Uterus

• Similar to that of endometrial endometrioid adenocarcinoma
• Age: fourth to sixth decades (peak fifth)
• Increased circulating estrogen
  • Body mass index (BMI): dose response relationship of BMI ≥ 25 and risk of hyperplasia (Am J Obstet Gynecol 2016;214:689.e1)
  • Nulliparous women (Cancer 1985;56:403, Am J Epidemiol 2008;168:563)
• No race predilection

• Increased endogenous or exogenous estrogen, unopposed by progesterone (Semin Oncol Nurs 2019;35:157)
  • Initially, estrogen has mitogenic effect on both endometrial glands and stroma
  • Chronic estrogenic stimulation without progesterone affects glands to a greater extent → glandular overgrowth (hyperplasia)

• Abnormal or dysfunctional uterine bleeding (Obstet Gynecol Surv 2004;59:368)
• Rare cases asymptomatic

• Endometrial hyperplasia
  • Presence / absence of atypia is most important feature
  • AH / EIN associated with
    • Progression to endometrial endometrioid adenocarcinoma in up to 28% of cases without hysterectomy after 20 year followup (J Clin Oncol 2010;28:788)
    • Concurrent endometrial carcinoma in up to 43% of cases (Cancer 2006;106:812)
      • Majority are low grade (FIGO grade 1) and low stage (FIGO stage IA or IB) (J Obstet Gynaecol Can 2008;30:896)
  • Hyperplasia without atypia: progression to endometrial endometrioid adenocarcinoma in up to 4.6% of cases after 20 year followup (J Clin Oncol 2010;28:788)

• Endometrial hyperplasia without atypia
  • Hysterectomy too aggressive; risk of progression to or simultaneous endometrial endometrioid adenocarcinoma is low (refer to Prognostic factors)
  • Treatments outlined below for AH / EIN acceptable within appropriate clinical context
  • Endometrial hyperplasia without atypia arising in endometrial polyp: polypectomy curative if completely excised under hysteroscopic guidance
  • Endometrial ablation can be used (not adequate alternate therapy for AH / EIN or refractory endometrial hyperplasia without atypia) (Am J Obstet Gynecol 1998;179:569)
• AH / EIN
  • Hysterectomy with or without bilateral salpingo-oophorectomy is definitive treatment
  • If patient desires fertility or is not a surgical candidate
    • AH / EIN arising in endometrial polyp
      • Polypectomy curative if completely excised under operative hysteroscopy
      • Hysterectomy occasionally warranted in appropriate clinical context
    • Progestin therapy: oral or intrauterine device (Am J Obstet Gynecol 2014;210:255.e1, Hum Reprod 2013;28:1231, Obstet Gynecol 2013;121:1165)
      • Latter considered superior for efficacy, compliance and prevention of recurrence
      • Can even be trialed for fertility preservation in cases up to nonmyoinvasive FIGO grade 1 endometrioid adenocarcinoma
    • Metformin controversial (Cochrane Database Syst Rev 2017;10:CD012214)

• Usually not grossly appreciable
• Florid to pseudopolypoid endometrium (similar to that of secretory phase)

Images hosted on other servers:

• Endometrial hyperplasia without atypia (Semin Diagn Pathol 2010;27:199)
  • Architecture
    • Closely packed glands such that gland to stroma ratio is > 3:1 but stroma is still present between glandular basement membranes (however minimal)
    • Variation in gland size with cystic dilatation or irregular luminal contours (budding, angulation, invagination, outpouching, papillary projections)
    • Associated with stromal breakdown (Diagn Cytopathol 2006;34:609)
    • Increased volume of endometrial tissue on biopsy / curetting is typical (especially in postmenopausal patient) but not required for diagnosis
  • Cytologic features
    • Must be assessed in comparison to cytological features of background endometrium (which even in nonneoplastic states can show hyperchromasia, nuclear enlargement and nucleoli due to cyclic hormonal changes)
    • Atypia is not defined with fixed cytologic descriptors but rather considered a cytologic distinction from the surrounding baseline endometrium; this may include metaplastic changes
    • In endometrial hyperplasia without atypia, the cytologic features of the crowded glands must be identical to those of the background endometrium
• AH / EIN
  • Architecture
    • Similar to the spectrum described above for hyperplasia without atypia
  • Cytologic features
    • Definition of cytologic atypia in the endometrium is not static; it is dependent on the appearance of the physiologic baseline endometrium
    • AH / EIN is a clonal expansion of endometrial glands with different cytomorphology than that of surrounding normal endometrium
    • Atypia may manifest as loss of cellular polarity, hyperchromasia, nuclear enlargement or even as benign appearing metaplastic changes (tubal, eosinophilic, mucinous) (Histopathology 2008;53:325)
    • In a focus of crowded glands, the presence of ciliated metaplasia (usually considered reassuring) does not negate the possibility of AH / EIN
    • Diagnosis of AH / EIN in a polyp should be made in cytologic comparison to polyp glands, not the nonpolyp endometrial tissue (Mod Pathol 2005;18:324)

Contributed by Aarti Sharma, M.D.

