Artifacts and sampling problems like the telescoping artifact seen below.:
Reactive changes: may be caused by infection, physical disruption, recent pregnancy, or recent instrumentation.
Menstrual endometrium: is one of the most common benign endometria overdiagnosed as a precancer or cancer. Breakdown may follow an ovulatory cycle (far left), after anovulation (left center, with fibrin thrombi), and persist into the transitional period between late menses and early proliferative endometrium (right center). Altered cytology is due to piling up of epithelial cells unsupported by stroma, and associated nuclear changes such as loss of polarity which may be accentuated under certain fixation conditions (right, Bouin's fixed).
Polyps :contain irregularly spaced glands whose cytology may differ from native endometrium due to their tendency to have reduced hormonal responsiveness.
Normal late secretory endometrium displays loss of nuclear polarity, nuclear enlargement, and variation in nuclear size which if measured objectively by computerized morphometry overlaps substantially with EIN lesions. Stromal responsiveness to progesterone is not homogenous at all endometrial depths. Lack of stromal pre-decidualization in the deeper functionalis and superficial basalis makes glands appear crowded, and these same glands may display a worrisome cytology and complicated saw-toothed luminal profile.
Hormone exposure: alters endometrial cytology, and architecture. Progesterone exposure may make a bona fide EIN hard to recognize, and a perfectly benign endometrium acquire the crowded architecture and "atypical" cytology of EIN. In its most extreme form, pregnant patients with Arias Stella phenomenon (left) have dramatic epithelial atypia caused by polyploidy, and these areas typically demonstrate minimal stromal decidualization, resulting in very crowded gland architecture. This contrasts to the extreme decidualization and glandular exhaustion caused by the Pill (right)
Premalignant lesions exposed to progesterone tend to display nuclear shrinkage and homogenization of coarse chromatin, with pseudodecidual change responsible for expansion of stromal volume and separation of glands to make them appear less crowded. This is apparent in the example below of an index EIN lesion with squamous morules (left, untreated) seen after six months of high dose progesterone therapy (right). Morules generally do not contain progesterone receptors, and have persisted in this patient to indicate the site of previous EIN lesion. Note the cytology of associated glands pre-and post progesterone. .
Carcinoma : Any of the following features may be present in carcinoma but none are characteristic of EIN. Illustrated from left to right by a series of endometrial carcinomas are: 1)Rambling or mazelike interconnected gland lumens; 2)significant cribriform growth pattern; 3)solid areas of neoplastic, non-squamous, epithelium, 4)Bizarre or high grade nuclei, or 5)myometrial invasion (not illustrated, rarely seen in a biopsy).
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