Author(s): J.G. Zeikus , R. Kerby and J.A. Krzycki
Source: Science. 227 (Mar. 8, 1985): p1167.
Document Type: Article
COPYRIGHT 1985 American Association for the Advancement of Science
http://www.sciencemag.org/
Single-Carbon Chemistry of Acetogenic and Methanogenic Bacteria
There has been considerable chemical research on the technological application of single-carbon (C1) transformations. Synthesis gas (syngas), a mixture of hydrogen and carbon monoxide has long been used as a feedstock for production of industrial chemicals. Although syngas has been derived from methane it is increasingly manufactured from coal and may be derived from nonfossilized forms of biomass. The role of syngas and C1 chemistry in the production of polymeric chemicals and fuels may increase as the supply of petroleum-derived chemicals becomes limiting (1).
The conversion of single-carbon compounds to higher molecular weight products depends on metal-containing catalysts (2). The conversion of syngas to methane and higher hydrocarbons (Fischer-Tropsch reaction) and of methane to ethanol occur in the presence of iron-, cobalt-, or nickel-containing catalysts. The conversion of methanol (itself derived from syngas by copper-zinc chromite-containing catalysts) and CO to acetic acid depends on homogeneous rhodium-containing catalysts (Monsanto process), although cobalt was used initially and efforts to produce suitable nickel-containing catalysts are under way.
Thursday 13 June 2013
Wednesday 12 June 2013
Treatment of traumatic myositis ossificans with acetic acid iontophoresis
Traumatic myositis ossificans is a reactive osseous lesion occurring in soft tissues and at times close to bone and periosteum. [1] It is a result of muscle injury and often reinjury. [1] The hemorrhagic area is organized by granulation and fibrous tissue with fibroblastic cells from the endomysium, which form broad sheets of immature fibroblasts. [1] Primitive mesenchymal cells proliferate within the injured connective tissue and give rise to osteoid and chondroid formation at the periphery progressing inward. [1] Eventually chondrogenesis occurs, and mature lamellar bone is formed. Calcification usually appears in 2 to 3 weeks. The ossification of heterotopic bone occurs within 4 to 8 weeks. [1] Full maturity is reached by 5 to 6 months, at which time the mass may show some decrease in size or resolution. The most common sites of incidence are the anterior high (quadricepts femoris muscle) and the anterior arm (brachialis muscle). [2]
Little recent literature exists regarding treatment for myositis ossificans. Traditionally, treatment for myositis ossificans has revovled primarily around controlling hemorrhage. Rest, ice, elevation, compression dressings, and immobilization are initiated with moderate to severe contusions. In addition, an anti-inflammatory agent may be prescribed. [3] Heat, continuous ultrasound, massage, stretching, and exercise shouldbe avoided initially so as not to induce further bleeding in the area. [3]
Immobilization is usually continued until all pain has disappeared, at which time range-of-motion maneuvers and strenthening exercises are slowly initiated. [3] Alternative treatments include surgery; aspiration of the hematoma with subsequent injection of 1% lidocaine hydrochloride, anti-inflammatory steroids, and lysosomal enzymes; cold laser therapy; radiation treatments; and acetic acid iontophoresis. [4,5]
The literature has shown that traumatic myositis ossificans may take up to 2 years to resolve. Surgical removal of the ossified mass is often a debilitating option. Physicial therapy protocols for this pathology have been argued in the literature. [3-5] Because traumatic myositis ossificans is an uncommon pathology, little research has been completed in this area of treatment. Treatment of this condition with acetic acid iontophoressis may result in a quicker, safer return to activity and may eliminate the need for surgical removal.
Iontophoresis is the introduction of topically applied, physiologically active ions through the epidermis using continuous direct current. Described initially by Le Duc in 1908, iontophoresis is based on the principle that an electrical charge will repel a similarly charged ion. [6] The clinical use of acetic acid iontophoresis in the treatment of patients with calcium deposits was first described in 1955 by Psaki and Carroll [7], and again in 1977 by Kahn. [8]
The acetate ion found in acetic acid is negative in polarity and has been cited as effective in reducing the size of calcium deposits through the absorption of calcium. [7] Prior to complete ossification, myositis ossificans usually consists of precipitates of calcium carbonate that are not soluble in normal blood pH levels. [8] It has been postulated that the acetate radical replaces the carbonate radical in the insoluble calcium carbonate deposit, forming a more soluble calcium acetate, as the following equation demonstrates [9]:
[CaCO.sub.2] + [2H(C.sub.2H.sub.3O.sub.2]) =Ca([C.sub.2H.sub.3O.sub.2.).sup.2] + [H.sub.2.O+CO.sub.2]
Iontophoresis would appear to be an alternative treatment to injection for introduction of the acetic acid. Because recurrent injury resulting in additional bleeding often is a precursor to the myositis ossificans formation, [10] additional damage to tissues and resultant bleeding may occur from invasive injection by a syringe and needle.
Case Report
A 16-year-old male soccer player was referred to my clinic by his physician for treatment of his "deep quadriceps contusion." The patient history revealed a diving accident 3 weeks prior to referral in which he dove from a diving board onto a swimmer below. A small contusion developed on his anterior superior iliac spine; however, he continued to swim and dive for the rest of the afternoon. One week later, the patient noticed increased swelling and pain in his right lateral anterior thigh. This pain became progressively worse until the patient was unable to play soccer. During the second week postinjury, pain was increasingly present on descending stairs. The patient was able to ambulate with full weight bearing without pain, although running produced sharp pain in the lateral thigh. He could remember no other traumatic incident since the diving accident. There was no history of prior injury or illness. The patient did not recall any joint pains or muscle aches and had no complaints of sickness or fatigue. He also could not recall having taken any prescribed medications, including aspirin, since the diving accident.
Examination by the physical therapist revealed that the patient had pain that restricted passive knee flexion greater than 80 degrees. The patient was able to achieve full hip ROM of 120 degrees. He had pain with isometric knee extension, but no pain with resisted hip flexion. He was able to achieve full passive knee extension, but was unable to perform an isometric quadriceps femoris muscle contraction in full extension. The patient experienced pain upon palpation of the vastus lateralis musculature, and a well-circumscribed firm mass approximately 10X6 cm was noted. the mass was fixed, nonpulsatile, and not warm. No signs of redness or streaking around the mass were found, and the patient had a normal body temperature.
The patient was then referred back to his physician with a suggestion that the physician investigate the possibility of myositis ossificans. The physician ordered anterior-posterior and lateral radiographs of the right femur, which revealed a maturing myositis ossificans located in the region of the vastus lateralis musculature (Fig. 1). Radiographic measurements revealed the mass to be 7.1 cm in length, 4.2 cm in width, and 2.1 cm in thickness. The physician hypothesized that the small anterior superior iliac spine contusion may have bled into the lateral thigh musculature, therefore contributing to the formation of the myositis ossificans.
The therapist discussed treatment options for myositis ossificans with the physician. In an attempt to decrease the size and possible progression of the calcium formation, acetic acid iontophoresis was chosen to supplement the physician's prescription of rest and inactivity. The patient was treated with acetic acid iontophoresis in accordance with Sharp's protocol [11] for 3 weeks. Both electrode sites were thoroughly cleansed with an isopropyl alcohol wipe, and the active (negative) drug electrode was placed over the site of ossification. Three milliliters of a 2% acetic acid solution using a distilled water dilution medium was introduced into the active drug electrode. The drug electrode (IOMED model EL501*) consisted of a closed polyurethane reservoir with a semipermeable membrane and an adhesive border for fixation. The treatment area of the electrode was approximately 2.5 cm in diameter. A 4.2-cm [2] karaya pad was used as the dispersive electrode and was placed 8 cm distal to the active electrode. Using an iontophoresis unit (IOMED model PM600 Phoresor Iontophoretic Drug Delivery System*), the patient was treated with 4 mA of direct current for 20 minutes, for a total of 80 mA.min, in accordance with Sharp's protocol. [11] This treatment was followed by 9 minutes of 1.5 W/cm [2] of pulsed ultrasound at a 50% duty cycle. An ultrasonic coupling gel was used as the transfer medium.
