—  INTERNATIONAL SOCIETY OF GYNECOLOGICAL PATHOLOGISTS   —

The Morphological Definition of Well Differentiated Endometrial Carcinoma


Michael R. Hendrickson
Stanford University Medical Center
Stanford, CA


Introduction

History Of The Endometrial Classification Problem
Fashioning the current definition of well differentiated endometrial carcinoma over the past few decades has largely involved the sequential elimination of clinically benign proliferations from the cancer group. In the 1970's and 1980's there was a growing concern that the label 'carcinoma' was being attached to a large number of proliferations for which there was no evidence that they behaved in a clinically malignant fashion. In those days, when preoperative radiotherapy for endometrial carcinoma was the standard of care, the diagnostic stakes were high and, to the extent that preoperative radiation was a morbid procedure, the over-diagnosis of cancer had its costs. The Stanford 1982 study of Clinical Stage I endometrial carcinoma 4, 6  eliminated fully 40% of the cases that had been diagnosed as carcinoma over the past several decades at Stanford. Whittling away at the 'pseudo-malignancies' has taken two main forms: 1) recognition of the endometrial epithelial 'metaplasias' and 2) 'right shifting' the line dividing atypical hyperplasia/metaplasia (=CAHM) and well differentiated carcinoma (=WDCA). These two changes are indicated schematically in Figure 1.

Some preliminary observations and terminology

Malignant and pre-malignant (or 'invasive' carcinoma and 'pre-invasive' proliferations)
The distinction is between a proliferation that at the time of diagnosis has the capacity to invade the myometrium and metastasize and one that must first evolve into something else before it acquires the ability to invade and metastasize. This distinction is clear-cut when dealing, for example, with squamous proliferations of the uterine cervix: CIN3 vs. invasive squamous carcinoma; it is problematic in the endometrium. Here there is no stable anatomic boundary to be violated and both precursor lesions and well differentiated carcinoma often involve the simultaneous proliferation of epithelium and stroma.

There is no 'gold standard' for 'invasive' endometrial carcinoma
There is no crisp discontinuity at any level of examination (e.g., ultrastructural, immunohistochemical, oncogenetic).that serves to separate the 'invasive' (in the sense I've used above) from the 'non-invasive' endometrial proliferations. Given the bewildering complexity of descriptive genomics to date, there probably will not be one in the near future.

Eliminating the Metaplasias from the carcinoma group 1, 3, 5, 8, 13
In a variety of circumstances, benign endometrial cells may exhibit epithelial differentiation other than the well-known differentiated patterns seen in proliferative and secretory endometria. It is important to realize that these benign alternative epithelial types may be present in association with any of the non-secretory endometria (i.e., atrophic, weakly proliferative, disordered proliferative, hyperplastic, including atypical hyperplasia, and endometrioid carcinoma). The clinical significance that attaches to these patterns is, as far as we know, that of the underlying associated non-secretory pattern. For example, patients with atypical hyperplasia containing squamous metaplastic areas presumably have the same risk of developing endometrial carcinoma as those patients with hyperplasia with the same degree of cytologic atypia but uncomplicated by this differentiated feature. Benign metaplastic cells often cause diagnostic difficulties because of their unusual appearance and because they may grow in architectural arrangements also found in complex hyperplasia and in carcinoma. In particular, they may stratify (e.g., morules) or they may have cribriform patterns (e.g., ciliary metaplasia). When benign metaplastic epithelium co-exists with carcinoma, the metaplastic cells do not warrant a change in the classification of the carcinoma; the classification of the carcinoma is based on the morphology of the malignant epithelium. However, cells with aberrant differentiation may themselves be malignant, and when this occurs, the term "metaplasia" is no longer appropriate; rather, the term "special variant carcinoma" is employed. A final important differential diagnostic point: the subclassification of metaplasias into a variety of types is for descriptive and differential diagnostic purposes. Once a proliferation is determined to be a metaplasia and its degree of atypia determined, an unequivocal assignment to a particular metaplastic type is of little clinical (and probably less scientific) interest. Indeed, most metaplastic endometria are of mixed type and it is likely that many of the patterns overlap (e.g. morules and syncytial papillary metaplasia).

