Case 2 -

Atypical Glandular Cells, Favor Endometrial Cells Barbara A. Crothers Walter Reed Army Medical Center Washington, DC

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Endometrial cells, direct collection from uterine canal in trachelectomy patient Cervicovaginal Thin Prep® Pap test, Papanicolaou stain Clinical History A 33 year old woman presented for follow-up Pap test four months following definitive treatment for invasive adenocarcinoma of the cervix arising from endocervical adenocarcinoma in-situ. The tumor was stage T1b N0 MX. The clinical history on the Pap test indicated a "history of cervical cancer" and was submitted as a cervicovaginal Thin Prep specimen. Case 2 - Figure 1 - Low power appearance of Pap test with scant cellularity, few squamous cells, occasional glandular groups and abundant background debris consisting of lysed blood and neutrophils. Thin Prep® Pap test, Papanicolaou stain, 20X. Case 2 - Figure 2 - Menstrual- type endometrial glandular cells with admixed neutrophils and bloody debris. The cells have uniform nuclear and nucleolar sizes and moderate cytoplasm. Thin Prep® Pap test, Papanicolaou stain, 60X. Case 2 - Figure 3 - Reparative columnar cells, likely from the endocervical-endometrial junction. Despite some irregularity of the nuclear membranes, they are smooth, the chromatin is finely granular and evenly distributed, nucleoli are small and the cells have abundant cytoplasm. Thin Prep® Pap test, Papanicolaou stain, 100X. Case 2 - Figure 4 - Reparative columnar cells. Notice the distinct cytoplasmic boundaries between the cells. Nucleoli, while large, are smooth and round. The enlarged cell has abundant cytoplasm. Thin Prep® Pap test, Papanicolaou stain, 100X. Case 2 - Figure 5 - Reparative columnar cells. This group shows the "taffy pull" effect of repair. Nuclei are smooth with even chromatin, despite multiple prominent nucleoli. There are two squamous cells in the upper left; one is parakeratotic. Thin Prep® Pap test, Papanicolaou stain, 40X. Cytology The background of the smear is "dirty" with cellular debris from lysed red blood cells and fragments of inflammatory cells. It is nearly devoid of squamous cells and appears unsatisfactory for evaluation, except for the presence of a glandular component. Atypical glandular cells occur primarily in small, cohesive groups and have a moderate amount of cytoplasm. Most are admixed with neutrophils and some groups show cellular disorder. Other groups show columnar cells with a high nuclear to cytoplasmic (N:C) ratio, less cytoplasm and small but conspicuous nucleoli. There are 3-dimensional groups of cells with nuclei that are uniform, round to oval and with small, regular nucleoli. The nuclear sizes within the glandular cells vary from that of an intermediate cell up to 2x the area. Some groups contain hemosiderin-laden macrophages. There are only very rare single, atypical glandular cells in the background. Differential Diagnosis Recurrent endocervical adenocarcinoma Endocervical adenocarcinoma in situ Endocervical repair Endometrial adenocarcinoma Cytological Diagnosis - Initial: Endocervical Adenocarcinoma, recurrent - After tumor planning conference: Atypical glandular cells, favor endometrial cells (See comment). - Comment: This case is amended from a prior diagnosis of endocervical adenocarcinoma after discussion in tumor planning conference. The sample was directly collected from the endocervical/ endometrial canal, which would explain the cytological features and the absence of squamous cells. The corresponding endocervical curettage is negative. Pap tests are not sensitive or specific for glandular lesions and may not be an adequate screening test for recurrence in this patient. Histological Diagnosis Endometrium, curettage: Weakly proliferative endometrium with stromal hemorrhage and inflammation. Endocervix, curettage: No significant pathologic changes. Discussion A critical piece of clinical information missing during the initial interpretation of this case was an understanding of the surgical procedure performed, an abdominal trachelectomy, which involves amputating the cervix from the uterus and suturing the vaginal cuff directly to the uterine isthmus. A recent review of post-trachelectomy Pap tests in the United Kingdom [8] highlighted the potential to over-call these specimens due to the large numbers of endometrial cells. These cells are often directly collected from the lower uterine segment with aggressive use of an endocervical brush. Pap tests are recommended to screen for recurrence of disease after trachelectomy, typically at 3 month intervals for the first 2 years and then every 6 months for 3 years [2]. If the neocervix fails to heal adequately, hematometria can occur, as did in this case. The cytological features of directly collected endometrial and lower uterine segment cells can vary greatly from those obviously uniform and benign, with a typical flat, honeycomb architecture, to those in various stages of hormonal influence. Pathologists may be unfamiliar with the appearance of cells collected directly from the endometrial cavity. When well-preserved, the nuclei of endometrial cells approximate those of endocervical cells; they show prominent single nucleoli and fine, uniform chromatin. Typically, endometrial cells in the secretory phase contain more abundant cytoplasm. Endometrial cells from the surface can proliferate in a pseudopapillary fashion (papillary syncytial metaplasia) that can mimic endometrial adenocarcinoma by virtue of abundant cytoplasm with admixed neutrophils. Cells at the endocervical–endometrial junction often display features of both types of cells. They are shorter than endocervical cells, with less abundant cytoplasm, but contain finer chromatin than endometrial cells, larger nuclei and more conspicuous nucleoli. Small groups may show nuclear pseudostratification. With