—  SPECIALTY CONFERENCE  —

Gynecologic Pathology

Case 1 - PRO: EIN is Superior to WHO in the Diagnosis and Management of Precursors of Endometrioid Adenocarcinoma

Marisa R. Nucci, Brigham & Women’s Hosp, Boston, MA





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Clinical History
59 year old with postmenopausal bleeding; endometrial sampling.


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Historical perspective
Since the turn of the twentieth century, pathologists have attempted to categorize the spectrum of endometrial glandular proliferations in order to distinguish normal (proliferative phase) from those proliferations that are not diagnostic of carcinoma. The terminology used to describe these lesions has changed many times and new definitions have been applied to the same term, which has led to diagnostic confusion. In a attempt to clarify a diagnostically difficult area, a classification scheme [1] was endorsed by the WHO, which divides endometrial hyperplasia into four categories based on morphologic criteria alone, namely architecture and cytologic atypia. These four categories as issued by the WHO in 1994, and carried forward unchanged in 2003 include: simple hyperplasia without atypia, simple hyperplasia with atypia, complex hyperplasia without atypia and complex hyperplasia with atypia. There have been innumerable proposed modifications of this 4-class WHO system before and since, both in terminology and number of categories, but the EIN proposal is the only one that is based upon new experimental evidence and precisely defined H&E diagnostic criteria.

New biologic data: there are two diseases.
This WHO94 classification system continues to be the most widely used system today in diagnostic practice; however, since 1995, important evidence has emerged which requires integration into practice under a new scheme. These new data includes objective morphometry, which has the advantage of high reproducibility and the ability to separate component variables and assess their importance independently. [2] In addition, molecular genetic assessment of precancer characteristics such as monoclonal growth, acquisition of mutations, and documentation of lineage continuity with subsequent carcinomas has been informative in definitive identification of individual examples of precancers. [2, 3] This new data set has confirmed that there are two biologic processes that need to be diagnosed: 1) hormonal field effect, an exaggerated but not uncontrolled form of a natural process (estrogenic stimulation) that affects all cells within the endometrial compartment (polyclonal process) and 2) endometrial precancerous change, a monoclonal neoplasm of uncontrolled proliferation that arises from a transformed cell. Initial proposal of the 2-class diagnostic terminology employing EIN as the moniker for the precancer group was done by an international panel of 17 gynecologic pathologists (The Endometrial Collaborative Group) in response to the newly generated data above. [4]

New diagnostic criteria for two diseases:
As part of this new evidence, key parameters – lesion size, lesion architecture and relative standard of cytologic appearance- were objectively identified de novo by correlation of these features with: 1)fundamental biologic properties (clonal growth and continuity with cancer), and 2) clinical cancer outcomes. [2, 4] This was done using fragmented curetting and pipelle biopsy specimens. As it turned out, the histologic features discovered by these independent correlations with either molecular properties or clinical cancer outcomes were identical. Such objectively defined morphologic features thus were concordant with this newly defined biologic model, as well as the need to manage patients based upon clinical outcomes. The discovered features, which were never part of the WHO criteria set, were expressed as diagnostic criteria for routine histopathologic diagnosis of the precancerous lesions, which were called EIN (Table 1). Subjective application of these criteria has similar diagnostic performance to the more sophisticated morphometric and molecular approaches which are impractical in a routine clinical setting. [5]

Table 1. EIN Diagnostic Criteria.

EIN Criterion Comments
Architecture Area of glands greater than stroma (volume glands >50%)
Cytology Cytology differs between architecturally crowded focus and background
Size >1 mm Maximum linear dimension in 1 fragment exceeds 1mm.
exclude mimics such as normal LUS and basalis, secretory endometrium, artifact.
exclude cancer cancer if (nonsquamous) solid, villoglandular, or maze-like architecture.

