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Anal Intraepithelial Neoplasia and Anal Cancer: An Increasing Concern in Women
HPV is not only associated with cervical neoplasias and cervical cancer, it is now an established pathologic factor in other cancers, including cancer of the anus, penis, vulva, vagina, and oropharynx.1 Anal cancer has been receiving increased attention and steadily increasing over the last 30 years, with a 2.8-fold increase in the incidence between 1973 and 1998.2 There have been 6230 new cases and 780 deaths from anal cancer in the US in 2012.3 This incidence rise in anal cancer has been more in women than in men.4 Yearly estimates from the CDC show that there are 1600 HPV-related anal cancers in women compared with 900 in men.5
HPV is even more prevalent than cervical infections with HPV in HIV-infected women and HIV-negative women at high risk for HPV.6 Several risk factors have been identified for anal intraepithelial neoplasia (AIN), including anal intercourse, intravenous drug use, abnormal cervical cytology, young age, HIV infection/low CD4 count, and anal or cervical HPV infection. A cervical infection with high-risk HPV has been associated with an increased risk of acquiring high-risk anal HPV infection in a study of healthy women in Hawaii.7 Other studies have shown that women with CIN were at 3 times greater risk of having an abnormal anal Pap test along with anal HPV infection.8,9
An estimated 12.2% prevalence of AIN in women with intraepithelial neoplasia of the cervix, vulva, or vagina was observed in another study.10 Even more worrisome, women with in situ and invasive cancer of the cervix, vulva, or vagina have a 13-fold increase rate of anal carcinoma sometime during their lives.11
AIN is similar to CIN in terms of classifications of severity into 3 groups, AIN 1, 2, and 3. Also similar to CIN, high-risk HPV types are associated with high-grade neoplasia, which if left untreated, can progress to invasive carcinoma. HPV type 16 in particular has been linked to anal squamous cell tumors, and this appears to be the most common HPV strain detected in anal cancer specimens.12
As of this writing, there are no established guidelines for routine screening for anal neoplasia. Part of the problem is the lack of accuracy and adequacy of anorectal cytology specimens, and none of the available HPV detection tests are FDA approved for use in anal samples. The range of sensitivity of anal cytology can be from 42% to 98% and specificity ranges from 42% to 96%.13 Anoscopic guided biopsy is more accurate. Similar to colposcopy for the cervix, high-resolution anoscopy can be done in patients with abnormal anal cytologic findings. Some researchers recommend that patients with anal atypical squamous cells of undetermined significance or worse be referred for this high-resolution anoscopy with directed biopsies. Unfortunately, it is not widely available.
While the role and benefit of HPV testing as a screening method for anal dysplasia and anal cancer is not established or well delineated, there are some clinical operating principles that can be adopted for this developing area of women's health.
Digital anal-rectal examination and anal cytologic screening followed by annual screening is recommended in the following women:
- HIV-infected women
- women with a history of cervical, vaginal, and/or vulvar dysplasia
- women with a history of cervical, vaginal, and/or vulvar cancer
- chronically immunosuppressed individuals due to reasons other than HIV – ex/transplant patients14
Screening with anal-rectal exams and HPV testing for other high-risk populations, let alone low-risk populations, is currently left up to our clinical judgment, until further research is done to demonstrate value for screening.
A Few of My Favorite Natural Medicine Studies from 2012
Red Clover Helps Anxiety and Depression in Menopausal Women
One hundred and nine postmenopausal women were randomly assigned to take either 2 capsules daily of a red clover extract totaling 80 mg of isoflavones, or a placebo, for 3 months. At the end of the 90 days, there was a one week break, and the two groups switched to take the opposite pills for another 3 months. Their anxiety and depressive symptoms were measured using two common research methods, the Hospital Anxiety and Depression Scale (HADS) and the Zung's Self Rating Depression Scale (SDS). These measurements were taken prior to the start of the red clover or placebo, then again at 90 days and 187 days.
After taking the red clover extract, women had a significant reduction (improvement) in the scores in both of the rating scales, with a 75% reduction for anxiety and 78.3% reduction for depression using the HADS tool, and an 80.6% reduction in the total SDS score. After taking the placebo pills, the HADS and SDS scores only reduced by an average of 21.7%.
The current study revitalizes my interest in red clover for the management of perimenopause/menopause symptoms, and depression/anxiety in particular.
