Final Diagnosis & Discussions: Liquid-Based Pap Test on 54-Year-Old Post-Menopausal Woman

FINAL DIAGNOSIS: Endometrial Adenocarcinoma

 

DISCUSSION
Endometrial adenocarcinoma (EMAC) is a disease of predominantly postmenopausal women that frequently presents with bleeding. Other patients are asymptomatic and may be first fortuitously recognized on a Pap test. Although, the Pap test is primarily used to screen for cervical squamous based lesions, it is possible to see cells from beyond the endocervical canal and recognize endometrial adenocarcinomas. Despite a 6.5-fold rise in the frequency of reporting benign endometrial cells after the Bethesda 2001 reporting system, the frequency of subsequent diagnosis of endometrial malignancies has not increased (1). Risk factors for EMAC include obesity, prolonged estrogen exposure and smoking. Human papilloma virus high risk subtypes 16 and 18 DNA has been identified in many malignancies (including endometrial adenocarcinoma); however, HPV does not appear to contribute to pathogenesis of EMAC (2).

The most common subtype of EMAC is endometrioid and other variants include papillary serous, clear cell, and adenosquamous which all have specific morphologies. Besides the variant morphology, the degree of differentiation affects the cytological features that may be seen on the slide. Cytomorphologic features exhibited by any particular neoplasm can vary from mild deviation from normal endometrial cells to marked cellular pleomorphism. The current case is most consistent with a FIGO grade 2 (moderately differentiated) adenocarcinoma, although grading of tumor is not typically reported on Pap tests. The remainder of discussion applies to the endometrioid variant of EMAC.

Some characteristic cytological features include:

• Small crowded three dimensional groups or isolated round cells.
• Nuclear enlargement with hyperchromasia.
• The nucleoli are prominent and variable in number and size depending on tumor grade.
• Cytoplasm may be scant but is frequently vacuolated.
• Intracytoplasmic neutrophils are common and can be a helpful feature.
• Tumor diathesis and the presence of macrophages are inconsistent as diagnostic clues.

The differential diagnosis of endometrial carcinoma includes several commonly encountered benign, pre-malignant and malignant lesions.

Of the benign entities, IUD (intrauterine device), reactive endocervical cells, menstrual phase endometrium, endometrial polyps and Arias-Stella cells are some of the more common mimickers. IUDs produce a number of changes that can be misleading for a diagnosis of atypical glandular cells or even adenocarcinoma. The cytoplasm frequently has vacuoles that are very similar in appearance to EMAC. Lack of intracytoplasmic neutrophils, clinical history of IUD and patient’s age can be helpful in making the differentiation from EMAC. Reactive endocervical cells, including atypical repair may paradoxically show greater variation in nuclear and nucleolar size but retain smooth nuclear contours. They also tend form sheets and not the three dimensional balls seen in adenocarcinoma (3). Menstrual endometrium may shed as crowded groups and single cells, therefore diagnosis of EMAC should be made carefully in actively menstruating women. Endometrial polyps may shed atypical endometrial cells and therefore any diagnosis of EMAC should trigger histological evaluation of the endometrium (4). Arias-Stella cells are large and hyperchromatic with finely vacuolated cytoplasm and are seen in pregnancy. Because of the predominance of EMAC in older, postmenopausal women, clinical history can be critically important in making a distinction between these benign entities and adenocarcinoma.

Endometrial hyperplasia is a recognized precursor to endometrial adenocarcinoma. Cytologically, cells of atypical hyperplasia cannot be differentiated from well differentiated EMAC. As with diagnosis of atypical glandular cells (AGC), further classification and investigation by histology is important.

Because there are many similarities between adenocarcinomas arising in the gynecological tract (vagina, cervix, endometrium, fallopian tubes, and ovaries), they should be considered together when evaluating a Pap test. When adenocarcinoma cells are present, the two main primary sources are endocervical and endometrial adenocarcinoma. The younger age of the patient favors a presence of an endocervical primary since endometrial adenocarcinoma tends to arise in postmenopausal women. The edges of cellular groups of EMAC tend to be scalloped versus more smooth edges of endocervical adenocarcinoma. Endocervical adenocarcinoma does not usually have large numbers of intracytoplasmic neutrophils. Adenocarcinoma of the vagina is rare and associated with maternal history of exposure to DES during pregnancy. Fallopian tube and ovarian origin neoplasms typically require clinical correlation in the absence of endocervical and/or endometrial histologic disease.

Endometrial adenocarcinoma is primarily a disease of postmenopausal women which can be seen on Pap test. The cytomorphologic features and clinical history are important in assessing the differential diagnosis and accurate classification.

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References

1. Thrall, MM et al. Rate of endometrial adenocarcinoma in women screened before and after implementation of the Bethesda 2001 reporting system. Acta Cytol 2008;52:1–7.
   
   
2. Giatromanolaki A. et al. Human papillomavirus in endometrial adenocarcinomas: infectious agent or a mere "passenger"? Infect Dis Obstet Gynecol 2007.
   
   
3. Cibas ES, Ducatman BS. 2003. Cytology: diagnostic principles and clinical correlates. Saunders Ltd., 2nd ed.
   
   
4. Koss L, Melamed M. 2006. Koss’ diagnostic cytopathology and its histopathologic bases. Philadelphia: Lippencott Williams & Wilkins.