Images hosted on other servers:

• Benign:
  • Compression artifact:
    • Telescoping and pseudocompression of glands due to procedure / processing artifact may create appearance of packed and back to back glands
    • Absence of peripheral stromal elements to lesion in question is a clue to artificial density
  • Cystic atrophy:
    • Can have similar low power appearance to hyperplastic endometrium with closely apposed and cystically dilated glands but these do not have the irregular contours of hyperplasia
    • Glandular lining is low cuboidal to flattened without mitotic activity, in contrast to proliferative endometrium
    • Stroma is dense and resembles that of endometrium basalis
  • Endometrial polyp:
    • Similar low power appearance in biopsies (by definition, altered, disorganized or irregular glands)
    • Glands can be slightly crowded at baseline in endometrial polyp and should not be diagnosed as hyperplasia
    • Distinct densely fibrotic stroma with thick walled blood vessels
    • Endometrial polyps can contain foci of AH / EIN (see above in Microscopic (histologic) description)
  • Disordered proliferative / anovulatory endometrium:
    • No well delineated criteria
    • Histologically considered as degree below hyperplasia without atypia on a shared morphologic spectrum and distinction is often not reproducible
      • Cystic glandular dilation with focal / diffuse loss of spatial organization
    • Changes are secondary to excess estrogenic influence on the endometrium and should prompt pathologist to search carefully for AH / EIN
    • Both have similar treatment (exogenous progestin)
  • Metaplastic changes:
    • Metaplastic changes must always be interpreted within the context of glandular architecture and background endometrium (as above); their presence is not definitionally benign despite bland cytology
    • Squamous and squamous morular metaplasia
      • When involving nonhyperplastic glands, can create false appearance of solid crowding
      • As in endometrial endometrioid adenocarcinoma, squamous component should be subtracted in assessment of glandular architecture
    • Surface syncytial and eosinophilic metaplasia
      • Similar low power appearance due to cytoplasmic eosinophilia and epithelial proliferation
      • Metaplasia is usually cytologically bland
  • Endometrial stromal / glandular breakdown:
    • Menstrual endometrium may demonstrate altered cytology, such as loss of polarity due to nuclear piling and coarsening of chromatin
    • Collapse of glands creates artificial crowding without stromal scaffolding
    • Presence of glandular aggregation amidst necrotic predecidua can mimic carcinoma
• Malignant:
  • Endometrioid adenocarcinoma, FIGO grade 1:
    • Degree of atypia between the two is usually similar
    • AH / EIN should not have
      • Cribriforming, confluent glands
      • Labyrinthine intraluminal connections
      • Areas of purely solid epithelium
      • Stromal alteration suggesting invasion - desmoplasia (myofibroblasts, edema, inflammation) or necrosis (intervening endometrial stroma replaced by pools of neutrophilic debris)

• Mod Pathol 2000;13:309, WHO Classification of Tumours Editorial Board: Female Genital Tumours, 5th Edition, 2020

The uterine lesion in the image above is commonly associated with which of the following?

1. Anovulatory menstrual cycles
2. Brown-red and firm infiltrative gross appearance
3. Intrauterine device is considered definitive therapy
4. No increased risk of endometrial carcinoma
5. Weak staining for WT1 and GATA3

A. Anovulatory menstrual cycles. The photomicrograph shows an image of endometrioid intraepithelial neoplasia (EIN). Answer B is incorrect because EIN is not grossly appreciable. Answer C is incorrect because progestin eluting IUD is one avenue of treatment for EIN; however, it is not considered definitive. Answer D is incorrect because EIN is associated with an increased risk (up to 40%) of concurrent or subsequent carcinoma. Answer E is incorrect because immunohistochemical stains for WT1 and GATA3 have no role in the diagnosis of EIN.

Comment Here

Reference: Endometrial hyperplasia

Which of the following features is one of the requirements of a diagnosis of endometrial hyperplasia?

1. Crowded glands with minimal residual intervening stroma
2. Diffuse nuclear staining for p53
3. Documentation of a PTEN mutation or loss of PTEN by IHC
4. Glands with cribriforming architecture and cytologic alterations distinct from surrounding glands
5. Loss of mismatch repair proteins

A. Crowded glands with minimal residual intervening stroma. Answer A is correct because the diagnostic criteria for endometrial hyperplasia, as outlined by WHO, includes the presence of a crowded proliferative endometrium and increased gland to stroma ratio. Answer B is incorrect because p53 has no role in the diagnosis of endometrioid intraepithelial neoplasia (EIN). Answer C is incorrect because PTEN abnormality by mutational analysis or IHC is nonspecific and not considered a requirement for the diagnosis of EIN. Answer D is incorrect because glands with cribriform architecture are features of endometrioid carcinoma rather than EIN. EIN, however, does require distinct cytology from the background endometrium. Answer E is incorrect because while loss of mismatch repair proteins may be observed in EIN, it is neither a requirement nor should be employed towards the diagnosis in the absence of appropriate morphologic features.

Comment Here

Reference: Endometrial hyperplasia