Validation of EIN diagnostic criteria
These objective diagnostic criteria, which can be assessed by routine H&E examination, have been subsequently clinically validated:

1) Patients with EIN have a significant risk of concurrent carcinoma. A recent Gynecologic Oncology Group trial of immediate hysterectomy in women diagnosed with EIN on endometrial biopsy or curettage shows 38% (of 148 patients with EIN) had concurrent adenocarcinoma at the time of hysterectomy. [6] Of these cancers, 67% (37/55) had no myoinvasion, 25% (14/55) had myoinvasion within the inner half of the myometrium and 7% (4/55) had deep myoinvasion into the outer half of the myometrium;

2)The risk of developing endometrial cancer is significantly increased in women with EIN. [2] Cancer outcomes that occur more than one year after an EIN diagnosis support the bona-fide progression from pre-malignant to malignant tumor. Progression to cancer more than one year following a diagnosis of EIN is 45 times more likely compared to women without EIN. A recent study by Lacey et al [7] states that atypical hyperplasia and EIN have equivalent risk of cancer outcome; however, a revised 2-class form of hyperplasia (which is not the same as WHO94) is used, similar to EIN. Diagnostic drift also emerged as a phenomenon in the Lacey study, where there was no correlation between community and expert "WHO" atypical hyperplasia diagnosis, but the academic expert diagnosis of atypical hyperplasia was highly correlated with expert EIN diagnosis.

3) Excluding EIN has a strong negative predictive value for a cancer outcome. [5] EIN outperforms cancer prediction when compared to WHO hyperplasia criteria. In a study of 97 endometrial biopsies initially diagnosed by WHO criteria and re-diagnosed by EIN criteria shows all 8 cancer outcomes followed a diagnosis of EIN; however, 2/8 cancer occurrences were seen in the non-atypical hyperplasia group. These criteria are also diagnostically reproducible, with kappa values ranging from 0.73-0.90 [5], even in a study including only diagnostically challenging cases. [8]

Limitations of WHO94
In diagnostic practice, the four tiered WHO scheme lacks reproducibility as the histologic criteria are largely subjectively defined. Reproducibility of the critical assessment of atypical cytology is low, even among expert gynecologic pathologists. [9, 10, 11, 12] This is even more dramatically evident between expert gynecologic pathologists and the community, as data from a Gynecologic Oncology Group study showed that the WHO94 diagnostic criteria are commonly misinterpreted in the community, as almost 30% of cases submitted as complex atypical hyperplasia were diagnostic of adenocarcinoma upon expert review, while an additional 25% were considered non-atypical hyperplasia or benign. [9] This is mirrored in a more recent study in which the diagnosis rendered in the community significantly different from two panels of expert gynecologic pathologists. [7] Another limitation is that the four diagnostic entities of WHO94 do not correspond to biologically distinct and clinically relevant clinicopathologic groups, which is reflected by the tacit acceptance in the literature (and increasingly in practice) to collapse simple hyperplasia with atypia and complex hyperplasia with atypia into one diagnostic subgroup of atypical hyperplasia. [7, 10, 13, 14, 15] Evaluation of cytologic atypia represents the key histologic criterion in this collapsed WHO scenario, a problem because it is so poorly reproducible as a single variable, and because it ignores the substantial diagnostic value of lesion architecture. [16]

Benefits of EIN
There seems to be a practical consensus amongst expert gynecologic pathologists that fewer than four diagnostic entities should be diagnosed, and there is an observed trend for drift towards practice of EIN style criteria amongst experts aspiring to implement this goal (as shown in the Lacey study). The EIN classification system, unlikeWHO94, is tailored to this purpose, using objectively defined diagnostic criteria which accurately identify clinically relevant precancerous endometrial lesions. It is easy to use with substantial diagnostic reproducibility. With the EIN classification system, endometrial precancers are distinguished from benign hormonal changes (termed benign endometrial hyperplasia), which not only reflects a more accurate understanding of the pathophysiology of endometrial carcinogenesis, but also has a more practical binary diagnostic scheme – is it premalignant or not?

