■ brie f r e p o r t Atypical Glandular Cells of Undetermined Significance and Adenocarcinoma In Situ: Summoning Colposcopic Expertise? Daron G. Ferris, MI); Burton A. Krumholz, MD; David M. Jester", MD; John H. Crosby, MI); Mark G. Hardy, MD; and Mark J. Messing, MD Augusta, Georgia, and New Hyde Park, New York

In comparison with cervical squamous neoplasia, glandular cell neoplasia is uncommon. The evaluation of a patient with atypical glandular cells of undetermined significance is challenging because subtle colposcopic signs are frequently inaccessible to view and cytologic interpretations are extremely challenging for many cytopathologists.

KEY WORDS. Vaginal smears; adenocarcinoma; colposcopy; cervical intraepithelial neoplasia. (J Fam Pract 1996; 43:181-187)

ompared with cervical squamous cell the poorly accessed endocervical canal. The cyto­ neoplasia, glandular cell neoplasia is logic diagnosis of adenocarcinoma in situ, or “atyp­ uncommon.1 Several studies, however, ical endocervical cells, probably neoplastic,” is have indicated an increasing incidence especially difficult for many pathologists.89 The of cervical adenocarcinoma in situ (AIS) colposcopic evaluation of AIS is hampered by sub­ andC adenocarcinoma in women." The apparent tle colposcopic signs that are frequently inaccessi­ increased incidence of disease may be due in part ble to view, diagnostically controversial, and con­ to increased detection provided by improved cyto­ sidered by many colposcopists to be nonspecific or logic sampling of the endocervical canal. The nat­ otherwise not apparent.6 Controversy also exists ural history of cervical glandular neoplasia is, at regarding the proper treatment of AIS of the present, poorly understood, but human papillo­ cervix.10,11 mavirus (HPV) likely plays a role/’ Although less Because of the insidious nature of the glandular severe glandular neoplasias do not have as clear a neoplasias, diagnosis, treatment, and posttherapy progressive potential as that encountered with monitoring demand special attention and exper­ squamous neoplasia, AIS also appears to be a pre­ tise. The following report illustrates a case of AIS cursor of adenocarcinoma.1 of the cervix detected in a young woman following The early detection and diagnosis of AIS and a routine Papanicolaou (Pap) smear. adenocarcinoma of the cervix are problematic and extremely challenging." Cytologic sampling can be ■ Case Report hindered if glandular neoplasia occupies only the deep recesses of endocervical clefts, if it is covered A 27-year-old single woman, gravida 0 para 0, pre­ by metaplastic epithelium, or if it is located within sented for a routine physical examination and Pap Submitted, revised, February 26, 1996. smear in January 1995. She considered herself to From the Medical Effectiveness Education and Research be in good health and had no complaints. Program (D.G.F.), and the Department of Family Medicine Her gynecologic history noted regular menses (D.G.F., D.M.J.), Department of Obstetrics and Gynecology (M.J.M.), and Department of Pathology (M.G.H.), The with mild dysmenorrhea. She denied a history of Medical College of Georgia; the Pathology and Laboratory abnormal Pap smears or sexually transmitted dis­ Medicine Service, Veterans Administration Medical Center eases. Her family history was significant for lung (J.H.C.), Augusta, Georgia; and the Department of Obstetrics and Gynecology (B.A.K.), Albert Einstein College of cancer and an aunt who had some type of cervical Medicine, Long Island Jewish Medical Center, New Hyde neoplasia. Park, New York. Requests for reprints should be addressed to Her physical examination was essentially nor­ Daron G. Ferris, MD, Department of Family Medicine, Medical College of Georgia, Laney-Walkei' Blvd, Augusta, GA mal, except for a white vaginal discharge and a 30912. cervix that bled readily to touch. A Pap smear was

© 1996 A ppleton & Lange ISSN 0094-3509 The Journal of Family Practice, Vol. 43, No. 2 (Aug), 1996 1 81 j§J AGUS AND ADENOCARCINOMA IN SITU Ferris, Krumholz, Jester, et al

