**3.1 Endometrial hyperplasia and cancer**

Endometrial cancer is the fourth cancer in women from developed countries [110], and actually there are 2 types of endometrial cancer, with different natural history, carcinogenesis and evolution.

According to the molecular mechanisms, to the dualistic model of endometrial cancer development, first time described by Bokhman [111], the last classification at the Endometrial Cancer Workshop sponsored by the International Society of Gynecological Pathologists in 2016 [112], and the most recent discussion of the International Society of Gynecological Pathologists in 2019 [113] describes low grade and high grade endometrial cancers, both types being discussed to have MHT in perimenopause and late postmenopausal stages of women's life.


**73**

CI: (0.17–0.88).

endometrial cancer risk.

IUS of up to 10 years.

*Endometrial Histology and Safety on Non-Oral Routes of Hormone Therapy...*

The FIGO grading 1, 2 and 3 of endometrioid endometrial adenocarcinomas are actually nominated only in two grades, as follows: former grade 1 and 2 are the actual "low" grade endometrioid endometrial carcinomas, and former grade 3 is the actual "high grade" [119], although FIGO, the ACOG, and the College of American

Hyperplasia and endometrioid endometrial cancer risk is associated to excess levels of estrogen, or to non-balanced/non-opposed estrogens by progesterone/ progestogens-proved by PEPI trial (1996) [122], after the well-known paper of Kurman et al. [32], and recently reconfirmed by the "European Prospective Investigation Into Cancer and Nutrition" [62]. Mutter [106, 109] is describing benign hyperplasia—with low risk for malignancy, type that was discovered in the studies listed in **Table 3** and "Endometrial Intraepithelial Neoplasia" (EIN) the

The terminology of "Endometrial Intraepithelial Neoplasia" (EIN) [109, 116] was previously termed in the World Health Organization system (1994) as atypical endometrial hyperplasia — simple, and complex. There is no direct concordance of WHO to EIN categories because the two strategies employ different criteria that are often nonequivalent [123]. On must remember that approximately 50% of women

The WHO (1994) system largely relies on relatively fixed notions of how atypical endometrial cells appear, whereas an EIN criterion combines crowded architec-

"Endometrial Intraepithelial Carcinoma" (EIC) [125] is considered as precursor for high grade/type 2 endometrial cancer, and it represents malignant transformation of atrophic surface endometrium, discovered in 89% of cases. "Endometrial intraepithelial neoplasia" should never be confused with "endometrial intraepithelial carcinoma", which refers clearly to type 2 endometrial cancer, usually named as serous carcinoma, and is driven by a p53 mutation. Awareness of these 2 entities and their

The data regarding endometrial hyperplasia/cancer on or after non-oral route of MHT are few, but generally they may be comparable to those on oral drugs. The Finnish Cancer Registry [74], which evaluated cancer risk from 1995 to 2007 recorded 1364 type 1 and 38 type 2 endometrial cancers by the end of 2006, and the study analyzed duration and type of regimen, route and type of progestogen: oral/ non oral sequential (10–14 days once a month—"monthly sequential" or every three months—"long-cycle"), or continuous combined (E2 patch or gel plus NETA or LNG), or E2 transdermal + LNG-releasing intrauterine device system (LNG-IUS).

• For use of <5 years, the OR for sequential EPT was 0.67 (95% CI: 0.52–0.86), for continuous E2+ P was 0.45 (CI: 0.27–0.73), and for E2 plus LNG-IUS = 0.39,

• A decreased risk persisted for the use of continuous E2+ P and E2 plus LNG-

The conclusion of the Finnish study was that the use of a continuous rather than a sequential E2-progestogen regimen decreases the risk of endometrial cancer, whereas the route of administration or type of progestin does not differ in terms of

A recent North American study [126] revealed that compared with non-MHT users, cases who reported using E+ P Therapy had lowered all-cause (HR = 0.65, 95% CI = 0.43–0.99) and endometrial cancer-specific mortality (HR = 0.51, 95% CI = 0.26–0.98), study which can be added to a previous study from Sweden [127],

*DOI: http://dx.doi.org/10.5772/intechopen.89046*

Pathologists are considering this grading as standard.

precursor for the endometrioid endometrial/type 1 cancer.

diagnosed with atypical hyperplasia have concurrent carcinoma [124].

ture and a relative change in cytology in the high-risk category.

histologic features is critical for avoiding misclassification [109, 118].