Future directions
Consolidation of current routine diagnostic practices under an EIN umbrella will not solve the problem of predicting which individual precancer will progress based on its histologic appearance. While it is possible that adjunctive biomarker or functional studies could increase overall prediction performance, this has yet to be realized at a clinically significant level, much less with something that justifies routine use. Biomarkers such as PTEN can highlight the clonal growth of EIN, but are not necessary (or even advised) for diagnosis, nor should they modify management decisions of an EIN diagnosed routinely. Current research is investigating the role of histomorphometry in accurately predicting myoinvasive tumor, but even if successful must be translated to a non-computerized measure to be practical in the US . [6] Whether these studies translate into improved histologic criteria that are validated by clinical outcome studies remains to be seen and merits further study.

References
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  2. Baak JP, Mutter GL, Robboy S, et al. The molecular genetics and morphometry-based endometrial intraepithelial neoplasia classification system predicts disease progression in endometrial hyperplasia more accurately than the 1994 World Health Organization classification system. Cancer 2005;103:2304-12.

  3. Mutter GL, Baak JP, Crum CP, et al. Endometrial precancer diagnosis by histopathology, clonal analysis, and computerized morphometry. J Pathol 2000;190:462-9.

  4. Mutter GL. Endometrial intraepithelial neoplasia (EIN): will it bring order to chaos? The Endometrial Collaborative Group. Gynecol Oncol 2000;76:287-90.

  5. Hecht JL, Ince TA, Baak JP, et al. Prediction of endometrial carcinoma by subjective endometrial intraepithelial neoplasia diagnosis. Mod Pathol 2005;18:324-30.

  6. Mutter GL, Kauderer J, Baak JP, Alberts D. Biopsy histomorphometry predicts uterine myoinvasion by endometrial carcinoma: a Gynecologic Oncology Group study. Hum Pathol 2008;39:866-74.

  7. Lacey JV, Jr., Mutter GL, Nucci MR, et al. Risk of subsequent endometrial carcinoma associated with endometrial intraepithelial neoplasia classification of endometrial biopsies. Cancer 2008;113:2073-81.

  8. Marotti JD, Glatz K, Parkash V, Hecht JL. International Internet-based assessment of observer variability for diagnostically challenging endometrial biopsies. Arch Pathol Lab Med 2011;135:464-70.

  9. Zaino RJ, Kauderer J, Trimble CL, et al. Reproducibility of the diagnosis of atypical endometrial hyperplasia: a Gynecologic Oncology Group study. Cancer 2006;106:804-11.

  10. Bergeron C, Nogales FF, Masseroli M, et al. A multicentric European study testing the reproducibility of the WHO classification of endometrial hyperplasia with a proposal of a simplified working classification for biopsy and curettage specimens. Am J Surg Pathol 1999;23:1102-8.

  11. Kendall BS, Ronnett BM, Isacson C, et al. Reproducibility of the diagnosis of endometrial hyperplasia, atypical hyperplasia, and well-differentiated carcinoma. Am J Surg Pathol 1998;22:1012-9.

  12. Skov BG, Broholm H, Engel U, et al. Comparison of the reproducibility of the WHO classifications of 1975 and 1994 of endometrial hyperplasia. Int J Gynecol Pathol 1997;16:33-7.

  13. Giede KC, Yen TW, Chibbar R, Pierson RA. Significance of concurrent endometrial cancer in women with a preoperative diagnosis of atypical endometrial hyperplasia. J Obstet Gynaecol Can 2008;30:896-901.

  14. Lacey JV, Jr., Ioffe OB, Ronnett BM, et al. Endometrial carcinoma risk among women diagnosed with endometrial hyperplasia: the 34-year experience in a large health plan. Br J Cancer 2008;98:45-53.

  15. Lacey JV, Jr., Sherman ME, Rush BB, et al. Absolute risk of endometrial carcinoma during 20-year follow-up among women with endometrial hyperplasia. J Clin Oncol 2010;28:788-92.

  16. Allison KH, Reed SD, Voigt LF, et al. Diagnosing endometrial hyperplasia: why is it so difficult to agree? Am J Surg Pathol 2008;32:691-8.