FIGURE 1 cance (AGUS) were also noted. Based on this Papanicolaou smear showing atypical glandular result, the patient was scheduled for a repeat Pap cells. Elongated cells are arranged radially in a partial smear in 6 months. “rosette” formation, indicating a columnar or glandular nature. Nuclei are enlarged, and nuclear chromatin is A Pap smear was repeated 7 months later. It was dark and granular (Papanicolaou stain; magnification reported as satisfactory with atypical endocervical x400). cells (Figure 1). An additional comment by the pathologist suggested that endocervical glandular dysplasia or adenocarcinoma in situ could not be ruled out. Colposcopy was then performed. The colposcopic examination (Figure 2) was satisfactory, and revealed the late stages of active squamous metaplasia extending within the endo­ cervical canal. There appeared to be two small ill- defined areas of atypical columnar epithelium located at the 7 and 10 o’clock positions on the anterior and posterior lips of the cervix, respec­ tively. The abnormal epithelium was a denser, yel- low-acetowhite color compared with the more translucent surrounding metaplastic epithelium. Several “root-like” atypical vessels were also obtained, along with a vaginal saline wet prep, noted. Examination of the distal 1.5 cm of the potassium hydroxide, and Chlamydia trachomatis endocervical canal using an endocervical specu­ test. Except for the Pap smear, these tests were lum revealed no significant abnormalities in this within normal limits. The Pap smear adequacy was area. Two cervical biopsies were taken from the satisfactory but limited by inflammation and blood. abnormal epithelium, and an endocervical curet­ Atypical glandular cells of undetermined signifi­ tage was performed. The colposcopic impression was AIS, rule out occult adenocarcinoma. FIGURE 2 The patient was also found to have bacte­ rial vaginosis and was treated with Colpophotograph (x15) of cervix demonstrating the complete squamo- metronidazole. columnar junction and an ectropion. Active immature squamous meta­ plasia is noted. The subtle features of adenocarcinoma in situ cannot The histologic specimen of the biop- be appreciated at this level of magnification. sied tissue revealed cervical AIS (Figure 3). The endocervical curettage revealed fragments of benign endocervical epithe­ lium. The cytologic and histologic inter­ pretations and colposcopic impression correlated within 1 degree of severity. The patient was referred to a gynecologic oncologist for treatment. A cold-knife conization was subsequently performed. The excised cervical specimen revealed adenocarcinoma in situ with no invasive carcinoma. The resected margins were free of neoplasia.

D iscussion

The diagnosis of AIS of the cervix is gen­ erally fortuitous. The case in this report demonstrates many of the features of