The rightward shift of the line dividing 'premalignant' from 'malignant'

Some background: The Kurman and Norris study7
Kurman & Norris made the first serious attempt to formulate objective, validated conventional light microscopic criteria for 'invasive' endometrial carcinoma. They carefully described a set of patterns they labeled 'Endometrial stromal invasion ( = ESI)'; the presence of a minimal amount of any of these patterns warranted a diagnosis of cancer. These patterns included

  • Extensive PAPILLARY pattern (2.1 mm)
  • Replacement of stroma by masses of SQUAMOUS epithelium (2.1 mm)
  • CONFLUENT glandular pattern (2.1 mm)
  • Irregular infiltration of glands associated with a desmoplastic or FIBROBLASTIC STROMAL response

Kurman & Norris kept track of performance of ESI criteria when applied to endometrial samplings by examining the accompanying hysterectomy specimens for these cases. The finding of ESI in the uterus was counted as a true positive although not all ESI positive uteri were associated with myoinvasion.

Our concerns with the ESI definition of WDCA:

  • The PROCESS OF CRITERIA SELECTION not investigated. Where did the ESI criteria came from?
  • No operational DEFINITION OF CLINICAL "CANCER." What was the cancer group supposed to capture?
  • No COMPARISON WITH COMPETING CRITERIA; largely because the Kurman & Norris criteria were the only ones set out with sufficient clarity to be evaluated.
  • Kurman & Norris didn't exploit CYTOLOGICAL FEATURES.
The Stanford study 9
  • Study design: Supervised classification study (or predictor-outcome study) using Classification And Regression Tree (= CART)2
  • MATERIAL: 520 paired endometria and hysterectomy specimens
  • OUTCOME: myoinvasive glands that produced a host response
  • PREDICTORS: every feature that had been used in previous classifications with the following qualifications
  1. We eliminated features that we could not reproducibly identify e.g., rounding of nuclei, clearing of nuclei, stromal fibrosis 
  2. Pre-processing of architectural features (see Figure 2): We undertook a careful analysis of the complex 2D profiles encountered in these proliferations and constructed 3D images that corresponded to those profiles. This analysis yielded a number of standard proliferative patterns

CART PRODUCED A REMARKABLY SIMPLE RULE THAT RELIED ON TWO FEATURES: ARCHITECTURE AND CYTOLOGY

Architectural complexity as depicted in the Growth chart ( Figures 3 and 4) stratifies endometrial samplings into those with low, intermediate and high growth indices.

Cytological criterion:
extreme nuclear pleomorphism and/or extreme prominence of nucleoli; CART recommended ignoring all the rest

The translation of this scheme into practical managerial categories is set out in (Figure 5)

SOME IMPORTANT FEATURES OF THE STUDY

  • Avoided the circularities and the ad hoc character of previous rules by using myoinvasion as a stand-in for clinical malignancy; a self-consciously outcome driven classification procedure.
  • Provided a reasonably sharp answer to the question: what endometrial proliferations are clinically malignant?
  • Recruited the statistical common sense embodied in CART: tracked on redundancy in predictors, used cross-validation to separate 'signal' from 'noise.'
  • Eliminated as non-discriminating some old favorites: squamous differentiation and endometrial stromal foam cells

Minimal Deviation Endometrial Adenocarcinoma11 
Recall that we used host response to intramyometrial neoplastic glands as a definition of myoinvasion for the purposes of the larger study. The question naturally arises: are there instances where undoubted invasion has occurred and yet the intramyometrial component has not induced a host response? The answer is yes, but only in minority of cases. The survival appears to be the same as in conventional host-response-associated myoinvasion. This pattern has to be distinguished from adenomyosis involvement by intraendometrial carcinoma.