*Endometrial Histology and Safety on Non-Oral Routes of Hormone Therapy... DOI: http://dx.doi.org/10.5772/intechopen.89046*

The FIGO grading 1, 2 and 3 of endometrioid endometrial adenocarcinomas are actually nominated only in two grades, as follows: former grade 1 and 2 are the actual "low" grade endometrioid endometrial carcinomas, and former grade 3 is the actual "high grade" [119], although FIGO, the ACOG, and the College of American Pathologists are considering this grading as standard.

Hyperplasia and endometrioid endometrial cancer risk is associated to excess levels of estrogen, or to non-balanced/non-opposed estrogens by progesterone/ progestogens-proved by PEPI trial (1996) [122], after the well-known paper of Kurman et al. [32], and recently reconfirmed by the "European Prospective Investigation Into Cancer and Nutrition" [62]. Mutter [106, 109] is describing benign hyperplasia—with low risk for malignancy, type that was discovered in the studies listed in **Table 3** and "Endometrial Intraepithelial Neoplasia" (EIN) the precursor for the endometrioid endometrial/type 1 cancer.

The terminology of "Endometrial Intraepithelial Neoplasia" (EIN) [109, 116] was previously termed in the World Health Organization system (1994) as atypical endometrial hyperplasia — simple, and complex. There is no direct concordance of WHO to EIN categories because the two strategies employ different criteria that are often nonequivalent [123]. On must remember that approximately 50% of women diagnosed with atypical hyperplasia have concurrent carcinoma [124].

The WHO (1994) system largely relies on relatively fixed notions of how atypical endometrial cells appear, whereas an EIN criterion combines crowded architecture and a relative change in cytology in the high-risk category.

"Endometrial Intraepithelial Carcinoma" (EIC) [125] is considered as precursor for high grade/type 2 endometrial cancer, and it represents malignant transformation of atrophic surface endometrium, discovered in 89% of cases. "Endometrial intraepithelial neoplasia" should never be confused with "endometrial intraepithelial carcinoma", which refers clearly to type 2 endometrial cancer, usually named as serous carcinoma, and is driven by a p53 mutation. Awareness of these 2 entities and their histologic features is critical for avoiding misclassification [109, 118].

The data regarding endometrial hyperplasia/cancer on or after non-oral route of MHT are few, but generally they may be comparable to those on oral drugs. The Finnish Cancer Registry [74], which evaluated cancer risk from 1995 to 2007 recorded 1364 type 1 and 38 type 2 endometrial cancers by the end of 2006, and the study analyzed duration and type of regimen, route and type of progestogen: oral/ non oral sequential (10–14 days once a month—"monthly sequential" or every three months—"long-cycle"), or continuous combined (E2 patch or gel plus NETA or LNG), or E2 transdermal + LNG-releasing intrauterine device system (LNG-IUS).


The conclusion of the Finnish study was that the use of a continuous rather than a sequential E2-progestogen regimen decreases the risk of endometrial cancer, whereas the route of administration or type of progestin does not differ in terms of endometrial cancer risk.

A recent North American study [126] revealed that compared with non-MHT users, cases who reported using E+ P Therapy had lowered all-cause (HR = 0.65, 95% CI = 0.43–0.99) and endometrial cancer-specific mortality (HR = 0.51, 95% CI = 0.26–0.98), study which can be added to a previous study from Sweden [127],

*Hormone Therapy and Replacement in Cancer and Aging-Related Diseases*

two important aspects to be discussed:

**in MHT**

endometrium and the iatrogenic one.

