pre-treatment workup required for the management of carcinoma endometrium

1. CARCINOMA
ENDOMETRIUM-
PRETREATMENT
MANAGEMENT AND WORK-
UP
BY- DR. PALLAVI JAIN
MODERATOR- DR. NILESH MANI

2. CONTENTS
❖ INTRODUCTION
❖ ANATOMY OF ENDOMETRIUM
❖ PATHOPHYSIOLOGY OF ENDOMETRIAL CARCINOMA
❖ STAGING OF CARCINOMA ENDOMETRIUM
❖ PRETREATMENT WORKUP

3. INTRODUCTION
❖ Carcinoma endometrium is the most common gynecological cancer in
developed countries.
❖ In developing countries, cervical cancer still remains the leading gynecological
cancer but recently there has been an increase in the incidence of endometrial
cancer.
❖ The rise in endometrial cancer in India is mainly attributed to changing trends in
the lifestyle and reproductive profile of women, especially in urban areas.
❖ The majority of cases present in the 6th and 7th decades of life, with the mean
age being 60 years at the time of diagnosis.
REF: PEREZ AND BRADY PRINCIPLE AND PRACTICE OF RADIATION ONCOLOGY 8 ED

4. ANATOMY
❖ UTERUS- HOLLOW, MUSCULAR ORGAN
❖ LENGTH- 8 cm WIDHT- 5 cm THICKNESS- 2.5 cm WEIGHT- 30-40gm

5. RELATIONS OF THE UTERUS
❖ Anteriorly
1. body of uterus - uterovesical pouch and the superior surface of urinary bladder.
2. supravaginal portion of cervix -posterior surface of urinary bladder.
3. vaginal portion of cervix- anterior fornix of the vagina.
❖ Posteriorly
1. body of uterus -rectouterine pouch with coils of ileum and sigmoid colon in it.
2. supravaginal portion of cervix -rectouterine pouch(coils of ileum and sigmoid colon)
3. vaginal portion of cervix -posterior fornix.
❖ Laterally
1. body of uterus -the broad ligament and uterine artery and vein.
2. supravaginal portion of cervix- ureter and uterine artery.
3. vaginal portion of cervix -lateral fornices of the vagina.

7. ARTERIAL SUPPLY
❖ mainly by two uterine arteries and partly by two ovarian arteries.

8. Venous drainage
The veins of the uterus correspond to arteries.
They form venous plexus along the lateral borders of the uterus, which drains
into internal iliac veins through uterine and vaginal veins.

9. LYMPHATIC DRAINAGE
❖ fundus and upper part of the body-
❖ Most pre- and para-aortic lymph nodes along the ovarian vessels
❖ Few lymphatic vessels from the lateral angles of the uterus drain into superficial inguinal
lymph nodes along the round ligaments of the uterus.
❖ lower part of the body-external iliac nodes via broad ligament.
❖ From cervix, on each side the lymph vessels drain in three directions:
(a) Laterally- external iliac and obturator nodes by passing parametric tissue, few of these
vessels are intercepted by paracervical nodes.
(b) Posterolaterally- internal iliac nodes by passing along the uterine vessels.
(c) Posteriorly- sacral nodes by passing along the uterosacral ligaments.

11. Risk factors of endometrial carcinoma
❖ Age - peak age 55 and 70 years
❖ Race- white race (less in Indians and south asians)
❖ Obesity- BMI> 30kg/m2 (RR- 2.5 – 4.5)
❖ Diet- high fat and low fibre diet
❖ Diabetes mellitus - non insulin dependent (RR-2)
❖ Parity -more in nulliparous and infertile (RR-3)
❖ Hypertension- RR- 2 ;As common association with obesity and diabetes (corpus cancer
syndrome)
❖ Menstrual history -Early menarche(RR-1.5-2), late menopause(RR – 2-3), long menstruation span

12. ❖ Hyperoestrogenic states -
❖ Oestrogen replacement therapy without progesterone
❖ PCOS
❖ oestrogen-producing tumours
❖ Lynch syndrome- Inherited autosomal dominant disease (20-50% lifetime risk)
❖ Use of tamoxifen-
❖ Pre menopausal woman- antiestrogenic effect
❖ Postmenopausal women- weak estrogenic
❖ Family history-Family history of endometrial, ovarian and breast cancers
❖ Prior pelvic RT- RR-8
❖ Molecular alterations -Mutation of the PTEN and p53 genes is a frequent event in
endometrial cancers