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glandular cell neoplasia of the cervix. The woman’s FIGURE 3 age of 27 years, although quite young, is consistent Biopsy showing endocervical adenocarcinoma in situ. with a reported younger mean age for AIS (39 years) Endocervical glands have crowded, elongated, hyper- as compared with adenocarcinoma (57 years).1 The chromatic nuclei in some areas with decreased mucin production (hematoxylin and eosin stain; magnification patient was asymptomatic and her disease was x200). detected by routine Pap smear screening, as would be expected.07. Her case also demonstrates some of the challenges in the diagnosis and management of glandular neoplasia of the cervix. The difficulty of detecting early glandular neo­ plasia by cytologic testing is attributed to failure to retrieve cells from typically small lesions located in the endocervical canal and deep gland clefts and to difficulties in microscopic interpretation. The use of cytologic brushes rather than cotton swabs for endocervical sampling minimizes the risk of a false-negative Pap smear. The specificity and sen- sivity of cervical cytologic testing for glandular neoplasia suffers from the challenge of differenti­ ating many premalignant changes from benign changes at one extreme to malignant conditions at Most physicians believe it is impossible to diag­ the other.1912 For glandular cells reflecting nonspe­ nose AIS colposeopically.1113 The colposcopic fea­ cific features that are more severe than reactive or tures of AIS are most often nonspecific and are not reparative changes but less severe than invasive as well described, agreed upon, or clinically obvi­ adenocarcinoma, the Bethesda System of Pap ous. Coppelson,10 however, suggests that AIS smear classification uses the designation “atypical lesions have a “stark acetowhiteness of either indi­ glandular cells of undetermined significance” vidual or fused villi in discrete patches of varying (AGUS). In other words, in contrast to ASCUS size.” The lesions are usually within or near the (“atypical squamous cells of undetermined signifi­ transformation zone and may be surrounded by cance”), AGUS potentially represents the full spec­ normal-appearing villi. It is clear that it is extreme­ trum of premalignant glandular changes. Our ly difficult, if not impossible, to distinguish imma­ patient’s first abnormal Pap smear was reported as ture metaplasia from AIS. In the case presented, AGUS.8 The AGUS diagnosis should be qualified to the colposeopically directed cervical biopsies were indicate origin of atypical cells, either endocervical successful in revealing AIS. The colposcopic or endometrial, and the degree of atypia, ie, “favor impression of this abnormal tissue could be uncrit­ reactive” or “favor neoplastic.”8 This latter classifi­ ically described as “just not looking right”; howev­ cation would be more suggestive of a possible AIS, er, the yellowish acetowhite tint of the epithelium, which would lead to more intensive evaluation. the small, vaguely atypical blood vessels, and the This was the report of the woman’s repeat Pap contrasting density when compared with the sur­ smear. The differential diagnosis of the AIS Pap rounding more translucent, thin, immature squa­ smear report is broad, including benign cervical mous metaplasia subtly guided the experienced changes, premalignant changes, and possibly inva­ colposcopist to the correct location. Similar find­ sive cancer of the endocervical canal. The cytolog­ ings may be present in atypical squamous metapla­ ic diagnosis of AIS is easily confused with tubal sia. It must be emphasized that histologic confir­ metaplasia9 or invasive cancer.8 Until better cyto­ mation by biopsy or conization is essential. logic discrimination between AGUS and AIS can be Because AIS may be multifocal, small, or secluded developed, great care should be exercised in the in the endocervical canal, cervical conization is diagnosis and evaluation of these glandular abnor­ generally recommended to confirm the diagnosis, malities of the endocervix. At the present time, dif­ exclude an occult invasive adenocarcinoma, and ferentiation necessitates a histologic specimen. serve as possible therapy.

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FIGURE 4

Suggested evaluation and management of women with an repeated every 4 to 6 months until 3 successive smears are normal. unspecified Papanicolaou (Pap) smear reported as atypical If any repeat Pap smear reveals glandular neoplasia, colposcopy or glandular cells of undetermined significance (AGUS), favor cervical conization, or both, should be performed. Review pathol­ reactive or AGUS. Solid arrows indicate preferred path­ ogy7 indicates that if histologic test results are negative and cyto­ ways and dotted arrow indicates alternative pathway. logic testing suggests AIS, site undetermined, further evaluation by, for example, hysteroscopy, endometrial biopsy, dilation and curet­ AGUS' denotes atypical glandular cells of undetermined signifi­ tage, cervical conization, or pelvic ultrasound, should be considered. cance: Repeat Pap smear2 indicates that it may be appropriate to Cervical conization8 denotes conization 20 to 25 mm deep; review the cytologic test results before repeating the Pap smear or Margins negative8 refers to conization margins that are free of performing colposcopy; ECC3 denotes endocervical curettage; neoplasia; Margins positive10 refers to conization margins demon­ Abnormal4 refers to glandular neoplasia; LGN/AIS6 denotes low- strating glandular neoplasia; and Follow-up" refers to follow-up by grade glandular neoplasia or adenocarcinoma in situ. If adenocarci­ cytologic testing and colposcopy during the first postoperative year. noma in situ (AIS) is documented by histologic testing, cervical An exception to Hysterectomy12 is that if the patient is young and conization is appropriate for young women who have not completed the cone is of adequate depth, she may be followed carefully with childbearing; otherwise, hysterectomy should be considered; for Pap smear and ECC as an alternative. Radical hysterectomy, low-grade glandular neoplasia (LGN), cervical conization is appropri­ Radiation therapy13 indicates that this therapy assumes previous ate. Repeat Pap smear6 indicates that Pap smear should be histologic confirmation of adenocarcinoma.

