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

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

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.

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

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

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.

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

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.

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) 

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

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.

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).

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 .

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.

All AGC categories (except endometrial) Women with cervical cytology with a finding of AGC-NOS or AGC-endocervical are 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)

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.

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 – Cotest at 12 and 24 months. If co test : negative – Cotest 3 yrs later. If cytology or HPV are abnormal – Perform colposcopy. If the colposcopic findings are nondiagnostic, endometrial sampling should be performed.

Persistent abnormal cytology  For women with persistent findings of AGC-NOS or AGC-endocervical who 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.

AGC favor neoplasia, AIS, adenocarcinoma If initial evaluation is negative in women with a AGC, favor neoplasia; AIS; or adenocarcinoma , conization followed 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.

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 uterus and/or that endometrial sampling be repeated in 12 months. 

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.

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)

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)

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.

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.

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.

Conization indications 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

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.

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.)

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.

Clinical approach Laparoscopic approach, NO morcellation.

Clinical approach Prior to hysterectomy, for women who had positive margins on conization, a repeat conization to exclude invasive disease. (6 weeks prior to hysterectomy .)

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

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

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.

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 : counseled about the risk of persistent/recurrent AIS or adenocarcinoma. ECC is performed at the time of conization. ( a positive ECC is a positive margin).

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.