**3.1 Endometrial hyperplasia and cancer**

history, carcinogenesis and evolution.

white, Caucasian women.

atrophy was after oral HT. The analysis regarding endometrial stroma has revealed

• the increase of stroma the fibroblast-fibrocytic proliferation, and the reduction of fibrosis in all treated cases, indirectly the maintenance of the stroma volume (an important criteria when on discuss about EIN, with volume percentage of stroma <55%). This change makes the difference between normal cycling

• the increase of the granulocyte inflammatory reaction, which is like a pseudodecidualisation, not a sign of endometritis, which need to discover the presence of periglandular plasma cells, and leukocytes. In the natural menstrual cycle the presence in endometrial stroma of the leukocytes infiltration is normal in the premenstrual phase, when starts the decline of estrogen and progesterone, aspect which is rarely discovered, but it is discussed also by Deligdish [104] in sequential regimens, as a probable result of the iatrogenic hormones withdrawal.

**3. Endometrial hyperplasia and endometrial cancer risks in MHT:** 

**immunohistochemistry for biomarkers of endometrial transcriptome** 

Endometrial cancer is the fourth cancer in women from developed countries [110], and actually there are 2 types of endometrial cancer, with different natural

According to the molecular mechanisms, to the dualistic model of endometrial cancer development, first time described by Bokhman [111], the last classification at the Endometrial Cancer Workshop sponsored by the International Society of Gynecological Pathologists in 2016 [112], and the most recent discussion of the International Society of Gynecological Pathologists in 2019 [113] describes low grade and high grade endometrial cancers, both types being discussed to have MHT

• low grade or type 1 or endometrioid endometrial or the "indolent" cancer, which is estrogen dependent, has "atypical endometrial hyperplasia", as precursor (23% cases progress to endometrioid adenocarcinoma), a monoclonal lesion, with microsatellite instability, and *ras* and *PTEN* mutations [106, 107, 109, 114, 115], and PTEN gene loss in up to 65% cases with EIN and in 85% cases with endometrioid carcinoma [116]*,* with estrogen and progesterone receptors at immunohistochemistry analysis [110] discovered more frequent in

• high grade endometrial carcinomas or type 2 are represented by previous FIGO grade 3 endometrioid carcinoma, serous endometrial carcinoma, clear cells endometrial carcinoma, undifferentiated/dedifferentiated carcinoma, and carcinosarcoma. They are non-estrogen dependent, more aggressive, with atrophia or with a polyp rather than hyperplasia as precursor, and they are non-responsive to progestins [32]. They contain *p53* mutations and abnormal accumulation of p53 protein, and absence of ERs, PRs [117, 118]. In cases with serous endometrial carcinoma the estrogen level is low, but SHBG is high, women are 6 years elder, with lower BMI than the cases with type 1.

in perimenopause and late postmenopausal stages of women's life.

**72**

#### *Hormone Therapy and Replacement in Cancer and Aging-Related Diseases*

which investigated tumor grade and depth of myometrial invasion, and 5-year relative survival in postmenopausal endometrial cancer patients. In this analysis, ever use of any MHT entailed lower risks of having moderately and poorly differentiated tumors. The lowest OD for poorly differentiated tumors were seen for ever users of cyclically combined estrogen-progestin [OR = 0.23 (95% CI: 0.07–0.73)]. Ever users of any form of MHT, particularly medium potency MHT users, had significantly lower risks for tumors with deep myometrial invasion, and adjusted estimated relative excess HRs revealed significantly improved survival for ever users of any form of MHT [RER = 0.40 (95% CI: 0.16–0.97)]; in particular ever users of any form of oestrogens [RER = 0.38 (95% CI: 0.15–0.99)]. The authors' conclusions were that MHT ever used induces a more favorable tumor characteristics, less aggressive and with better patients' survival.
