Materials and Methods

Institutional review board approval was obtained for this study. All women who underwent a cervical conization for a diagnosis of ACIS followed by either repeat conization or hysterectomy (or both) between Jan. 1, 1995, and April 30, 2010, at Los Angeles County/University of Southern California Medical Center and Norris Cancer Center were identified using the CoPath pathology archive database and the surgical database maintained by the Division of Gynecologic Oncology. The corresponding patient files were retrieved from the archives. Information regarding patient demographics, Papanicolaou smear results, colposcopic findings, colposcopic biopsy results, method of conization as well as conization and hysterectomy histopathology results was abstracted. We included patients with a concurrent diagnosis of cervical intraepithelial neoplasia. We excluded those with any degree of invasive adenocarcinoma on either the initial cervical biopsy or on the initial cone procedure.

Eighty-eight patients were initially identified. After excluding patients who did not have a second procedure after their initial conization, 78 patients remained and constituted our study group. All conization procedures were performed by resident physicians under direct supervision of a staff member in gynecologic oncology. The techniques used for cold knife cone (CKC) and loop electrosurgical conization (LEEP) have been described previously. A postconization endocervical curettage (ECC) was performed above the conization bed after the cone specimen was removed. Histology was reviewed by a pathologist with particular expertise in gynecologic pathology (JCF). The diagnosis of ACIS was made on the basis of the morphologic appearance of the lesion including: endocervical glands lined by a stratified layer of enlarged endocervical cells that exhibit nuclear enlargement, marked nuclear atypia, increased mitotic activity, and/or apoptotic bodies. The architectural conformation of the glands involved had to be compatible with the conformation of benign endocervical glands. Complex glandular patterns, stromal desmoplasia, vascular or neural invasion all precluded the diagnosis of an in situ lesion, and classified the lesion as invasive adenocarcinoma.

Data were summarized using standard descriptive statistics. The association between categorical variables was tested using Fisher exact test. The 95% confidence intervals, negative and positive predictive values were also calculated.

We conducted a comprehensive English literature review of articles available on ACIS. We conducted a MEDLINE search from 1950 to 2012. All articles referenced in the retrieved articles were also reviewed to ensure that relevant publications were not missed. We excluded case reports and metaanalyses.

Results

Seventy-eight patients were identified in this review. The median age at diagnosis of ACIS was 40 years old (range, 21–64). Approximately one-third of patients were under the age of 35 years at time of diagnosis. The majority of the population was Hispanic comprising 73% of the total. The remaining patients described themselves as white (10%), Asian (8%), and African American (5%); in 3 (4%) race was unknown. Inconsistent information regarding use of oral contraception was available and, thus, that data could not be analyzed. Cervical cytology findings were as follows: 9 (12%) atypical squamous cells of undetermined signficiance, 1 (1%) atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion, 16 (20%) high-grade squamous intraepithial lesion, 2 (3%) low-grade squamous intraepithial lesion, 1 (1%) suspicious for squamous cell carcinoma, 21 (27%) atypical glandular cells of undetermined significance, 2 (3%) atypical endometrial cells, 5 (6%) ACIS, 6 (8%) suspicious for adenocarcinoma, 12 (15%) were unknown, and 3 (4%) were normal. Of 78 women, 32 (41%) had ACIS found on cervical biopsy, 27 (35%) had ACIS found in the ECC done at the time of colposcopy, and the remaining 19 cases of ACIS (24%) were diagnosed after cone biopsy for squamous dysplasia. The method used for the initial conization procedure was cold knife conization (CKC) in 26 (33%) women and LEEP conization in 52 (67%) women. A concurrent diagnosis of cervical intraepithelial neoplasia was made in 37% of the cases ( Table 1 ). Postconization ECC status could be assessed in 69 patients. Those that were not assessed were insufficient for evaluation at the time of pathologic interpretation.