Ultrasound was administered directly over the myositis ossificans site in an attempt to decrease skin irritation and to possibly further disperse the acetic acid throughout the injury site. Additional treatment consisted of mild treatment consisted of mild passive-range-of-motion (PROM) movements within pain-free limits for 5 minutes three times a week. The patient was instructed to avoid any painful activity including stair climbing. He was instructed not to participate in any sports during the 3-week treatment period. The iontophoresis, ultrasound, and passive stretching treatment was administered on alternate days three times per week for 3 weeks. After the fifth treatment, the mass became increasingly compressible, and the patient's pain-free ROM improved to 110 degrees of knee flexion.
At the conclusion of nine treatments, radiographs revealed the mass to be 2.8 cm in length, 0.3 cm in width, and 0.8 cm in thickness (Fig. 2). These results represent a 98.9% decrease in the size of the mass. The patient regained full knee ROM of 149 degrees and was able to resume playing soccer pain-free. He had no pain with any activities of daily living including running and descending stairs. A protective Orthoplast (+) "donut" thigh pad was then placed over the area of previous injury in an attempt to protect against future injury to the thigh musculature during athletic activity.
What caused the reabsorption of the calcifying myositis ossificans in this patient is unknown. Ultrasound may have enhanced the resorption of the soluble calcium acetate. It is also questionable whether the ultrasound treatment itself played a role in the resolution of the mass. It has been inconclusively argued in the literature as to whether bone reabsorption or formation is enhanced by ultrasound. [12,13] Properly controlled studies are necessary to determine the efficacy of the individual entities of the treatment program chosen.
Myositis ossificans seems to be a self-limiting disease. There is a spontaneous resolution after maturation in many cases, [14] but reports have shown that traumatic myositis ossificans may take up to 2 years to resolve. Only a small percentage seem to need surgical excision; however, this is often a debilitating option. Possible clinical implications for acetic acid iontophoresis may include myositis ossificans, calcific joint deposits, frozen shoulder, and heel spur formation.
Summary and Conclusions
As traumatic myositis ossificans is an uncommon pathology, little research has been completed in this area of treatment. This case report describes the treatment of a 16-year-old boy with a diagnosis of postraumatic myositis ossificans. The patient's 3-week physical therapy program consisted of a 2% acetic acid iontophoresis treatment followed by pulsed ultrasound and mild PROM movements. Following completion of the program, a 98.9% reduction in the size of the calcifying mass was demonstrated by radiographic evidence. Further studies are needed to support the use of acetic acid iontophoresis for both treatment and possible use as prevention once initial trauma has occurred. Controlled studies with acetic acid iontophoresis and myositis ossificans are necessary to establish a cause-effect relationship. Additional research, including single-subject designs, should be implemented to document the efficacy of this procedure.
References
[1] Tyler JL, Derbekyan V, Lisbona R. Early diagnosis of myositis ossificans with To99m diphosphonate imaging. Clin Nucl Med. 1984;9:460-462. 1984;9:460--462.
[2] Huss CD. Myositis ossificans of the upper arm. Am J Sports Med. 1980;8:419--424.
[3] Nalley J, Susan Jay M, Durant RH. Myositis osiificans in an adolescent following a sports injury. J Adolesc Health Care. 1985;6:460--462.
[4] Ellis M, Frank HG. Myositis ossificans traumatica: with special reference to the quadriceps femoris muscle. J Trauma. 1966;6:724--738.
[5] Jackson DW, Feagin JA. Quadriceps contusions in young athletes. J Bone Joint Surg [Am]. 1973;55:95--104.
[6] Cummings J. Iontophoresis. In: Nelson RM, Currier DP, eds. Clinical Electrotherapy. East Norwalk, Conn: Appleton & Lange; 1987:231.
[7] Psaki CG, Carroll J. Acetic acid ionization: a study to determine the absorptive effects upon calcified tendinitis of the should. Phys Ther Rev. 1955;35:84--87.
[8] Kahn J. Acetic acid iontophoresis for calcium deposits: suggestion from the field. Phys Ther. 1977;57:658--659.
[9] Kahn J. Principles and Practice of Electrotherapy. New York, NY: Churchill Livingstone Inc; 1987;165.
[10] Antao NA. Myositis of the hip in a professional soccer player. Am J Sports Med. 1988;16:82--83.
[11] Sharp N. Acetic: a solution for some frozen shoulders. Phoresor Forum. 1988;7(5):1.
[12] Cline PD. Radiographic follow-up of ultrasound therapy in calcific bursitis: case report. Phys. Ther. 1963;43:659--660.
[13] Ziskin MC, Michlovitz SL. Therapeutic ultrasound. In: Michlovitz SL, ed. Thermal Agents in Rehabilitation. Philadelphia, Pa: FA Davis Co; 1986:160.
[14] Thorndike A. Myositis ossificans traumatica. J. Bone Joint Surg [Am]. 1940;22:315--323.
Source Citation (MLA 7th Edition)
Wieder, Deborah L. "Treatment of traumatic myositis ossificans with acetic acid iontophoresis." Physical Therapy Feb. 1992: 133+. Academic OneFile. Web. 12 June 2013.
Saturday 4 May 2013
Acetic acid intoxication by rectal administration
Author(s):
Satoshi Fujita
,
Mikito Kawamata
,
Takahisa Mayumi
,
Akiyoshi Namiki
,
Keiichi Omote
and
Sinzou Sumita
Source:
Journal of Toxicology: Clinical Toxicology.
32.3 (May 1994): p333.
INTRODUCTION
While intoxication by acid ingestion is well recognized [1-3], acute acid intoxication by rectal administration is little known [4]. Acid burns of the colon and rectum are an unusual occurrence but may lead to more extensive damage than induced in the esophagus and stomach by ingestion [4].
Case Report
A 5-year-old, 16 kg boy experienced abdominal discomfort after swimming. At the doctor's office he received 50 mL of 9% acetic acid rather than the prescribed glycerin enema, but the error was not discovered. At 5 h after treatment he experienced severe abdominal pain and macrohematuria and was immediately hospitalized.
On admission oral temperature was 38.6 [degrees] C; systolic blood pressure 60 mm Hg; heart rate 180 bpm and respiratory rate 40/min. He was drowsy, the extremities showed signs of dehydration and cyanosis, the abdomen was distended and guarded with absent bowel sounds. Laboratory data included the following: WBC 25,500/[mm.sup.3]; hematocrit 44.9%; platelets 245,000/[mm.sup.3]; prothrombin time 16.8 sec (control below 12.0 sec); partial thromboplastin time 48 sec (control 32 sec); serum Na 140 mEq/L; K 5.4 mEq/L; AST 546 U; ALT 164 U; LDH 3379 U (up to 500 U); myoglobin in serum 610 ng/mL; myoglobin in urine 2660 ng/mL; [beta.sub.2] microglobulin in serum 2.1 mg/mL; and [beta.sub.2] microglobulin in urine 8000 mg/mL. The serum specimen was hemolyzed. Arterial blood gases (room air): pH 7.208; [PaO.sub.2] 63 mm Hg; [PaCO.sub.2] 24 mm Hg; and Base Excess -11.6 mEq/L. Abdominal ultrasonography showed ascites and a distended colon with fluid.
A laparotomy approximately 9 h after the enema showed colonic necrosis extending from the left transverse colon to the sigmoid colon but there was no perforation. A hemicolectomy and colorectostomy were accomplished despite wound bleeding. On proctoscopy the mucous membranes of the rectum were edematous and eroded. Post-operatively the administration of the acetic acid enema was discovered.
Shock and respiratory distress responded to fluids, fresh frozen
plasma, dopamine and mechanical ventilation. The hemolysis improved after
administration of haptoglobulin 2000 U but oliguria developed.