menstrual changes, endometrial cells develop degenerative changes such as nuclear hyperchromasia and cytoplasmic vacuoles. Neutrophils can be present admixed in the groups or in vacuoles, again simulating adenocarcinoma. Because the vaginal "cuff" is not always concurrently sampled with the neocervical os, the specimen may contain only glandular cells of various types, with or without a bloody background. In this case, the presence of "old" blood was a distracter, caused by the build up of menstrual blood within the uterine cavity. Singh et. al. [8] recommends that cases containing only squamous cells be considered unsatisfactory in this setting, since one must assume that the neocervical canal was not adequately sampled and would be the likely site of recurrence. When the newly formed os is small or becomes stenotic, Pap tests will contain only squamous cells from the vaginal vault. Pap tests should be clearly labeled as to the intended site of collection to avoid confusion. The recurrence rate in these women is less than 3% [6], similar to that of women who have had a radical hysterectomy for the same disease. While it is important to recognize recurrent carcinoma in these women, caution is advised when making that diagnosis. The differential diagnosis includes recurrent adenocarcinoma and endocervical adenocarcinoma in situ. Directly-collected adenocarcinoma is more cellular with similarities between the cells, including formation of 3-dimensional groups and sheets, uniform nuclear enlargement, and prominent nucleoli. Cytological features are dependent upon the degree of differentiation. Well-differentiated lesions may exfoliate as flat sheets with preservation of "honeycomb" architecture, but usually have evidence of nuclear abnormalities such as variation in size and shape. Abnormal single cells with enlarged nuclei, irregular nuclear membranes and variable cytoplasm are typically present. Adenocarcinoma in situ typically forms short strips of pseudostratified, hyperchromatic tall columnar cells and may form rosettes. Their nuclei are enlarged with inconspicuous or absent nucleoli and irregular nuclear membranes. Cytoplasmic volume is reduced, unlike endocervical and endometrial repair, and cell borders are indistinguishable. Repair in any cellular population typically reveals characteristic features: definition of cell borders, bidirectional "streaming" of the cells, maintenance of the normal nuclear to cytoplasmic ratio, nuclear enlargement with single or multiple prominent nucleoli, and neutrophils admixed into the cell groups. The radical trachelectomy procedure was developed in France in the 1987 by Dr. Daniel Dargent to preserve the childbearing potential of young women with FIGO stage I or II cervical carcinoma. The procedure has been used to treat both squamous and glandular carcinoma with a recurrence rate of 2-4% Women are at higher risk of recurrence if their tumor size is larger than 2 cm [6]. The usual indications for the procedure in the United States are the desire to maintain fertility in women less than 40 years, a tumor less than or equal to 2 cm, and lack of involvement of the tumor at the endocervical-endometrial margin. In France and at some institutions in the United States, the procedure is performed transvaginally with pelvic lymph nodes harvested through a laparoscope. At other institutions, the procedure is performed abdominally to ensure a wider parametrial surgical margin. For either approach, the standard of care is to perform a frozen section evaluation of the endocervical margin to exclude tumor involvement at the time of surgery. If negative, the vaginal cuff is purse-stringed (by a surgical cerclage) and tacked to the uterine stump. With healing, the surgical surface epithelializes and creates a smooth vaginal vault. A catheter is often introduced into the endocervical / endometrial canal during the procedure to prevent closure of the canal during healing. Women typically resume normal menstruation within 3 months. Despite a miscarriage rate of up to 25% [3], up to 72% of pregnancies reach the third trimester [6]. Of these, 78% have successfully borne children at term. Caesarian section is usually required for delivery. Since the majority of cervical cancers diagnosed annually are stage I tumors, this surgical procedure offers young women a chance to retain child-bearing capability despite a cancer diagnosis [7]. References Burnett AF, Roman LD, O'Meara AT, Morrow CP. Radical vaginal trachelectomy and pelvic lymphadenectomy for preservation of fertility in early cervical carcinoma. Gynecol Oncol. 2003;88(3):419-23. Covens A. Preserving fertility in early cervical carcinoma with radical trachelectomy. Contemporary Ob/Gyn. 2003;2:46-66. Dargent D. Radical trachelectomy: an operation that preserves the fertility of young women with invasive cervical cancer. Bull Acad Natl Med. 2001;187(7):1295-304. Dargent D, Martin X, Sacchetoni A, Mathevet P. Laparoscopic vaginal radical trachelectomy: a treatment to preserve fertility of cervical carcinoma patients. Cancer 2000;88(8):1877-82. Plante M, Renaud MC, Francois H, Roy M. Vaginal radical trachelectomy: an oncologically safe fertility-preserving surgery. An updated series of 72 cases and review of the literature. Gynecol Oncol. 2004;94(3):611-3. Plante M, Renaud MC, Hoskins IA, Roy M. Vaginal radical trachelectomy: a valuable fertility-preserving option in the management of early stage cervical cancer. A series of 50 pregnancies and review of the literature. Gynecol Oncol. 2005;98(1):3-10. Peck P. Abdominal trachelectomy preserves fertility in women with cervical cancer. Medscape Medical News, 29 Apr 2003. Available at http://www.medscape.com/viewarticle/453234 Singh N, Titmuss E, Chin Aleong J, Sheaff MT, Currran G, Jacobs IJ, Shepherd JH. A review of post-trachelectomy isthmic and vaginal smear cytology. Cytopathology 2004;15(2):97-103.