Lipovac M, Chedraui P, Gruenhut C, et al. Improvement of postmenopausal depressive and anxiety symptoms after treatment with isoflavones derived from red clover extracts. Maturitas. 2010;65:258–261.
Vitamin D and Menstrual Pain
Something as simple as vitamin D can help some with menstrual cramps. This study included 40 women ages 18 through 40 who had menstrual cramps for at least 4 consecutive months within the previous 6 months and who had a blood level of vitamin D <45 ng/mL. None of the women were taking calcium, vitamin D, birth control pills, or other medications or using an IUD within the previous 6 months as well. The study allowed them to take nonsteroidal anti-inflammatory drugs (NSAIDs), but they were to record their use of these medications.
Women were randomized to receive a single high dose of vitamin D of 300,000 IU or placebo 5 days before the anticipated onset of their next menstrual period. The primary measured outcome was the intensity of the menstrual pain and the secondary outcome was the use of NSAIDs. After 2 months/2 menstrual periods, the pain scores decreased 41% in the vitamin D group and there was no difference in the placebo group. The greatest reduction in pain was seen in the women in the vitamin D group who had the most severe pain at baseline. In addition, none of the women in the vitamin D group needed NSAIDs to manage their pain at 1 and 2 months, while 40% of the women in the placebo group used a NSAID at least one time.
Antonino L, Antonino C, Salvatore B. Improvement of primary dysmenorrhea caused by a single oral dose of vitamin D: results of a randomized, double-blind, placebo-controlled study. Arch Intern Med. 2012;172(4):366–367.
Ginger and Menstrual Cramps: Still a Contender
This study included 105 Iranian women aged 18 and older who had moderate-to-severe primary dysmenorrhea (menstrual cramps without an organic cause). Scoring was rated in a 4 grade system: grade 0 = pain free menses; grade 1 = painful menses but rare use of analgesics and able to maintain normal activity for the most part; grade 2 = moderately painful menses that influenced daily activity and analgesics were needed; grade 3 = severely painful menses and significantly limited activities, analgesic use did not mitigate the pain, and additional other symptoms such as headache, nausea, vomiting, or diarrhea were present.
Ginger capsules were given in one of two methods: (1) 500 mg ginger capsules or placebo 3×/daily starting 2 days before the beginning of menses and continued through day 3 of menses; (2) 500 mg ginger capsules or placebo 3×/daily on days 1,2 and 3 of menses. The severity and duration of the pain were assessed on the first 3 days of menses. The severity of pain was significantly reduced in the ginger group compared with the placebo group for both dosing methods with a lower p value (better results) in the first dosing method. It is important to note that these results in both dosing regimens were better than the baseline cramp severity before the study began and again, more meaningful for the first dosing method wherein the ginger is started 2 days prior to the onset of menses. A 1.4 to 2.0 point reduction in severity was seen with ginger, and with the first dosing method, ginger significantly reduced the duration of pain compared with placebo. There was a 4.6 ± 10.6 hour decrease in the duration of pain versus a 2.3 ± 18.2 hour increase in duration in the placebo group. The second ginger dosing method was not significant in pain duration between ginger and placebo. Ginger can cause heartburn, and 3% of women in the study experienced this.
Consider using ginger root either alone, or in combination with other important natural ingredients in the relief of menstrual cramps such as crampbark, niacin, vitamin B6, valerian, wild yam, and more.
Rahnama P, Montazeri A, Fallah Huseini H, Kianbakht S, Naseri M. Effect of Zingiber officinale R. rhizomes (ginger) on pain relief in primary dysmenorrhea: a placebo randomized trial. BMC Complement Altern Med. July 10, 2012;12(1):92.
Topical Zinc Solution and HPV
Design: A treatment group of 112 patients with HPV received twice weekly self-administered intravaginal infusions of 0.5mM zinc citrate solution containing CIZAR (zinc chloride and citric acid anhydrous) for 12 weeks; the control group were patients who met the inclusion criteria via data collected retrospectively and received no other treatment. The inclusion criteria were 20 to 60 years of age, HPV positive, no evidence of high-grade squamous intraepithelial lesions (HSIL) by Pap smear and colposcopy, no previous history of cervical dysplasia or cancer, not pregnant, and HIV negative.