The postoperative laboratory data indicated DIC, acute renal
failure and acute liver dysfunction. He was treated with 2 U of fresh blood
and 3 U of fresh-frozen plasma, and 8 U of fresh packed platelet for 2 days
with a gradual resolution. Acute renal failure was treated with
hemodiafiltration through d 15 by which time serum creatinine was normal. The
high level of serum transaminases returned to their normal ranges by day 15.
Sepsis with blood cultures positive for Staph. aureus was treated with
antibiotics through d 15.
The pathologic diagnosis of resected colon and rectum was
extensive necrosis of the colon down to smooth muscle with engorged vessels,
fibrin and neutrophilic infiltration.
DISCUSSION
A 9% acetic acid solution would not seem to pose a serious danger upon ingestion, as vinegar contains 4 - 6% acetic acid, but 5% acetic acid injected into the colon with immediate irrigation induced colitis in rats [5]. After acid ingestion the rapid transit through the esophagus, lined with squamous epithelium, the greater thickness of the three muscle layers of the gastric wall and dilution by gastric juice or food may contribute to the low incidence of gastric necrosis [6]. In contrast, an acid solution by enema has a longer contact time with little neutralization or dilution. Rectal administration of 40 mL of a 3 % acetic acid is fatal to rabbits within 1 h, but only after 6 d by gastric route [7].
We are aware of only one report describing an acid (95% sulfuric acid) burn of the colon and rectum [4]. In that case the rectum and transverse colon were gangrenous, but no perforation was noted [4]. Subtotal proctocolectomy was done soon after the burn, and the patient recovered uneventfully [4]. In contrast, our patient who had a hemicolectomy about 9 h after administration, developed hemolysis, acute renal failure, DIC and acute liver dysfunction. Acute renal failure is a well-known complication after acid ingestion [7], and DIC and acute liver dysfunction have also resulted from acid ingestion [8.9], but not all in the same patient [8-12].
The mechanism of caustic-induced DIC remains unclear, but extensive acid-induced tissue necrosis can lead to procoagulant formation and DIC [9]. Direct activation of the coagulation system by acetic acid is another possibility. DIC is also a complication of many disease states with many different causes, including acidosis, shock and sepsis [10].
Two patients who ingested glacial acetic acid developed acute necroinflammatory changes of the liver [11]. It is proposed that liver dysfunction is caused by thrombosis and circulatory disturbances in the portal vein and intralobular capillaries after acetic acid ingestion [12].
In toxicology, the route of administration is critical to the
prediction of risk. This case is a reminder that rectal administration of
relatively dilute caustic, 9% acetic acid, can cause bowel necrosis of high
morbidity and mortality.
REFERENCES
[1.] McLanahan S. Pyloric occlusion following the ingestion of corrosive liquids. JAMA 1934;102:735-739.
[2.] Boikan WS, Singer HA. Gastric sequelae of corrosive poisoning. Arch Intern Med 1930;46:342-357.
[3.] Strode EC, Dean ML. Acid burns of the stomach. Report of two cases. Ann Surg 1950;131:801-811.
[4.] Nallathambi MN, Sleeper R, Smith M, Ivatury RR. Acid burns of the rectum and colon: report of a case. Dis Col Rect 1987;30:469-471.
[5.] McPherson B, Pfeiffer CJ. Experimental colitis. Digestion 1976;14:424-452.
[6.] Allen RE, Thoshinsky MJ, Stallone RJ, Hunt TK. Corrosive injuries of the stomach. Arch Surg 1970;100:409-413.
[7.] von Oettingen WF. The aliphatic acids and their esters - toxicity and potential dangers. AMA Arch Ind Health 1960;21:40-77.
[8.] Greif F, Kaplan O. Acid ingestion: another cause of disseminated intravascular coagulopathy. Crit Care Med 1986;14:990-991.
[9.] Paar D, Heimsoth V, Werner M, Bock KD. Haemostatic failure due to consumption of coagulation factors in acute acetic acid poisoning. Germ Med Mth 1968;13:421-424.
[10.] Colman RW, Robboy SJ, Minna JD. Disseminated intravascular coagulation - A reappraisal. Ann Rev Med 1979;30:359-374.
[11.] Klunklin K. Liver function and liver histopathology in glacial acetic acid poisoning - case report. J Med Assoc Thai 1976;59:26-29.
[12.] Gerhartz H. Uber die Leberverdnderungen bei Einer EssigaureVergiftung and ihre Bedeutung far die Zeitliche Bemessung Von Leberregeneration and Cirrhotischer Narbebildung. Arch Path Anat 1949;316:456.
Are Papanicolaou smears enough? Acetic acid washes of the cervix as adjunctive therapy: a HARNET study
Author(s): Joshua H. Bennett , James M. Herman and David C. Slawson
Source: Journal of Family Practice. 35.3 (Sept. 1992): p271.
Routine screening for cervical disease with the Papanicolaou smear significantly reduces the incidence of invasive cervical cancer.[1,2] False-negative rates are reported, however, to range from 10% to 50%.[3-7] In addition, new cases of cervical cancer are predicted to sharply increase, especially among women who are now younger than 50 years old.[8] Concern, therefore, of failing to detect disease has increased interest in adjunctive screening methods.
Cervicography, human papillomavirus deoxyribonucleic acid (DNA) detection, and screening colposcopy have been proposed as methods to augment the detection of cervical disease.[9-11] Increased costs incurred by the use of these techniques may, however, prohibit widespread acceptance. In addition, no randomized controlled trials have demonstrated efficacy in the primary care setting.
An additional technique reported by Ottaviano and LaTorre[12] evaluated the use of an acetic acid wash in the detection of cervical disease. Findings from visual examination of the cervix following a 3% acetic acid wash were compared with those from colposcopy in 2400 women. Of the 312 women with an abnormal wash, 46% were confirmed to have abnormal cervical biopsies. Results obtained by Papanicolaou smear were not reported on any of these women.
Ficsor et al[13] found that 21% of the women reporting to their health clinic had acetowhite areas of the cervix on visual examination after application of acetic acid. Abnormal Papanicolaou smear findings were 6.6 times more likely to come from these women. Comparison between visual examination and colposcopic evaluation was not reported.
Neither study evaluated the cervical acetic acid wash as an adjunct to the Papanicolaou smear. The purpose of our study was to determine whether the use of the two procedures together would identify more cases of cervical disease than the Papanicolaou smear alone.
Methods
The Harrisburg Area Research Network (HARNET) consists of six practices in the Harrisburg, Pennsylvania, metropolitan area. Two practices are training sites for a family practice residency program. The remaining four are private practices. HARNET's patient population includes persons living in urban, suburban, and semirural areas.
All women (N = 2827) having Papanicolaou smears in HARNET offices from August 1989 through April 1990 were eligible for entry into the study. Exclusion criteria included pregnancy, history of squamous intraepithelial lesions (SIL) or invasive cervical cancer, age over 45 years, and prior treatment of the cervix, including cryotherapy, laser vaporization, or cone biopsy.
A Papanicolaou smear was obtained from each subject by sampling the endocervix with a Cytobrush and scraping the ectocervix with a wooden spatula. Slides made from these preparations were immediately fixed with ethanol. Cytology was performed by a qualified cytotechnologist, and all smears found to be abnormal were reviewed by a board-certified pathologist at Smith-Kline Bio-Science laboratory (Philadelphia) or at Harrisburg Hospital. Cytology laboratory personnel and the pathologists were not aware of the study being conducted.
Five percent acetic acid was next applied to each subject's cervix with a large cotton swab and left for 1 minute. The cervix was then examined with a 100-watt light source. Acetowhite areas detected outside the transformation zone were considered abnormal.
All clinicians participating in the study received standard instruction on the identification of abnormal results of acetic acid washes. This training included observation of photographs demonstrating normal and abnormal cervices Fi gures 1 to 3). No specific instruction in colposcopic technique was given.
Women with Papanicolaou smears showing SIL underwent immediate colposcopy. Consenting subjects with abnormal acetowhite areas detected on visual examination who had Papanicolaou smears reported as either atypical, inflammatory, or negative underwent colposcopy after a 4- to 6-month waiting period. Subjects requesting immediate colposcopy were analyzed separately. All suspected infections were appropriately treated.