The second procedures consisted of 40 conizations, and 38 hysterectomies. Four of the 38 hysterectomies were radical or modified radical hysterectomies. Third procedures included 2 conizations and 25 hysterectomies. Overall, the outcome after the subsequent procedures revealed 45 (58%) without residual ACIS, 28 (36%) with residual ACIS, and 5 (6%) with invasive adenocarcinoma.

On univariate analysis, the presence of ACIS at the internal conization margin or in the postconization ECC correlated with residual glandular neoplasia ( Table 2 ), although conization method, presence of squamous neoplasia and age did not. A margin positive for ACIS was associated with residual ACIS in 19 (56%) of the cases and was associated with invasive adenocarcinoma in 4 (12%) of the cases. An ECC positive for ACIS was associated with residual ACIS in 14 (78%) of the cases and was associated with invasive adenocarcinoma in 3 (17%) of the cases. If both the margins and the ECC were positive for the presence of ACIS, 1 (8%) specimen did not have residual disease, 10 (77%) had residual ACIS, and 2 (15%) had invasive adenocarcinoma. On the other hand, if both the internal conization margin and the postconization ECC were negative for the presence of ACIS, only 5 (14%) of the final specimens had residual ACIS and none had invasive cancer.

Invasive adenocarcinoma was diagnosed in 5 patients at the time of follow-up procedure. All cases of invasive adenocarcinoma were microinvasive (no more than 3 mm of stromal invasion and no lymphovascular space invasion). These patients were 40, 40, 53, 58, and 64 years old. Three patients had a simple hysterectomy after the initial cone biopsy and were found to have invasive adenocarcinoma in the hysterectomy specimen. Two patients were diagnosed with invasive disease on a follow-up cone biopsy after their initial cone biopsy. One of these women was counseled extensively on her options, however, declined surgery for reasons that remain unclear and opted for radiation rather than definitive surgical management. The other woman underwent a modified radical hysterectomy.

Results

Seventy-eight patients were identified in this review. The median age at diagnosis of ACIS was 40 years old (range, 21–64). Approximately one-third of patients were under the age of 35 years at time of diagnosis. The majority of the population was Hispanic comprising 73% of the total. The remaining patients described themselves as white (10%), Asian (8%), and African American (5%); in 3 (4%) race was unknown. Inconsistent information regarding use of oral contraception was available and, thus, that data could not be analyzed. Cervical cytology findings were as follows: 9 (12%) atypical squamous cells of undetermined signficiance, 1 (1%) atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion, 16 (20%) high-grade squamous intraepithial lesion, 2 (3%) low-grade squamous intraepithial lesion, 1 (1%) suspicious for squamous cell carcinoma, 21 (27%) atypical glandular cells of undetermined significance, 2 (3%) atypical endometrial cells, 5 (6%) ACIS, 6 (8%) suspicious for adenocarcinoma, 12 (15%) were unknown, and 3 (4%) were normal. Of 78 women, 32 (41%) had ACIS found on cervical biopsy, 27 (35%) had ACIS found in the ECC done at the time of colposcopy, and the remaining 19 cases of ACIS (24%) were diagnosed after cone biopsy for squamous dysplasia. The method used for the initial conization procedure was cold knife conization (CKC) in 26 (33%) women and LEEP conization in 52 (67%) women. A concurrent diagnosis of cervical intraepithelial neoplasia was made in 37% of the cases ( Table 1 ). Postconization ECC status could be assessed in 69 patients. Those that were not assessed were insufficient for evaluation at the time of pathologic interpretation.

Table 1

Conization characteristics

Variable	n (%)
Conization technique
CKC	26 (33)
LEEP	52 (67)
Internal margin status
Negative	44 (56)
Positive	34 (44)
Postconization ECC status
Negative	51 (65)
Positive	18 (23)
Missing	9 (12)
Presence of squamous dysplasia
Negative	49 (63)
Positive	29 (37)
Results of subsequent procedures
Negative	45 (58)
ACIS	28 (36)
Cancer	5 (6)

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