13. Premalignant Lesions of the Endometrium
Endometrial hyperplasia
❖ Proliferative lesion of the endometrium with architectural complexity and
cytologic atypia.
❖ Usually diffuse but it can occur focally
❖ World Health Organization classification of endometrial hyperplasia
❖ Hyperplasia(typical)
❖ Simple hyperplasia without atypia (<1%)
❖ Complex hyperplasia without atypia (3%)
❖ Atypical hyperplasia
❖ Simple atypical hyperplasia (8%)
❖ Complex atypical hyperplasia (29%)

14. WORLD HEALTH ORGANISATION
HISTOLOGIC CLASSIFICATION OF EPITHELIAL
TUMORS OF UTERUS
WORLD HEALTH ORGANISATION
HISTOLOGIC CLASSIFICATION OF MESENCHYMAL
AND MIXED TUMORS OF UTERUS

15. Endometrioid Adenocarcinoma
❖Most common type accounting for almost three-fourths of the cases.
❖Resembles a proliferative phase endometrium
❖Small, back-to-back glands without the stroma intervening.
❖Variants-
1. Endometrioid Adenocarcinoma with Squamous Differentiation
❖ At least 10 % of the tumour should have a squamous element in a well-sampled tumour to
qualify
❖ There are no differences in clinical features of this variant.
❖ graded on the basis of glandular component -well, moderately or poorly differentiated
❖ treatment is the same as for endometrioid carcinoma of comparable stage.

16. 2. Villoglandular Carcinoma
❖ papillary architecture with cells resembling usual endometrioid carcinoma.
❖ mild to moderate nuclear atypia.
❖ mitosis is variable
❖ myometrial invasion is usually superficial.
3. Secretory Carcinoma
❖ similar to secretory phase endometrium
❖ columnar cells that have abundant vacuolated cytoplasm.
❖ may have cribriform or villoglandular pattern.
❖ cellular atypia is minimal.
❖ low grade and prognosis is good
4. Ciliated Cell Carcinoma
❖ rare variant
❖ malignant glands lined by ciliated cells
Photomicrograph of serous
adenocarcinoma – nuclei are typically
poorly differentiated, macronucleoli

17. ❖ Mucinous Carcinoma
❖ adenocarcinoma with abundant intracellular mucin.
❖ more than 50 % of the cell population must contain mucin within the cytoplasm
❖ PAS positive and diastase resistant
❖ low grade with a good prognosis.
❖ Serous Carcinoma
❖ older women
❖ papillary architecture
❖ cytologic atypia is marked
❖ Psammoma bodies may be present.
❖ aggressive and have a poor prognosis.
❖ high-grade neoplasms and have a predilection for peritoneal spread, akin to ovarian serous
adenocarcinoma .
Papillary serous adenocarcinoma

18. ❖ Clear Cell Carcinoma
❖ prevalence is low
❖ elderly women
❖ exhibit solid, tubular, papillary and cystic pattern with typically hobnail-shaped cells.
❖ Nuclear atypia is moderate to marked.
❖ The clear cytoplasm -glycogen present in the cells -PAS staining with diastase digestion.
❖ high- grade tumours with aggressive behaviour and poor prognosis
❖ Squamous Cell Carcinoma
❖ extremely rare
❖ should be no connection with the squamous epithelium of the cervix, squamous cell carcinoma
should not be present in the cervix, and endometrial carcinoma should not be present in the
endometrium.
❖ strong association with pyometra and cervical stenosis and ichthyosis uteri has been seen in post-
menopausal women.
❖ aggressive tumour
❖ associated with deep myometrial invasion and extrauterine extension.
Clear cell carcinoma

19. ❖ Transitional Cell Carcinoma
❖ composed of cells resembling urothelial transitional cells.
❖ found admixed with another type of carcinoma, usually endometrioid.
❖ immunoprofile supports Müllerian rather than urothelial differentiation.
❖ Small Cell Carcinoma
❖ resembles small cell carcinoma of the lungs and other organs
❖ positive for neuroendocrine markers and for cytokeratin.
❖ Undifferentiated Carcinoma
❖ The tumour lacking any evidence of differentiation is defined as undifferentiated carcinoma as per WHO.
❖ These tumours have to be differentiated from small cell neuroendocrine tumours, large cell lymphoma,
lymphoepithelioma-like carcinoma and undifferentiated component of other endometrial carcinomas.
UNCOMMON SUBTYPES