Pap smear

Management

Outcomes

Further management

184 The Journal of Family Practice, Vol. 43, No. 2 (Aug), 1996 Ferris, Krumholz, Jester, et al AGUS AND ADENOCARCINOMA IN SITU ■

The histologic diagnosis of adenocarcinoma in The management of AIS is also controversial situ must consider multiple anatomical and archi­ (Figure 5).10 Many argue that the cytologic or histo­ tectural patterns and cytologic features.14 The logic diagnosis of AIS demands cervical conization. epithelium is multilayered or pseudostratified in That one third of patients with glandular neoplasia contrast to normal single-layered columnar epithe­ on Pap smears have invasive cancer strongly sup­ lium.7 The nuclei are vertically oriented, and there ports this approach.17 This comment, however, rep­ is an increased nuclear-to-cytoplasmic ratio, resents one investigator’s findings and is based on increased nuclear hyperchromasia, and a variable the “microinvasive” classification of many cancers degree of pleomorphism and mitotic activity.7 that other pathologists find difficult to diagnose. Because of varied distribution of endocervical Colposcopic evaluation may lead to a definitive glands within the stroma, the histologic discrimi­ diagnosis, but until a diagnosis is obtained, a nega­ nation of AIS vs adenocarcinoma is extremely tive colposcopic examination of a woman with AIS challenging.15 requires a cervical conization. Luesley et al11 The differential diagnosis of a Pap smear report­ demonstrated that colposcopy and biopsy predict­ ed as AGUS is broad and includes benign and neo­ ed less than one third of women in whom glandu­ plastic changes of both squamous cell and glandu­ lar dysplasia was later detected by subsequent cer­ lar cell origin. After careful evaluation, a signifi­ vical conization or hysterectomy. The colposcopic cant number of women with an AGUS Pap smear examination, however, may be additionally useful report are found to have squamous neoplasia. to exclude the presence of coexisting squamous Furthermore, AGUS is rarely reported by laborato­ cell neoplasia.18 ries (<1 % of the cases of abnormal Pap smear) and Cervical conization may be used concomitantly the majority of AGUS reports are classified as for diagnosis and t herapy. A cone biopsy should be “unspecified” or “favor reactive changes.” The performed when colposcopy, biopsy, and endocer­ additional definition of “favor neoplasia or AIS” is vical curettage do not fully explain the abnormal nearly as broad but slants toward the neoplastic endocervical cells confirmed by secondary review spectrum. Clearly, cytologic testing alone is unreli­ of the Pap smear or when subsequent Pap smears able either to diagnose or to exclude glandular indicate a continued glandular abnormality. A neoplasia. The evaluation of the patient with atyp­ cylindrical conization 25-mm deep has been shown ical glandular cells in her Pap smear demands cau­ to be curative for the majority of women.7 Provided tion and the experience of experts. the cervical conization surgical margins are free of One example of AGUS management is shown in disease, women may be followed postoperatively Figure 4. The frequency of this finding and its pos­ by colposcopy, cervical cytologic testing, and itive predictive value for neoplasia is uncertain. endocervical curettage. A positive conization mar­ Because of this uncertainty, the spectrum of evalu­ gin is thought to require hysterectomy. Cullimore ation ranges from aggressive to conservative. It et a l11’ demonstrated that the majority of women may be appropriate to repeat a Pap smear for the who have positive conization margins do not have patient reported to have “AGUS unspecified” or residual disease detected at hysterectomy. “AGUS favor reactive.”11’ This was the management Nevertheless, some physicians continue to advo­ selected for our patient’s first Pap smear report. cate mandatory simple hysterectomy for treatment Aggressive evaluation by colposcopy, endocervical of AIS.11 Such an approach is more persuasive if a curettage, and cervical biopsy may be more apt woman has completed her childbearing or has than cytologic testing alone to detect the rare another indication for hysterectomy. When elect­ occult malignancy. Negative findings using either ing conization instead of hysterectomy, it is approach, however, do not ensure the absence of extremely important to have a reliable patient who glandular neoplasia in the more proximal genital has been informed of the need for posttreatment tract, where it would be secluded from sampling or cytologic and colposcopic follow-up. visualization. Other diagnostic options should What, then, is the role of colposcopy in evaluat­ therefore be considered. For the patient with per­ ing women with abnormal glandular cell cytologic sistent cytologic atypia, cervical conization or uter­ test results? As demonstrated in this case, AIS can ine curettage or both may be necessary. be presumptively diagnosed, albeit tenuously, by