After acetic acid application and immediately before colposcopy, a visual examination was repeated. The colposcopist was blind to what area of the cervix was abnormally acetowhite following the first acetic acid wash.
Colposcopy and directed biopsies were performed by physicians with training and certification in performing colposcopic techniques. Endocervical currettage was performed on all subjects. The vaginal side walls and vulvar areas were also examined and biopsied when indicated. Selected photographs were taken for documentation by means of an Olympus OM1 camera adapted for the colposcope. Colposcopic biopsies were reviewed by board-certified pathologists at Harrisburg Hospital who were not informed of the research protocol.
Predictive values and their associated confidence intervals were calculated using standard techniques.
Results
The mean age of the women was 25 years (range 15 to 45 years). Of the 2827 women screened, 358 (13%) were found to have an abnormal result on the acetic acid wash or the Papanicolaou smear or both (Figure 4). Of these, 74 were ineligible and did not undergo colposcopy. Forty-seven of the ineligible women were over 45 years of age, 20 had a history of cryotherapy, and 7 were pregnant. Sixty-three eligible subjects refused colposcopy. Of these, 25 had abnormal results only on acetic acid wash, 3 had abnormal results on both acetic acid wash and Papanicolaou smear, and 35 had abnormal Papanicolaou smear results only. Subjects accepting and refusing colposcopy were compared. There were no statistically significant differences between these groups with respect to age, ethnicity, or history of cervical disease.
The remaining subjects were eligible and participated in the study. Results of colposcopy for the three groups of these subjects are reported below and summarized in Table 1.
Group I: Abnormal Acetic Acid Wash Only
Sixty-three eligible women with an abnormal acetic acid wash and either an inflammatory or negative Papanicolaou smear result agreed to undergo colposcopy. Abnormalities were found on biopsy in 33 (52%) of the women, including 15 with condyloma, 14 with cervical intraepithelial neoplasia (CIN) I, and 4 with CIN II to III. Eleven of the 63 subjects requested immediate colposcopy after abnormal results were obtained on the initial acetic acid wash. Of these, seven (64%) had abnormal colposcopic findings (Group Ia).
Of the remaining 52 subjects who had a second wash after 4 to 6 months, 30 had persistently abnormal [TABULAR DATA OMITTED wash results. Nineteen (63%) of these 30 had abnormal colposcopic findings (Group Ib). Twenty-two women had a normal second acetic acid wash result after a 4- to 6-month waiting period. Of these, seven (32%) had abnormal colposcopic findings (Group Ic).
We wished to examine whether clinicians improved in their ability to detect abnormal areas as the study progressed. Forty-five women were evaluated in the first 6 months of the study. Of these, 21 (47%) had abnormal colposcopic findings. This was compared with the remaining 18 subjects who were evaluated 6 months after introduction of this technique in the study setting. Of these, 12 (67%) had abnormal colposcopic findings.
Of the 63 consenting subjects with abnormal acetic acid wash findings, 6 (10%) had a Papanicolaou smear showing moderate to severe inflammation. Colposcopic findings were abnormal in 2 (33%) of these subjects. Both demonstrated condyloma or CIN I. Results of Papanicolaou smears on the remaining 57 women were either normal or showed mild inflammation. Thus, the rest of the abnormal colposcopic results were in women with normal or mildly inflammatory Papanicolaou smears.
Group II: Abnormal Acetic Acid Wash and Abnormal Papanicolaou Smear
Twenty-two eligible subjects with abnormal results on both an acetic acid wash and a Papanicolaou smear agreed to colposcopy. The Papanicolaou smears of these women showed atypia of undetermined significance (12), low-grade SIL (7), and high-grade SIL (3). Of these, findings in 14 (64%) were abnormal on biopsy [TABULAR DATA OMITTED]
including 3 women with condyloma, 6 with CIN I, and 5 with CIN II to III.
Group III: Abnormal Papanicolaou Smear Only
One hundred thirty-six women with normal results on acetic acid wash and abnormal Papanicolaou smear findings agreed to colposcopy. Papanicolaou smears on these subjects demonstrated atypia of undetermined significance (70), low-grade SIL (44), and high-grade SIL (22). Biopsies on these subjects were abnormal in 93 (68%), including 38 with condyloma, 33 with CIN I, and 22 with CIN II to III.
Overall, 47 of 85 eligible and consenting subjects with abnormal results on acetic acid wash had biopsy-proven abnormalities seen on colposcopy. The positive predictive value of abnormal results on acetic acid wash was therefore .55 (95% CI = .43 to .63) (Table 2). The acetic acid wash was well tolerated by all patients participating in the study.
Fifty-six cases of condyloma and 84 cases of CIN were found in a population of 2827 women screened for cervical disease using the Papanicolaou smear and an acetic acid wash. The prevalence rate of CIN was, therefore, 3%. One hundred seven cases of condyloma or CIN were found in women with abnormal Papanicolaou smear results. Thirty-three additional cases were detected by adding the acetic acid wash to our screening protocol (Table 3). This represented a 30% increase in the detection of cervical disease.
Discussion
The acetic acid wash, when used to augment the Papanicolaou smear, allows the identification of significant lesions missed by using the Papanicolaou smear alone. It is a safe, simple, and effective adjunct to the Papanicolaou smear for cervical cancer screening. Although augmentation of the Papanicolaou smear has been documented with cervicography and DNA probe testing for human Table 3. Prevalence of Condyloma or Cervical Intraepithelial Neoplasm (CIN) and Method of Detection
No. of Cases of Condyloma or CIN Abnormal Pap smear alone 93 Positive acetic acid wash alone 33 Both tests positive 14 Total 140 papillomavirus, increased costs incurred may limit acceptance.[9-11] Widespread use of colposcopy as a screening tool is also expensive and impractical for many clinicians.
Of the women in this study in whom abnormal acetowhite areas of the cervix were found and negative Papanicolaou smear results were obtained, more than 50% had cervical disease. The detection rate of cervical disease was increased among women undergoing colposcopy immediately or after abnormal results were obtained on two consecutive acetic acid washes. These subgroups might represent higher risk populations for two reasons. First, women who considered themselves to be at an increased risk of cervical disease may have refused further delay in management and therefore self-selected inclusion in a high-risk group. Second, waiting the 4 to 6 months may have identified more women with truly abnormal findings. Some truly benign lesions detected on initial examination may have resolved during this time interval. We chose a 4- to 6-month waiting period because of previous studies showing maximal efficacy for the reevaluation of atypical Papanicolaou smear results.[14] As noted in the Results section, subsequent observers more accurately identified truly abnormal areas, indicating an improved expertise with time.
Colposcopy was not performed on all 2827 subjects having Papanicolaou smears for several reasons. First, performing 2827 colposcopies in the private practice setting would be overly time-consuming and prohibitive in cost. Second, referral bias would likely be introduced by including women with normal results on Papanicolaou smears and acetic acid washes who consent to colposcopy. Women who consider themselves to be at a higher-risk of cervical disease may be more inclined to participate. Third, and most important, such a large-scale intervention on normal women is not justified, given the goal of studying the acetic acid wash as an adjunct to the Papanicolaou smear. Nevertheless, some women not undergoing colposcopy may have had undetected CIN. It is unlikely, however, that a significant number of cases of CIN were missed. The 84 cases of CIN identified represent a prevalence rate of 3% in our study. This agrees closely with other reported prevalence rates for CIN.[15-20]
A significant percentage of women (20% to 35%) with atypical Papanicolaou smear results have been shown to have undetected CIN.[15,16,21-24] Eighty-three of our subjects with atypia did not undergo colposcopy because of exclusion or refusal. The majority of studies reporting non-detection rates of CIN, however, included all cases of atypia, including koilocytotic atypia. Under the Bethesda System,[25] women with koilocytotic atypia would be reclassified as having SIL. In our study, subjects refusing colposcopy included only those with atypia of undetermined significance. It is therefore unlikely that a significant number of cases of CIN were missed in this manner.
