Case 8 -

Adenocarcinoma in situ Kristen Atkins

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Diagnosis: Adenocarcinoma in situ Clinical History A 38-year-old woman presents for her annual exam. She has no significant history. Physical exam is normal. The images are from all the screening dots. Case 8 - Figure 1 Thin Prep slide from the pap test. Mature squamous cells and single cell with a high N:C. Case 8 - Figure 2 Single cell with an eccentrically placed nucleus and squamoid cytoplasm. Case 8 - Figure 3 Cluster of cells with high N:C. Case 8 - Figure 4 Cluster of cells with some nuclear enlargement and irregular nuclear contours. Cytologic Diagnosis: Atypical glandular cells, not otherwise specified Histologic Diagnosis: ECC: atypical glandular cells, cannot exclude carcinoma LEEP: Adenocarcinoma in situ Cytologic Findings: The Pap test has very few atypical cells. Those that are present have enlarged hyperchromatic nuclei, but the cell type is challenging. A single cell appears glandular but has metaplastic squamous cell- type cytoplasm. One cluster of atypical cells is haphazardly arranged, but there is no feathering or mitotic figures. One single cell is small with a high N:C ratio. Note: this case was shown to several cytopathologists. The interpretations ranged from reactive endocervical cells to atypical squamous cells to atypical glandular cells. Her concurrent HPV test was positive. Histologic and Clinical Follow-up: Endocervical adenocarcinoma in situ Given the AGUS interpretation, colposcopy was performed and was negative. A concurrent ECC showed detached fragments of atypical cells, not clearly neoplastic. A p16 was positive, supporting dysplasia or carcinoma. The endometrial biopsy was negative. Subsequent LEEP showed adenocarcinoma in situ. Although the Pap raised the possibility of squamous dysplasia, this was not seen on the LEEP. Discussion: Although there is a correct diagnosis for the Pap test, this is a case that does not clearly have a "right" interpretation. It is presented to highlight the managerial implications of our interpretations. Atypical glandular cells on the Pap test are often fraught with frustration cytologically and managerially. It is a rare interpretation, comprising less than 0.5% of Pap tests in the USA. [5]However, at least 10% of these women have at least high grade dysplasia on biopsy. [5] The majority of endocervical neoplasms are HPV associated. Endocervical carcinoma is increasing and occurs in women younger than those with squamous cell carcinoma. [1] The sensitivity of detecting endocervical lesions on Pap test is low, most likely secondary to sampling issues. The Pap interpretation of "atypical glandular cells" is reserved for changes that are beyond reactive atypia but still encompasses a large spectrum of changes (reactive, tubal metaplasia, neoplastic) and differentiating these on Pap test can be extremely challenging. Although AGC can be qualified as not otherwise specified, favor neoplasia, or AIS, subclassification is often challenging due to small numbers of cells. [1] This area is further compromised by identifying the origin of the atypical cells (endocervical, endometrial, tubal). Some have recommended using HPV results to aid in triaging how to sample. For instance if HPV negative, focus on endometrium, if HPV positive focus on cervix and endocervix. [2, 4] The 2006 consensus guidelines recommend that women with a Pap test interpretation of AGC (all categories) be treated with colposcopy and endocervical sampling. Women over 35 years of age should also receive an endometrial biopsy. Women under 35 with any risk for developing endometrial pathology also should have endometrial sampling. If HPV has not been done, it is recommended to be obtained at the time of colposcopy. NOTE: currently HPV testing alone or repeat cytology alone is not acceptable for initial triage of AGC. If colposcopic ECC and biopsy (if obtained) are negative then if HPV positive = repeat cytology and HPV at 6 months. Then if HPV positive and or cytology ASC or higher refer to colposcopy. HPV negative= repeat cytology and HPV at 12 months. If subsequent 6 month or 12 month HPV and cytology are negative, return to routine screening. ASC AGC HPV negative Return in 1 yr Colpo, ECC, EMB if >35 If neg, return in 1 yr HPV positive Colpo If negative, return in 1 yr Colpo, ECC, EMB if >35 If neg, return in 6 months HPV unknown Repeat cytology in 6 months x 2 Repeat cytology every 6 months x 4 Colposcopy Although HPV is a sensitive test, it has a low specificity. Since colposcopy is the suggested step in women with mildly abnormal cytology and positive HPV or AGC, the directed biopsy is very important in triaging women. Studies have indicated that regardless of expertise, sensitivity of colposcopy was improved by taking multiple biopsies, and not just from the perceived worst lesion. [3] References (select): Diaz-Montes TP, Farinola MA, Zahurak ML, Bristow RE, Rosenthal DL. Clinical utility of atypical glandular cells (AGC) classification: cytohistologic comparison and relationship to HPV results. Gynecol Oncol. 2007 Feb;104(2):366-71. Irvin W, Evans SR, Andersen W, Jazaeri A, Taylor P, Stoler M, Pastore L, Rice L. The utility of HPV DNA triage in the management of cytological AGC. Am J Obstet Gynecol. 2005 Aug;193(2):559-65 Jeronimo J, Shiffman M Colposcopy at a crossroads. Am J Obstet Gynecol 2006 195 (2):349-53. Saqi A, Gupta PK, Erroll M, Babiac A, Blackmun D, Mansukhani M, Vazquez M. High-risk human papillomavirus DNA testing: a marker for atypical glandular cells. Diagn Cytopathol. 2006 Mar;34(3):235-9. Wright TC Jr, Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D; 2006 American Society for Colposcopy and Cervical Pathology-sponsored Consensus Conference. 2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests. Am J Obstet Gynecol. 2007 Oct;197(4):346-55