The Journal of Family Practice, Vol. 43, No. 2 (Aug), 1996 1 85 fg AGUS AND ADENOCARCINOMA IN SITU Ferris, Krumholz, Jester, et al

FIGURE 5

Suggested evaluation and management of women with appropriate for young women who have not completed childbearing; AGUS, favor neoplastic or adenocarcinoma Pap smear otherwise, hysterectomy should be considered; for low-grade glandu­ report. Solid arrows indicate preferred pathways, and dot­ lar neoplasia (LGN), cervical conization is appropriate. Cervical ted arrow indicates alternative pathway. conization4 denotes conization 20- to 25-mm deep; Follow-up5 indicates follow-up by cytologic testing and colposcopy during the first AlS'denotes adenocarcinoma in situ; ECC3 denotes endocervical postoperative year; Radical hysterectomy, Radiation therapy6 curettage. Not cancer3 indicates that if histologic testing is negative indicates that this therapy assumes previous histologic confirmation of and cytologic testing suggests AIS, site undetermined, further evalua­ adenocarcinoma; LGN/AIS7denotes low-grade glandular neoplasia or tion by, for example, hysteroscopy, endometrial biopsy, dilation and adenocarcinoma in situ; Margins positive8 indicates that conization curettage, cervical conization, or pelvic ultrasound should be consid­ margins demonstrate glandular neoplasia; and Margins negative9 ered. If AIS is documented by histologic testing, cervical conization is indicates that conization margins are free of neoplasia.

Pap smear

Outcomes

Further management

colposcopy and directed cervical biopsy. tion of coexisting or independent squamous cell Somewhat nonspecific colposcopic signs that neoplasia, estimated to occur in 50% of cases. Still, implied “abnormality” were apparent in this case. a histologic biopsy finding positive for squamous Yet, because glandular dysplasia may be located cell neoplasia may not explain the origin of a glan­ within endocervical clefts or the proximal endo­ dular cell cytologic abnormality. cervical canal, a negative colposcopic examination An AGUS cytologic test report demands serious may indicate missed occult disease, and a positive assessment. To improve the diagnosis of glandular test may underestimate the severity of disease by neoplasias in the future, further critical appraisal simultaneously overlooking occult carcinoma. On and delineation of specific cytologic criteria for the contrary, colposcopy should detect flagrant these neoplasias is needed.20 Clarification of the invasive adenocarcinoma, and also allow recogni­ abnormal colposcopic signs for AdS is necessary