Similarly, 35% of women with Papanicolaou smears showing only moderate to severe inflammation have recently been reported to have undetected CIN on colposcopy.[26] Less than 10% of the subjects in our study with abnormal results obtained on acetic acid washes had moderate to severe inflammation detected by Papanicolaou smear. Thus, the finding of moderate to severe inflammation by Papanicolaou smear would not have predicted the presence of undetected CIN for the majority of the subjects in this study.
It is conceivable that the discovery of additional cases of CIN was related only to performing additional colposcopies, and not to the acetic acid wash results. If this were true, however, the prevalence rate of condyloma or CIN in our population would have exceeded 50%. A prevalence rate this high has never been reported. In addition, the false-negative rate of the Papanicolaou smear under these circumstances would have been over 90%.
A significant number of women with biopsy-proven cervical lesions had negative results on acetic acid wash. Most abnormal cervical lesions are detected in the transformation zone. This area is less visible because of location near or inside the endocervical canal. Additional case findings with the acetic acid wash may be due to the increased detection of abnormal lesions on the cervical "face." This area is more visible to the examiner and may be less suitable for adequate cytologic sampling.
Concern has been raised over the use of colposcopic biopsies as the reference standard for detecting cervical disease, particularly in those women with mildly abnormal findings.[27] Future studies correlating histologic abnormalities with in situ hybridization for human papilomavirus DNA detection in biopsies from abnormal acetowhite epithelium seen on visual examination will be important in delineating the answer to this question.
It is possible that a longer acetic acid wash may improve the accuracy of identifying acetowhite areas on the cervix. No controlled trials have been published comparing the yield of cervical disease with varying lengths of acetic acid washes. We believe, however, that a 1-minute interval represents a practical compromise for the busy clinician who is also concerned with patient comfort.
We chose not to perform this study on patients of menopausal age for several reasons. First, colposcopy is more difficult in this population because of migration of the transformation zone into the endocervical canal.[28] Second, menopausal patients with atrophic vaginal changes are more likely to complain of a burning sensation after application of the acetic acid wash.
Most women in whom cervical disease was identified by acetic acid wash had benign lesions (condyloma or CIN I). Controversy exists regarding the management of these patients. Some clinicians elect to treat them immediately, whereas others choose to follow them closely and treat them only if the lesions progress. The recognition of women with these abnormalities is, however, important in both management scenarios.
Although one subject underwent unnecessary colposcopy for each case of condyloma or CIN discovered, only 8% of women in our entire study population underwent the procedure. False-positive results could be further decreased by reserving colposcopy for women with other risk factors for cervical disease or a history of previously abnormal results obtained on acetic acid wash.
In summary, we have shown that using a 1-minute 5% acetic acid wash improves the detection of cervical disease by 30%. Consideration should be given to using this safe, simple, and effective technique along with the Papanicolaou smear on premenopausal women during regular health maintenance examinations. Further studies are necessary to compare the cost and effectiveness of adjunctive screening between the acetic acid wash, cervicography, human papillomavirus testing, and routine colposcopy.
Acknowledgments
Funded in part by the George L. Laverty Foundation. The authors acknowledge support from International Cytobrush Incorporated, the SmithKline Bio-Science Laboratories, and the Olympus Corporation.
The authors thank Joanne Aiello and Gail Leduc for manuscript preparation; Him G. Kwee, MD, from the Department of Pathology, Harrisburg Hospital, for laboratory support; Alan Adelman, MD, MS, for editorial assistance; and Judith Blouch, MA, HARNET Research Assistant, for her expert network management.
The late Frederick D. Curcio III, MD, contributed to the study design and implementation.
References
[1.] Clarke EA, Anderson TW. Does screening for "Pap" smears help prevent cervical cancer? A case-control study. Lancet 1972; 2:1-4.
[2.] LaVecchia C, Decarli A, Gentile A, Franceschi S, Fasoli M, Tognoni G. "Pap" smears and the risk of cervical neoplasia: quantitative estimates from a case-control study. Lancet 1984; 2:779-82.
[3.] Anderson GH, Flynn KJ, Hickey LA, LeRiche JC, Matisic JP, Saen KC. A comprehensive internal quality control system for a large cytology laboratory. Acta Cytol 1981; 31:895-99.
[4.] Figge DC, Bennington JC, Schneid AI. Cervical cancer after initial negative and atypical vaginal cytology. Am J Obstet Gynecol 1970; 108:422-8.
[5.] Morell ND, Taylor JR, Snyder RN, Ziel HK, Saltz A, Willie S. False-negative cytology rates in patients in whom invasive cervical cancer subsequently developed. Obstet Gynecol 1982; 60:41-5.
[6.] van der Graff Y, Vooijs GP. False negative rate in cervical cytology. J Clin Pathol 1987; 40:138-42.
[7.] Yobs AR, Plott AE, Hicklin MD. Retrospective evaluations of gynecologic cytodiagnosis. II. Interlaboratory reproducibility as shown in rescreening large consecutive samples of reported cases. Acta Cytol 1987; 31:900-10.
[8.] Beral V, Booth M. Predictions of cervical cancer incidence and mortality in England and Wales. Lancet 1986; 1:495.
[9.] Reid R, Greenberg MD, Lorincz A, et al. Should cervical cytologic testing be augmented by cervicography or human papillomavirus deoxyribonucleic acid detection? Am J Obstet Gynecol 1991; 164:1461-71.
[10.] Spitzer M, Krumholz BA, Chernys AE, Seltzer V, Lightman AR. Comparative utility of repeat Papanicolaou smears, cervicography, and colposcopy in the evaluation of atypical Papanicolaou smears. Obstet Gynecol 1987; 69:731-5.
[11.] Tawa K, Forsythe A, Cove JK, Saltz A, Peters HW, Watring WG. A comparison of the Papanicolaou smear and the cervigram: sensitivity, specificity, and cost analysis. Obstet Gynecol 1988; 71:229-35.
[12.] Ottaviano M, LaTorre P. Examination of the cervix with the naked eye using the acetic acid test. Am J Obstet Gynecol 1987; 143: 139-42.
[13.] Ficsor G, Fuller SK, Jeromin JL, Beyer RD, Janca FC. Enhancing cervical cancer detection using nucleic acid hybridization and acetic acid tests. Nurse Pract 1990; 15(7):26-30.
[14.] Ridgley R, Hernandez E, Cruz C, Miyazawa K. Abnormal Papanicolaou smears after earlier smears with atypical squamous cells. J Reprod Med 1988; 33:285-8.
[15.] Maier RC, Schultenouer SJ. Evaluation of the atypical squamous cell Papanicolaou smear. Int J Gynecol Pathol 1986; 5:242-8.
[16.] Davis GL, Hernandez E, Davis JL, Miyazawa K. Atypical squamous cells in Papanicolaou smears. Obstet Gynecol 1987; 69:43-6.
[17.] Meisels A, Begin R, Schneider V. Dysplasias of uterine cervix. Epidemiological aspects: role of age at first coitus and use of oral contraceptives. Cancer 1977; 40:3076-81.
[18.] Sandmire HF, Austin SD, Bechtel RC. Experience with 40,000 Papanicolaou smears. Obstet Gynecol 1976; 48:56-60.
[19.] Frisch LE. Inflammatory atypia: an apparent link with subsequent cervical intraepithelial neoplasia explained by cytologic underreading. Acta Cytol 1987; 31:869-72.
[20.] Sadeghi SB, Sadeghi A, Robboy SJ. Prevalence of dysplasia and cancer of the cervix in a nationwide, planned parenthood population. Cancer 1988; 61:2359-61.
[21.] Noumoff JS. Atypia in cervical cytology as a risk factor for intraepithelial neoplasia. Am J Obstet Gynecol 1987; March:628-31.
[22.] Soutter WP, Wisdom S, Brough AK, Monaghan JM. Should patients with mild atypia in a cervical smear be referred for colposcopy? Br J Obstet Gynaecol 1986; 93:70-4.
