AGC&AIS

2. AGC&AIS Setareh Akhavan M.D Gynecologist Oncologist Tehran University of Medical Sciences

3. Introduction • AGC on cervical cytology usually originate from the glandular epithelium of the endocervix or endometrium. • AGC are found less commonly than abnormal squamous cells (incidence <1%; [0.1 to 2.1%] ) that is associated with a high rate of clinically significant underlying pathology, including malignancy. • AGC are found most commonly in women age 40 or older. • ASC-US: 15-29 yrs

4. Introduction • Women with AGC require further evaluation for premalignant conditions of the cervix, uterus, and rarely, ovary , fallopian tubes, and even the UT or GIT. • Pathological findings with AGC : squamous or glandular.

5. Introduction The terminology used to classify AGC is: 1)Endocervical, 2) endometrial, or 3) not otherwise specified (NOS) is noted as a subcategory.

6. Introduction(terminology ……) ●Atypical glandular cells, favorneoplasia :This designation is for specimens that show features suggestive of, but not sufficient for, an interpretation of adenocarcinoma. ●Endocervical adenocarcinoma in situ (AIS) ●Adenocarcinoma

7. RISK OF PREMALIGNANT OR MALIGNANT DISEASE • AGC: premalignant or malignant disease in 30 % of cases . • Squamo> Glandular • Two literature reviews that included approximately 4300 women with AGC: Findings were benign in 64 to 71 %of women.

9. Pre or malignant in AGC • CIN– 20 to 28 percent, including: - (CIN 1) – 9 percent - (CIN 2,3) – 11 percent • SCC– 0.3 to 1 percent • AIS– 3 to 4 percent • Cervical adenocarcinoma – 1 to 2 percent • Endometrial hyperplasia – 1 percent • Endometrial adenocarcinoma – 2 to 3 percent

10. Abnormalities in AGC Follow-up of the AGC cytology specimen within six months showed the following prevalences and histologies of cervical cancer: • Squamous cervical carcinoma – 0.3 percent • Cervical adenocarcinoma – 0.99 percent BMJ 2016; 352:i276.

11. AGC subcategory The cytologic subcategory is predictive of the histologic diagnosis. • AGC-NOS (endometrial adenocarcinoma: 10.2 percent), • AGC-endocervical (invasive cervical adenocarcinoma: 5.9 percent; adenocarcinoma in situ: 2.4 percent; and CIN 2,3: 5.3 percent), and • AGC-endometrial (endometrial adenocarcinoma: 27.8 percent; and atypical complex endometrial hyperplasia: 22.2 percent) 

12. Coexisting squamous cytologic abnormality • Approximately 50% of women with AGC have a coexisting squamous cytologic abnormality (ASC or a SIL).

13. Human papillomavirus infection •  A positive test for HR-HPV types in women with AGC is associated with a histologic diagnosis of CIN, particularly those with AGC-NOS . • Testing for HPV is not a reliable method of triaging follow-up of AGC cytology as it is for atypical squamous cells. • However, it is useful in the further evaluation of women with AGC.

14. Age • The risk of malignancy in women with AGC increases with age. • The rate of malignancy was highest in women 50 years or older (29-30%) compared with those ages 40 to 49 years (2.8 percent) or younger than 40 years (2.0 percent). • The most common lesion in women younger than 40 years was squamous and premalignant, ie, CIN 2,3 (approximately 15.4 percent).

15. Other factors •  Some data suggest that women with persistent AGC-NOS (two or more cytology results) are at especially high risk of significant glandular disease (60% women had endometrial adenocarcinoma in one study). • Based upon available data, the incidence of AGC and of significant neoplasia appears to be similar or higher in pregnancy than in other women.

16. INITIAL EVALUATION • For pregnant women with AGC, ECC and endometrial sampling should NOT be performed, the endocervical canal may be sampled gently with a cytobrush.

17. All AGC categories (except endometrial) • Women with cervical cytology with a finding of AGC-NOS or AGC-endocervicalare evaluated initially with : • Cervical colposcopy with directed cervical biopsies and sampling of the endocervical canal • Endometrial sampling is performed for all women ≥35 years old and for younger women at risk for endometrial neoplasia (risk factors or symptoms are present)

19. NEGATIVE OR LOW-GRADE FINDINGS ON INITIAL EVALUATION •  The management of women with AGC and negative or low-grade results on initial evaluation for cervical or endometrial neoplasia depends upon the AGC subcategory. • Glandular neoplasia of the cervix, in contrast with squamous disease, is often characterized "skip lesions". • In addition, some glandular disease may be located high in the cervical canal. Thus, some women will require cervical conization to detect disease.

20. AGC-NOS or endocervical Women with AGC-NOS or AGC-endocervical are managed based on the findings of the initial evaluation : • No (CIN2+), no (AIS), and no cancer – Cotestat 12 and 24 months. • If co test : negative – Cotest3 yrslater. • If cytology or HPV are abnormal – Perform colposcopy. If the colposcopic findings are nondiagnostic, endometrial sampling should be performed.

21. Persistent abnormal cytology •  For women with persistent findings of AGC-NOS or AGC-endocervicalwho have nondiagnostic findings with repeat colposcopy and endometrial biopsy, we suggest conization. • In addition, vaginal colposcopy should be performed in women with a history of exposure to diethylstilbestrol.