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agement. In: Coppleson M, ed. Gynecologic oncology. and would benefit the management of early glan­ Edinburgh, Scotland: Churchill Livingstone, 1992:571-607. dular cell neoplasia. 11. Brand E, Berek JS, Hacker NF. Controversies in the man­ agement of cervical adenocarcinoma. Obstet Gvnecol 1988; REFERENCES 71:261-9. 12. Ayer B, Pacey F, Greenberg M, Bousfield L. The cytologic 1. Boon ME, Baak JPA, Kurver PJH, Overdiep SH, Verdonk diagnosis of adenocarcinoma in situ of the cervix uteri and GW. Adenocarcinoma in situ of the cervix: an underdiag­ related lesions. I. Adenocarcinoma in situ. Acta Cytol 1987; nosed lesion. Cancer 1981; 48:768-73. 31:397-411. 2. Schwartz SM, Weiss NS. Increased incidence of adenocar­ 13. Luesley DM. Jordan JA, Woodman CBJ, Watson N, Williams cinoma of the cervix in young women in the United States. DR, Waddell C. A retrospective review of adenocarcinoma- Am J Epidemiol 1986; 124:1045-9. in-situ and glandular atypia of the uterine cervix. Br J 3. Shingleton HM, Gore H, Bradley DH, Soong SJ. Obstet Gynaecol 1987; 94:699-703. Adenocarcinoma of the cervix. I. Clinical evaluation and 14. Jaworski RC, Pacey NF, Greenberg ML, Osborn RA. The his­ pathologic features. Am J Obstet Gynecol 1981; 139:799- tologic diagnosis of adenocarcinoma in situ mid related 814. lesions of the cervix uteri. Cancer 1988; 61:1171-81. 4. Parazzini F, LaVecchia C. Epidemiology of adenocarcinoma 15. Koss LG. Diagnostic cytology and its histopathologic bases. of the cervix. Gynecol Oncol 1990; 39:40-6. Philadelphia, Pa: JB Lippincott, 1992:513-34. 5. Hording U, Teglbjaerg CS, Visfeldt J, Bock JE. Human papil­ 16. Kurman RJ, Henson DE, Herbst AL, Noller KL, Schiffman lomavirus types 16 and 18 in adenocarcinoma of the uterine MIL Interim guidelines for management of abnormal cervi­ cervix. Gynecol Oncol 1992; 46:313-6. cal cytology. JAMA 1994; 271:1866-9. 6. Campion MJ, Ferris DG, DiPaolo FM, Reid R, Miller MD. 17. Laverty CR, Farnsworth A, Thurloe J, Bowditch R. The reli­ Modem colposcopy. Augusta, Ga: Educational Systems, ability of a cytologic prediction of cervical adenocarcinoma Inc, 1991. in situ. Aust N Z J Obstet Gynaecol 1988; 28:307-11. 7. Bertrand M, Lickrish GM, Colgan TJ. The anatomic distrib­ 18. Anderson MC. Glandular lesions of the cervix. In: Jones ution of cervical adenocarcinoma in situ: implications for HW, ed. Cervical intraepithelial neoplasia, Bailliere’s clini­ treatment. Am J Obstet Gynecol 1987; 157:21-5. cal obstetrics and gynecology. London, England: Bailliere- 8. Kurman RJ, Solomon D. The Bethesda System for reporting Tindall, 1995. cervical/vaginal cytologic diagnoses: definitions, criteria 19. Cullimore JE, Luesley DM, Rollason TP, et al. A prospective and explanatory notes for terminology and specimen ade­ study of conization of t he cervix in the management of cer­ quacy. New York, NY: Springer-Verlag, 1994. vical intraepithelial glandular neoplasia (CIGN)—a prelimi­ 9. Pacey F, Ayer B, Greenberg M. The cytologic diagnosis of nary report. Br J Obstet Gynaecol 1992; 99:314-8. adenocarcinoma in situ of the cervix uteri and related 20. Raab SS, Isacson C, Layfield LI, Lenel JC, Slagel DD, lesions, III. Pitfalls in diagnosis. Acta Cytol 1988; 32:325-30. Thomas PA. Atypical glandular cells of undetermined sig­ 10. Coppleson M, Atkinson KH, Dalrymple JC. Cervical squamous nificance. Cytologic criteria to separate clinically signifi­ and glandular neoplasia: clinical features and review of man­ cant from benign lesions. Am J Clin Pathol 1995; 104:574-82.

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