[23.] Reiter RC. Management of initial atypical cervical cytology: a randomized, prospective study. Obstet Gynecol 1986; 68:237-40.
[24.] Shaw CT. Colposcopic examination of patients with class II Papanicolaou smears. J Am Osteopath Assoc 1986; June:355-9.
[25.] Lundberg GD. The 1988 Bethesda System for reporting cervical/vaginal cytologic diagnosis. National Cancer Institute Workshop. JAMA 1989; 262:931-4.
[26.] Lawley TB, Lee RB, Kapela R. The significance of moderate and severe inflammation on class I Papanicolaou smear. Obstet Gynecol 1990; 76:997-9.
[27.] Richart RM, Nuovo GJ. HPV DNA in-situ hybridization may be used for the quality control of genital tract biopsies. Obstet Gynecol 1990; 75:223-6.
[28.] Roberts AD, Denholm RB, Cordiner JW. Cervical intraepithelial neoplasia in postmenopausal women with negative cervical cytology. Br Med J 1985; 290:281.
Harrisburg Area Research Network Harrisburg Family Practice Center: Joshua Bennett, MD, Ellen Geminiani, MD, James Herman, MD, MSPH, Susan Herman, CRNP, Michael Lustig, MD, David Slawson, MD, Ellen Smith, MD, Daniel Weber, MD, and Family Practice residents. Mechanicsburg Family Practice Center: Ann Bogdan, MD, Karen Campbell, MD, Daniel Coller, MD, Michael Cordas, DO, Oscar Hoerner, MD, David Long, MD, Gary Luttermoser, MD, Pamela McAnich, CRNP, Robert Muscalus, DO, Kathleen Sempeles, MD, Susan Severino, RN, PAC, Lisa Stokes, CRNP, Bradford K. Strock, MD, and Family Practice residents. Cumberland Family Physicians: Richard Davis, MD, and Jonathan Tocks, MD. Colonial Park Family Physicians: Kevin Kelly, MD, and Robert Robison, MD. Good Hope Family Physicians: Michael Gawlas, DO, Kenneth Harm, MD, Jane Rowehl, MD, Michael Riggleman, MD, and Cathleen Sangillo, MD. Shepherdstown Family Practice: Elizabeth Alwine, CRNP, Michael Blanchard, MD, Janet Cincotta, MD, Joseph Cincotta, MD, Geoffrey James, MD, and Gary Schwartz, MD.
Routine screening for cervical disease with the Papanicolaou smear significantly reduces the incidence of invasive cervical cancer.[1,2] False-negative rates are reported, however, to range from 10% to 50%.[3-7] In addition, new cases of cervical cancer are predicted to sharply increase, especially among women who are now younger than 50 years old.[8] Concern, therefore, of failing to detect disease has increased interest in adjunctive screening methods.
Cervicography, human papillomavirus deoxyribonucleic acid (DNA) detection, and screening colposcopy have been proposed as methods to augment the detection of cervical disease.[9-11] Increased costs incurred by the use of these techniques may, however, prohibit widespread acceptance. In addition, no randomized controlled trials have demonstrated efficacy in the primary care setting.
An additional technique reported by Ottaviano and LaTorre[12] evaluated the use of an acetic acid wash in the detection of cervical disease. Findings from visual examination of the cervix following a 3% acetic acid wash were compared with those from colposcopy in 2400 women. Of the 312 women with an abnormal wash, 46% were confirmed to have abnormal cervical biopsies. Results obtained by Papanicolaou smear were not reported on any of these women.
Ficsor et al[13] found that 21% of the women reporting to their health clinic had acetowhite areas of the cervix on visual examination after application of acetic acid. Abnormal Papanicolaou smear findings were 6.6 times more likely to come from these women. Comparison between visual examination and colposcopic evaluation was not reported.
Neither study evaluated the cervical acetic acid wash as an adjunct to the Papanicolaou smear. The purpose of our study was to determine whether the use of the two procedures together would identify more cases of cervical disease than the Papanicolaou smear alone.
Methods
The Harrisburg Area Research Network (HARNET) consists of six practices in the Harrisburg, Pennsylvania, metropolitan area. Two practices are training sites for a family practice residency program. The remaining four are private practices. HARNET's patient population includes persons living in urban, suburban, and semirural areas.
All women (N = 2827) having Papanicolaou smears in HARNET offices from August 1989 through April 1990 were eligible for entry into the study. Exclusion criteria included pregnancy, history of squamous intraepithelial lesions (SIL) or invasive cervical cancer, age over 45 years, and prior treatment of the cervix, including cryotherapy, laser vaporization, or cone biopsy.
A Papanicolaou smear was obtained from each subject by sampling the endocervix with a Cytobrush and scraping the ectocervix with a wooden spatula. Slides made from these preparations were immediately fixed with ethanol. Cytology was performed by a qualified cytotechnologist, and all smears found to be abnormal were reviewed by a board-certified pathologist at Smith-Kline Bio-Science laboratory (Philadelphia) or at Harrisburg Hospital. Cytology laboratory personnel and the pathologists were not aware of the study being conducted.
Five percent acetic acid was next applied to each subject's cervix with a large cotton swab and left for 1 minute. The cervix was then examined with a 100-watt light source. Acetowhite areas detected outside the transformation zone were considered abnormal.
All clinicians participating in the study received standard instruction on the identification of abnormal results of acetic acid washes. This training included observation of photographs demonstrating normal and abnormal cervices Fi gures 1 to 3). No specific instruction in colposcopic technique was given.
Women with Papanicolaou smears showing SIL underwent immediate colposcopy. Consenting subjects with abnormal acetowhite areas detected on visual examination who had Papanicolaou smears reported as either atypical, inflammatory, or negative underwent colposcopy after a 4- to 6-month waiting period. Subjects requesting immediate colposcopy were analyzed separately. All suspected infections were appropriately treated.
After acetic acid application and immediately before colposcopy, a visual examination was repeated. The colposcopist was blind to what area of the cervix was abnormally acetowhite following the first acetic acid wash.
Colposcopy and directed biopsies were performed by physicians with training and certification in performing colposcopic techniques. Endocervical currettage was performed on all subjects. The vaginal side walls and vulvar areas were also examined and biopsied when indicated. Selected photographs were taken for documentation by means of an Olympus OM1 camera adapted for the colposcope. Colposcopic biopsies were reviewed by board-certified pathologists at Harrisburg Hospital who were not informed of the research protocol.
Predictive values and their associated confidence intervals were calculated using standard techniques.
Results
The mean age of the women was 25 years (range 15 to 45 years). Of the 2827 women screened, 358 (13%) were found to have an abnormal result on the acetic acid wash or the Papanicolaou smear or both (Figure 4). Of these, 74 were ineligible and did not undergo colposcopy. Forty-seven of the ineligible women were over 45 years of age, 20 had a history of cryotherapy, and 7 were pregnant. Sixty-three eligible subjects refused colposcopy. Of these, 25 had abnormal results only on acetic acid wash, 3 had abnormal results on both acetic acid wash and Papanicolaou smear, and 35 had abnormal Papanicolaou smear results only. Subjects accepting and refusing colposcopy were compared. There were no statistically significant differences between these groups with respect to age, ethnicity, or history of cervical disease.
The remaining subjects were eligible and participated in the study. Results of colposcopy for the three groups of these subjects are reported below and summarized in Table 1.
Group I: Abnormal Acetic Acid Wash Only
Sixty-three eligible women with an abnormal acetic acid wash and either an inflammatory or negative Papanicolaou smear result agreed to undergo colposcopy. Abnormalities were found on biopsy in 33 (52%) of the women, including 15 with condyloma, 14 with cervical intraepithelial neoplasia (CIN) I, and 4 with CIN II to III. Eleven of the 63 subjects requested immediate colposcopy after abnormal results were obtained on the initial acetic acid wash. Of these, seven (64%) had abnormal colposcopic findings (Group Ia).