Atypical polypoid Adenomyofibroma10, 12, 14 
Atypical polypoid adenomyoma, APA as the name suggests, is a lesion that is biphasic, polypoid and features atypical endometrial hyperplasia. Morular metaplasia is present in over 90% of cases. Most occur in the lower uterine segment. APA in the hysterectomy specimen is typically a sharply circumscribed lesion commonly associated with some distinctly different endometrial proliferation elsewhere in the endometrium, not infrequently, with a normal secretory pattern. APA is a persisting or recurring but noninvasive and non-metastasizing process that has, with rare exceptions, not been reported to be clinically aggressive. Its importance is that it may mimic carcinoma (sometimes myoinvasive carcinoma) in an endometrial sampling and prompt a hysterectomy in a reproductive aged woman.

Conclusions
Why should we care about fine-tuning the CAHM / WDCA dividing line?

GYNECOLOGIC ONCOLOGY ISSUES:

Important to know the level of risk assumed by patients when treated with less than hysterectomy, particularly, premenopausal women who are concerned with fertility conservation and medically compromised postmenopausal patient

GENERAL CLINICOPATHOLOGICAL ISSUES:

Provides us with insights into the creation of any managerially relevant classification including those that deal with the 'benign/malignant' distinction and those that produce grading schemes.

References

  1. Anderson, W., P. Taylor, R. Fechner, and J. Pinkerton, Endometrial metaplasia associated with endometrial adenocarcinoma. Am J Obstet Gynecol, 1987. 157(597-604).
  2. Breiman, L., J.H. Friedman, and R.A. Olshen, Classification and Regression Trees. 1984, Belmont, CA: Wadsworth International Group.
  3. Demopoulos, R. and M. Greco, Mucinous metaplasia of the endometrium: ultrastructural and histochemical characteristics. Int J Gynecol Pathol, 1983. 1(4): p. 383-90.
  4. Eifel, P., J. Ross, M. Hendrickson, R. Cox, R. Kempson, and A. Martinez, Adenocarcinoma of the endometrium. Analysis of 256 cases with disease limited to the uterine corpus: treatment comparisons. Cancer, 1983. 52(6): p. 1026-31.
  5. Hendrickson, M. and R. Kempson, Endometrial epithelial metaplasias: proliferations frequently misdiagnosed as adenocarcinoma. Report of 89 cases and proposed classification. Am J Surg Pathol, 1980. 4(6): p. 525-42.
  6. Hendrickson, M., J. Ross, P. Eifel, R. Cox, A. Martinez, and R. Kempson, Adenocarcinoma of the endometrium: analysis of 256 cases with carcinoma limited to the uterine corpus. Pathology review and analysis of prognostic variables. Gynecol Oncol, 1982. 13(3): p. 373-92.
  7. Kurman, R. and H. Norris, Evaluation of criteria for distinguishing atypical endometrial hyperplasia from well-differentiated carcinoma. Cancer, 1982. 49(12): p. 2547-59.
  8. Lauchlan, S., Metaplasias and neoplasias of Müllerian epithelium. Histopathology, 1984. 8(4): p. 543-57.
  9. Longacre, T.A., M.H. Chung, D.N. Jensen, and M.R. Hendrickson, Proposed criteria for the diagnosis of well-differentiated endometrial carcinoma. A diagnostic test for myoinvasion. Am J Surg Pathol, 1995. 19(4): p. 371-406.
  10. Longacre, T.A., M.H. Chung, R.V. Rouse, and M.R. Hendrickson, Atypical polypoid adenomyofibromas (atypical polypoid adenomyomas) of the uterus. A clinicopathologic study of 55 cases. Am J Surg Pathol, 1996. 20(1): p. 1-20.
  11. Longacre, T.A. and M.R. Hendrickson, Diffusely infiltrative endometrial adenocarcinoma: an adenoma malignum pattern of myoinvasion. Am J Surg Pathol, 1999. 23(1): p. 69-78.
  12. Mazur, M., Atypical polypoid adenomyomas of the endometrium. Am J Surg Pathol, 1981. 5(5): p. 473-82.
  13. Rorat, E. and R. Wallach, Papillary metaplasia of the endometrium: clinical and histopathologic considerations. Obstet Gynecol, 1984. 64(3 Suppl): p. 90S-92S.
  14. Young, R., T. Treger, and R. Scully, Atypical polypoid adenomyoma of the uterus. A report of 27 cases. Am J Clin Pathol, 1986. 86(2): p. 139-45.