receiving ALA, showed return to baseline values by 2 weeks. Protoporphyrin IX also tends, in contrast to several other photoreactive agents, to be more selectively accumulated by abnormal cells,5 and PDT with ALA does not result in stricture formation. The latter can occur with the use of other photosensitizing agents as well as with thermal destruction using a laser or cryoablation because the depth of tissue destruction can be difficult to control with these modalities. A laser is used in PDT to energize the sensitized cells to undergo a photooxidative reaction, rather than photocoagulation or photothermal ablation as occurs with conventional laser therapy.
A potential problem with the present as well as other studies using PDT for dysplastic epithelium is a biopsy sampling error. The present study used site-directed biopsy, relying on visual detection of acetowhitening of abnormal epithelium exposed to dilute acetic acid. The accuracy might be increased by sophisticated quantitative methods such as measurement of light-scattering properties or reflectance patterns. However, given biopsy results that show carcinoma in situ or high-grade dysplasia, the advantage of PDT is that it can be used to treat the entire circumference of the anus without significant morbidity. Although subsequent anal Pap tests and lack of acetowhitening after application of acetic acid do not absolutely exclude residual disease, these 2 tests are reasonable.
The importance of the present results is that they indicate that PDT can be used as a successful alternative to surgical excision for patients with anal carcinoma in situ. Furthermore, it appears that ALA can be safely administered to patients undergoing treatment for HIV and who have mild abnormalities in liver function test results. The durability of PDT will be difficult to determine, because the majority of seropositive-HIV individuals with squamous intraepithelial lesions of the anus also harbor HPV. However, one of the advantages of PDT is that prior treatment does not preclude subsequent treatment. A potential problem with PDT is that replacement of the destroyed high-grade dysplastic epithelium by healthier epithelium may cover microscopic islands of residual high-grade dysplasia, as has been observed in a few patients who have undergone PDT for high-grade dysplasia involving Barrett esophagus.11 Thus, there is the requirement for long-term surveillance.
Corresponding author: John Webber, MD, Department of Surgery, Wayne State University, 6C-University Health Center, 4201 St Antoine, Detroit, MI 48201 (e-mail: email@example.com).
Accepted for publication September 30, 2003.
We thank Kathy Terry Lewis, RN, for help in conducting this study.
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