Of the remaining 52 subjects who had a second wash after 4 to 6 months, 30 had persistently abnormal [TABULAR DATA OMITTED wash results. Nineteen (63%) of these 30 had abnormal colposcopic findings (Group Ib). Twenty-two women had a normal second acetic acid wash result after a 4- to 6-month waiting period. Of these, seven (32%) had abnormal colposcopic findings (Group Ic).
We wished to examine whether clinicians improved in their ability to detect abnormal areas as the study progressed. Forty-five women were evaluated in the first 6 months of the study. Of these, 21 (47%) had abnormal colposcopic findings. This was compared with the remaining 18 subjects who were evaluated 6 months after introduction of this technique in the study setting. Of these, 12 (67%) had abnormal colposcopic findings.
Of the 63 consenting subjects with abnormal acetic acid wash findings, 6 (10%) had a Papanicolaou smear showing moderate to severe inflammation. Colposcopic findings were abnormal in 2 (33%) of these subjects. Both demonstrated condyloma or CIN I. Results of Papanicolaou smears on the remaining 57 women were either normal or showed mild inflammation. Thus, the rest of the abnormal colposcopic results were in women with normal or mildly inflammatory Papanicolaou smears.
Group II: Abnormal Acetic Acid Wash and Abnormal Papanicolaou Smear
Twenty-two eligible subjects with abnormal results on both an acetic acid wash and a Papanicolaou smear agreed to colposcopy. The Papanicolaou smears of these women showed atypia of undetermined significance (12), low-grade SIL (7), and high-grade SIL (3). Of these, findings in 14 (64%) were abnormal on biopsy [TABULAR DATA OMITTED]
including 3 women with condyloma, 6 with CIN I, and 5 with CIN II to III.
Group III: Abnormal Papanicolaou Smear Only
One hundred thirty-six women with normal results on acetic acid wash and abnormal Papanicolaou smear findings agreed to colposcopy. Papanicolaou smears on these subjects demonstrated atypia of undetermined significance (70), low-grade SIL (44), and high-grade SIL (22). Biopsies on these subjects were abnormal in 93 (68%), including 38 with condyloma, 33 with CIN I, and 22 with CIN II to III.
Overall, 47 of 85 eligible and consenting subjects with abnormal results on acetic acid wash had biopsy-proven abnormalities seen on colposcopy. The positive predictive value of abnormal results on acetic acid wash was therefore .55 (95% CI = .43 to .63) (Table 2). The acetic acid wash was well tolerated by all patients participating in the study.
Fifty-six cases of condyloma and 84 cases of CIN were found in a population of 2827 women screened for cervical disease using the Papanicolaou smear and an acetic acid wash. The prevalence rate of CIN was, therefore, 3%. One hundred seven cases of condyloma or CIN were found in women with abnormal Papanicolaou smear results. Thirty-three additional cases were detected by adding the acetic acid wash to our screening protocol (Table 3). This represented a 30% increase in the detection of cervical disease.
Discussion
The acetic acid wash, when used to augment the Papanicolaou smear, allows the identification of significant lesions missed by using the Papanicolaou smear alone. It is a safe, simple, and effective adjunct to the Papanicolaou smear for cervical cancer screening. Although augmentation of the Papanicolaou smear has been documented with cervicography and DNA probe testing for human Table 3. Prevalence of Condyloma or Cervical Intraepithelial Neoplasm (CIN) and Method of Detection
No. of Cases of Condyloma or CIN Abnormal Pap smear alone 93 Positive acetic acid wash alone 33 Both tests positive 14 Total 140 papillomavirus, increased costs incurred may limit acceptance.[9-11] Widespread use of colposcopy as a screening tool is also expensive and impractical for many clinicians.
Of the women in this study in whom abnormal acetowhite areas of the cervix were found and negative Papanicolaou smear results were obtained, more than 50% had cervical disease. The detection rate of cervical disease was increased among women undergoing colposcopy immediately or after abnormal results were obtained on two consecutive acetic acid washes. These subgroups might represent higher risk populations for two reasons. First, women who considered themselves to be at an increased risk of cervical disease may have refused further delay in management and therefore self-selected inclusion in a high-risk group. Second, waiting the 4 to 6 months may have identified more women with truly abnormal findings. Some truly benign lesions detected on initial examination may have resolved during this time interval. We chose a 4- to 6-month waiting period because of previous studies showing maximal efficacy for the reevaluation of atypical Papanicolaou smear results.[14] As noted in the Results section, subsequent observers more accurately identified truly abnormal areas, indicating an improved expertise with time.
Colposcopy was not performed on all 2827 subjects having Papanicolaou smears for several reasons. First, performing 2827 colposcopies in the private practice setting would be overly time-consuming and prohibitive in cost. Second, referral bias would likely be introduced by including women with normal results on Papanicolaou smears and acetic acid washes who consent to colposcopy. Women who consider themselves to be at a higher-risk of cervical disease may be more inclined to participate. Third, and most important, such a large-scale intervention on normal women is not justified, given the goal of studying the acetic acid wash as an adjunct to the Papanicolaou smear. Nevertheless, some women not undergoing colposcopy may have had undetected CIN. It is unlikely, however, that a significant number of cases of CIN were missed. The 84 cases of CIN identified represent a prevalence rate of 3% in our study. This agrees closely with other reported prevalence rates for CIN.[15-20]
A significant percentage of women (20% to 35%) with atypical Papanicolaou smear results have been shown to have undetected CIN.[15,16,21-24] Eighty-three of our subjects with atypia did not undergo colposcopy because of exclusion or refusal. The majority of studies reporting non-detection rates of CIN, however, included all cases of atypia, including koilocytotic atypia. Under the Bethesda System,[25] women with koilocytotic atypia would be reclassified as having SIL. In our study, subjects refusing colposcopy included only those with atypia of undetermined significance. It is therefore unlikely that a significant number of cases of CIN were missed in this manner.
Similarly, 35% of women with Papanicolaou smears showing only moderate to severe inflammation have recently been reported to have undetected CIN on colposcopy.[26] Less than 10% of the subjects in our study with abnormal results obtained on acetic acid washes had moderate to severe inflammation detected by Papanicolaou smear. Thus, the finding of moderate to severe inflammation by Papanicolaou smear would not have predicted the presence of undetected CIN for the majority of the subjects in this study.
It is conceivable that the discovery of additional cases of CIN was related only to performing additional colposcopies, and not to the acetic acid wash results. If this were true, however, the prevalence rate of condyloma or CIN in our population would have exceeded 50%. A prevalence rate this high has never been reported. In addition, the false-negative rate of the Papanicolaou smear under these circumstances would have been over 90%.
A significant number of women with biopsy-proven cervical lesions had negative results on acetic acid wash. Most abnormal cervical lesions are detected in the transformation zone. This area is less visible because of location near or inside the endocervical canal. Additional case findings with the acetic acid wash may be due to the increased detection of abnormal lesions on the cervical "face." This area is more visible to the examiner and may be less suitable for adequate cytologic sampling.
Concern has been raised over the use of colposcopic biopsies as the reference standard for detecting cervical disease, particularly in those women with mildly abnormal findings.[27] Future studies correlating histologic abnormalities with in situ hybridization for human papilomavirus DNA detection in biopsies from abnormal acetowhite epithelium seen on visual examination will be important in delineating the answer to this question.
It is possible that a longer acetic acid wash may improve the accuracy of identifying acetowhite areas on the cervix. No controlled trials have been published comparing the yield of cervical disease with varying lengths of acetic acid washes. We believe, however, that a 1-minute interval represents a practical compromise for the busy clinician who is also concerned with patient comfort.
We chose not to perform this study on patients of menopausal age for several reasons. First, colposcopy is more difficult in this population because of migration of the transformation zone into the endocervical canal.[28] Second, menopausal patients with atrophic vaginal changes are more likely to complain of a burning sensation after application of the acetic acid wash.
Most women in whom cervical disease was identified by acetic acid wash had benign lesions (condyloma or CIN I). Controversy exists regarding the management of these patients. Some clinicians elect to treat them immediately, whereas others choose to follow them closely and treat them only if the lesions progress. The recognition of women with these abnormalities is, however, important in both management scenarios.