22. AGC favor neoplasia, AIS, adenocarcinoma • If initial evaluation is negative in women with a AGC, favor neoplasia; AIS; or adenocarcinoma , conizationfollowed by an ECC of the remaining endocervix is required . • We suggest a CKC rather than a LEEP . A D&C is recommended at the same time as the cone biopsy. • If the results of the diagnostic excisional procedure and endometrial sampling are negative TVS is performed to look for a fallopian tube or ovarian lesion.

23. AGC-endometrial If evaluation with endometrial biopsy and colposcopy are negative, the patient may resume routine screening for cervical cancer. • Some experts advise that if the patient has a persistent finding of AGC-endometrial or has symptoms of other malignancies associated with AGC, the patient be evaluated for disease at sites other than the cervix or uterusand/or that endometrial sampling be repeated in 12 months.

24. EVALUATION FOR OVARIAN CANCER OR OTHER MALIGNANCIES • The first-line study is a TVS. • Women with no adnexal mass should be evaluated for colon or other intra-abdominal malignancy with colonoscopy and abdominal CT or MRI.

25. AIS • The usual interval between clinically detectable AIS and early invasion appears to be at least five years. • The average age of diagnosis of cervical AIS = 36.9 years. • The incidences of both AIS and adenocarcinoma of the cervix have increased over the past several decades, particularly among young women. (6 times)

26. Why increase • Increased rates and efficacy of screening, • Changes in the Bethesda cervical cytology classification system and • Increased exposure to factors that cause or promote glandular neoplasia (HR- HPV, oral contraceptives)

27. HISTOPATHOLOGY . • Lesions usually originate at the T- zone with contiguous extension proximally within the endocervical canal. • 10% to 15%of patients with AIS have multifocal disease ("skip" lesions) with foci of AIS that are separated by at least 2 mm of normal mucosa . • AIS lesions may also be located high in the endocervical canal and involve the deeper portions of the endocervical clefts.

28. CLINICAL FEATURES •  AIS :asymptomatic , not visible in gross examination. • Detected due to an abnormal cervical cytology. • Rarely, AIS present with cervical bleeding. • The cervix can only be identified as the site of bleeding with pelvic examination.

29. DIAGNOSIS • Colposcopy, biopsy, and endocervical curettage:AIS has no colposcopic features that differentiate it from other cervical lesions. • For women with AGC , if biopsy and ECC are negative, further evaluation with endometrial biopsy and conization may be warranted.

30. Conizationindications • Cytology with AIS (or adenocarcinoma) and a negative biopsy and ECC • Cytology with AGC-NOS, and a negative biopsy, ECC, and endometrial biopsy • Persistent AGC, classified as endocervical or NOS , and negative results after biopsy, ECC, and endometrial biopsy

31. MANAGEMENT • The management : challenging. • Because of the pattern of disease distribution of AIS (multifocal, high in the endocervical canal, inside endocervical clefts): negative margins on a cone biopsy specimen or a negative ECC not necessarily : completely excised.

32. Clinical approach •  Hysterectomy : the standard treatment for AIS;(Ovaries may be conserved.) • Conization: the alternative followed by surveillance. • Conization alone : a high risk of residual AIS or adenocarcinoma, while the incidence of adenocarcinoma after hysterectomy is limited to rare case reports . • (a positive conization margin.)

33. Clinical approach • We recommend hysterectomy for women with a positive conization margin following two or more conizations. • These recommendations are consistent with guidelines from the ASCCP, NCCN, and ACOG. • Based upon the complexity of managing AIS, treatment by a gynecologic oncologist is generally preferred.

34. Clinical approach • Laparoscopic approach, NO morcellation.

35. Clinical approach • Prior to hysterectomy, for women who had positive margins on conization, a repeat conizationto exclude invasive disease. (6 weeksprior to hysterectomy .)

36. Clinical approach • Women in whom adenocarcinoma is discovered at time of hysterectomy should be managed as appropriate. • Further surgical staging and treatment with radical parametrectomyand lymph node dissection may be required. In addition, chemotherapy and/or radiation may be indicated.

37. surveillance •  Following hysterectomy for AIS, the optimal surveillance = ???? Assuming the hysterectomy specimen did not show invasive cancer, the following protocol: • Vaginal cytology and high-risk HPV testing of the vaginal fornix at 6 and 12 months after hysterectomy • If normal, once a year indefinitely

38. Clinical approach • If vaginal cytology results are abnormal, vaginal colposcopy. • If colposcopy and biopsy are positive for high-grade dysplasia (glandular or squamous), the patient is treated either with an ablative procedure (eg, CO2 laser or ultrasonic surgical aspiration) or excision. • If HPV testing is positive and vaginal cytology negative, the HPV test and cytology repeat : at the next surveillance visit.

39. Conization margin status • Negative margin — Women with a negative conization have a risk of residual AIS or adenocarcinoma of 20 and 1 percent, respectively, based upon data from hysterectomy or repeat conisation. • Conservative management : counseledabout the risk of persistent/recurrent AIS or adenocarcinoma. • ECC is performed at the time of conization. ( a positive ECC is a positive margin).

40. Conization margin status • Positive margin — Women who desire to preserve fertility : a repeat conization. • If the repeat conization margin is negative, we offer surveillance. • Women typically do not undergo more than two conization procedures. • A third conization is sometimes feasible, but the risk of operative complications and preterm delivery in subsequent pregnancy increases with repeat procedures. • We recommend hysterectomy for women with a positive conization margin following two or more conizations.