After 12 weeks of the zinc citrate solution vaginal infusion twice per week, HR-HPV was eliminated in 49/76 (64.47%) of patients compared with the spontaneous clearance rate in 18/118 (15.25%) of patients in the control group. This difference was significant. The treatment group had 29/56 (51.8%) return to normal cytology and the control group had 24/53 (45.3%) return to normal, although it was not considered statistically significant. When just LSIL lesions were evaluated, the return to normal was 17/39 (44.6%) in the treatment group and 6/28 (21.4%) in the control group.
The results of this study bode well for women with HPV and/or low-grade cervical dysplasia although this is the first study to demonstrate the potential of zinc in women with 13 types of HR-HPV. These results are similar to earlier studies that have reported that zinc has a significant therapeutic effect on HPV.15,16
Kim JH, Bae SN, Lee CW, et al. A pilot study to investigate the treatment of cervical human papillomavirus infection with zinc-citrate compound (CIZAR). Gyn Onc. 2011;122:303–306.
1. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Human papillomavirus. IARC Monogr Eval Carcinog Risks Hum. 2007;90:1–636.
2. Maggard M, Beanes S, Ko C. Anal canal cancer: a population-based reappraisal. Dis Colon Rectum. 2003;46(1):1517–1523.
3. National Cancer Institute. Anal cancer [Web page]. www.cancer.gov/cancertopics/types/anal. Accessed February 24, 2012.
4. Joseph D, Miller J, Wu S, et al. Understanding the burden of human papillomavirus-associated anal cancers in the U.S. Cancer. 2008;113 (10 suppl):2892–2900.
5. Centers for Disease Control and Prevention. HPV-associated anal cancer rates by race and ethnicity [Web page]. www.cdc.gov/cancer/hpv/statistics/anal.htm. Updated June 22, 2009. Accessed February 24, 2012.
6. Palefsky J, Holly E, Ralston M, et al. Prevalence and risk factors for anal human papillomavirus infection in human immunodeficiency virus (HIV)-positive and high-risk HIV-negative women. J Infect Dis. 2001;183 (3):383–391.
7. Moscicki A, Hills N, Shiboski S, et al. Risk factors for abnormal and cytology in young heterosexual women. Cancer Epidemiol Biomarkers Prev. 1999;8(2):173–178.
8. Abar A, Fenger C, Elfron J, et al. The pathology and molecular biology of anal intraepithelial neoplasia: comparisons with cervical and vulvar intraepithelial carcinoma. Int J Colorectal Dis. 2002;17(4):203–215.
9. Hernandez B, McDuffie K, Zhu X, et al. Anal human papillomavirus infection in women and its relationship with cervical infection. Cancer Epidemiol Biomarkers Prev. 2005;14(11 pt 1):2550–2556.
10. Santoso J, Long M, Crigger M, et al. Anal intraepithelial neoplasia in women with genital intraepithelial neoplasia. Obstet Gynecol. 2010;116(3):578–582. Erratum in: Obstet Gynecol. 2010:116(5):1224.
11. Saleem A, Paulus J, Shapter A, et al. Al cancer in a cohort with human papillomavirus-related gynecologic neoplasm. Obstet Gynecol. 2011; 117(3):643–649.
12. Daling J, Madeleine M, Johnson L, et al. Human papillomavirus, smoking, and sexual practices in the etiology of anal cancer. Cancer. 2004;101 (2):1270–1280
13. Bean S, Chhieng D. Anal-rectal cytology: a review. Diagn Cytopathol. 2010;38(7):538–546.
14. New York State Department of Public Health; 2012.
15. Liu T, Soong S, Alvarez R, Butterworth Jr C. A longitudinal analysis of human papillomavirus 16 infection, nutritional status, and cervical dysplasia progression. Cancer Epidemiol Biomarkers Prev. 1995;4:373–380.
16. Scirpa P, Scambia G, Masciullo V, et al. A zinc sulfate and usnic acid preparation used as post-surgical adjuvant therapy in genital lesions by human papillomavirus. Minerva Ginecol. 1999;51:255–260.
Dr. Tori Hudson graduated from the National College of Naturopathic Medicine (NCNM) in 1984 and has served the college in many capacities over the last 285 years. She is currently a clinical professor at NCNM and Bastyr University; has been in practice for over 28 years; and is the medical director of the clinic A Woman's Time in Portland, OR, and director of research and development for Vitanica, a supplement company for women. She is also a nationally recognized author, speaker, educator, researcher, and clinician.
Tori Hudson, ND
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