Although one subject underwent unnecessary colposcopy for each case of condyloma or CIN discovered, only 8% of women in our entire study population underwent the procedure. False-positive results could be further decreased by reserving colposcopy for women with other risk factors for cervical disease or a history of previously abnormal results obtained on acetic acid wash.
In summary, we have shown that using a 1-minute 5% acetic acid wash improves the detection of cervical disease by 30%. Consideration should be given to using this safe, simple, and effective technique along with the Papanicolaou smear on premenopausal women during regular health maintenance examinations. Further studies are necessary to compare the cost and effectiveness of adjunctive screening between the acetic acid wash, cervicography, human papillomavirus testing, and routine colposcopy.
Acknowledgments
Funded in part by the George L. Laverty Foundation. The authors acknowledge support from International Cytobrush Incorporated, the SmithKline Bio-Science Laboratories, and the Olympus Corporation.
The authors thank Joanne Aiello and Gail Leduc for manuscript preparation; Him G. Kwee, MD, from the Department of Pathology, Harrisburg Hospital, for laboratory support; Alan Adelman, MD, MS, for editorial assistance; and Judith Blouch, MA, HARNET Research Assistant, for her expert network management.
The late Frederick D. Curcio III, MD, contributed to the study design and implementation.
References
[1.] Clarke EA, Anderson TW. Does screening for "Pap" smears help prevent cervical cancer? A case-control study. Lancet 1972; 2:1-4.
[2.] LaVecchia C, Decarli A, Gentile A, Franceschi S, Fasoli M, Tognoni G. "Pap" smears and the risk of cervical neoplasia: quantitative estimates from a case-control study. Lancet 1984; 2:779-82.
[3.] Anderson GH, Flynn KJ, Hickey LA, LeRiche JC, Matisic JP, Saen KC. A comprehensive internal quality control system for a large cytology laboratory. Acta Cytol 1981; 31:895-99.
[4.] Figge DC, Bennington JC, Schneid AI. Cervical cancer after initial negative and atypical vaginal cytology. Am J Obstet Gynecol 1970; 108:422-8.
[5.] Morell ND, Taylor JR, Snyder RN, Ziel HK, Saltz A, Willie S. False-negative cytology rates in patients in whom invasive cervical cancer subsequently developed. Obstet Gynecol 1982; 60:41-5.
[6.] van der Graff Y, Vooijs GP. False negative rate in cervical cytology. J Clin Pathol 1987; 40:138-42.
[7.] Yobs AR, Plott AE, Hicklin MD. Retrospective evaluations of gynecologic cytodiagnosis. II. Interlaboratory reproducibility as shown in rescreening large consecutive samples of reported cases. Acta Cytol 1987; 31:900-10.
[8.] Beral V, Booth M. Predictions of cervical cancer incidence and mortality in England and Wales. Lancet 1986; 1:495.
[9.] Reid R, Greenberg MD, Lorincz A, et al. Should cervical cytologic testing be augmented by cervicography or human papillomavirus deoxyribonucleic acid detection? Am J Obstet Gynecol 1991; 164:1461-71.
[10.] Spitzer M, Krumholz BA, Chernys AE, Seltzer V, Lightman AR. Comparative utility of repeat Papanicolaou smears, cervicography, and colposcopy in the evaluation of atypical Papanicolaou smears. Obstet Gynecol 1987; 69:731-5.
[11.] Tawa K, Forsythe A, Cove JK, Saltz A, Peters HW, Watring WG. A comparison of the Papanicolaou smear and the cervigram: sensitivity, specificity, and cost analysis. Obstet Gynecol 1988; 71:229-35.
[12.] Ottaviano M, LaTorre P. Examination of the cervix with the naked eye using the acetic acid test. Am J Obstet Gynecol 1987; 143: 139-42.
[13.] Ficsor G, Fuller SK, Jeromin JL, Beyer RD, Janca FC. Enhancing cervical cancer detection using nucleic acid hybridization and acetic acid tests. Nurse Pract 1990; 15(7):26-30.
[14.] Ridgley R, Hernandez E, Cruz C, Miyazawa K. Abnormal Papanicolaou smears after earlier smears with atypical squamous cells. J Reprod Med 1988; 33:285-8.
[15.] Maier RC, Schultenouer SJ. Evaluation of the atypical squamous cell Papanicolaou smear. Int J Gynecol Pathol 1986; 5:242-8.
[16.] Davis GL, Hernandez E, Davis JL, Miyazawa K. Atypical squamous cells in Papanicolaou smears. Obstet Gynecol 1987; 69:43-6.
[17.] Meisels A, Begin R, Schneider V. Dysplasias of uterine cervix. Epidemiological aspects: role of age at first coitus and use of oral contraceptives. Cancer 1977; 40:3076-81.
[18.] Sandmire HF, Austin SD, Bechtel RC. Experience with 40,000 Papanicolaou smears. Obstet Gynecol 1976; 48:56-60.
[19.] Frisch LE. Inflammatory atypia: an apparent link with subsequent cervical intraepithelial neoplasia explained by cytologic underreading. Acta Cytol 1987; 31:869-72.
[20.] Sadeghi SB, Sadeghi A, Robboy SJ. Prevalence of dysplasia and cancer of the cervix in a nationwide, planned parenthood population. Cancer 1988; 61:2359-61.
[21.] Noumoff JS. Atypia in cervical cytology as a risk factor for intraepithelial neoplasia. Am J Obstet Gynecol 1987; March:628-31.
[22.] Soutter WP, Wisdom S, Brough AK, Monaghan JM. Should patients with mild atypia in a cervical smear be referred for colposcopy? Br J Obstet Gynaecol 1986; 93:70-4.
[23.] Reiter RC. Management of initial atypical cervical cytology: a randomized, prospective study. Obstet Gynecol 1986; 68:237-40.
[24.] Shaw CT. Colposcopic examination of patients with class II Papanicolaou smears. J Am Osteopath Assoc 1986; June:355-9.
[25.] Lundberg GD. The 1988 Bethesda System for reporting cervical/vaginal cytologic diagnosis. National Cancer Institute Workshop. JAMA 1989; 262:931-4.
[26.] Lawley TB, Lee RB, Kapela R. The significance of moderate and severe inflammation on class I Papanicolaou smear. Obstet Gynecol 1990; 76:997-9.
[27.] Richart RM, Nuovo GJ. HPV DNA in-situ hybridization may be used for the quality control of genital tract biopsies. Obstet Gynecol 1990; 75:223-6.
[28.] Roberts AD, Denholm RB, Cordiner JW. Cervical intraepithelial neoplasia in postmenopausal women with negative cervical cytology. Br Med J 1985; 290:281.
Harrisburg Area Research Network Harrisburg Family Practice Center: Joshua Bennett, MD, Ellen Geminiani, MD, James Herman, MD, MSPH, Susan Herman, CRNP, Michael Lustig, MD, David Slawson, MD, Ellen Smith, MD, Daniel Weber, MD, and Family Practice residents. Mechanicsburg Family Practice Center: Ann Bogdan, MD, Karen Campbell, MD, Daniel Coller, MD, Michael Cordas, DO, Oscar Hoerner, MD, David Long, MD, Gary Luttermoser, MD, Pamela McAnich, CRNP, Robert Muscalus, DO, Kathleen Sempeles, MD, Susan Severino, RN, PAC, Lisa Stokes, CRNP, Bradford K. Strock, MD, and Family Practice residents. Cumberland Family Physicians: Richard Davis, MD, and Jonathan Tocks, MD. Colonial Park Family Physicians: Kevin Kelly, MD, and Robert Robison, MD. Good Hope Family Physicians: Michael Gawlas, DO, Kenneth Harm, MD, Jane Rowehl, MD, Michael Riggleman, MD, and Cathleen Sangillo, MD. Shepherdstown Family Practice: Elizabeth Alwine, CRNP, Michael Blanchard, MD, Janet Cincotta, MD, Joseph Cincotta, MD, Geoffrey James, MD, and Gary Schwartz, MD.
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