20. Molecular biology
❖ Based on molecular biology of endometrial cancer ,it is divided into two distict
types-
❖ Type 1
❖ Type 2

21. Type 1 Endometrial Carcinoma:
❖ Comprise 80% of uterine carcinoma.
❖ Estrogen responsive
❖ Pre- or perimenopausal age group
❖ Endometrioid histology
❖ Usually well differentiated.
❖ Linked with chronic and unopposed estrogen exposure -obesity, anovulatory cycles, infertility, and
estrogen- secreting tumors.
❖ Favorable prognosis with >90% 5-year survival rate
❖ Characterized by K-RAS over expression, PTEN, PiK3CA, K-RAS mutations, and microsatellite
instability.

22. Type 2 Endometrial Carcinoma:
❖ 10-20% of cases
❖ Estrogen independent
❖ Arise in an atrophic endometrial background.
❖ Old, postmenopausal, multiparous, non-obese, smokers, and tamoxifen users.
❖ The histological types include grade 3 endometrioid adenocarcinoma, serous, clear cell, mucinous and
squamous varieties.
❖ Aggressive tumors
❖ Deep myometrial invasion and extrauterine spread.
❖ Worse prognosis with a recurrence rate of 50% and overall survival (OS) of 35%.
❖ Genetic alteration in E-cadherin, p53 and HER2/neu expression.

23. TNM AND FIGO STAGING
The staging system given by FIGO has evolved over time from clinical staging in 1971 to surgico-pathological staging in
1988 and finally surgical staging in 2009

24. Cases should also be stratified based on degree of differentiation
•G1: 5% or less of a non-squamous or non-morular solid growth pattern
•G2: 6%-50% of a non-squamous or non-morular solid growth pattern
•G3: more than 50% of a non-squamous or non-morular solid growth pattern

25. FIGO Staging
of endometrial
carcinoma

26. CLINICAL FEATURES
❖ Abnormal uterine bleeding in younger women and postmenopausal bleeding
in older women.
❖ Occasionally asymptomatic women may be diagnosed during investigation
for infertility.
❖ Clinical presentation with advanced disease includes urinary or rectal
bleeding, constipation, pain, lower extremity lymphedema, abdominal
distention due to ascites, hepatomegaly, jaundice, cough and/or hemoptysis.

27. DIAGNOSIS
❖ History and clinical examination
❖ CBC including platelets and Blood sugar examination
❖ Liver function and renal function tests
❖ Chest x-ray
❖ Urinalysis
❖ Viral markers
❖ Office endometrial biopsy
❖ Pap smear
❖ Transvaginal ultrasound

28. ❖ Color Doppler
❖ Sonohysterogram
❖ Hysteroscopy and guided biopsy
❖ Dilatation and curettage
❖ CECT of the abdomen and pelvis
❖ MRI of the abdomen and pelvis
REF: NCCN 2016 and ESMO 2015

29. • Serum Cancer Antigen 125 (CA 125) -
• elevated in extrauterine spread of the disease especially nodal involvement in
high risk types
• monitoring the clinical response after therapy in selected patients.
• Serum Human Epididymis Protein (HE4) -
• correlate with aggressive types of disease
• identifying high risk endometrial cancer cases.
• detecting early disease recurrence
• Immunohistochemistry (IHC) and microsatellite instability (MSI) screening to
identify individuals at risk for Lynch syndrome.
• FDG PET-CT - suspected distant metastases
Special investigations

30. HISTORY AND CLINICAL EXAMINATION
❖ General physical examination is to be done, including assessment of lymph
node enlargement (supraclavicular and inguinal lymph nodes) and breast
examination
❖ complete systemic and gynecological examination
❖ per speculum
❖ per vaginum
❖ per rectum
❖ bimanual pelvic examination: assessment of uterine size and mobility, and
involvement of cervix, parametrium, lateral pelvic wall, bladder or rectum.

31. BIMANUAL PALPATION OF UTERUS PER SPECULUM EXAMINATION

32. Office Endometrial Biopsy
❖ The first step in the evaluation
❖ Different devices -Novak curette, Pipelle endometrial suction
curette, and Vabra aspirator
❖ The yield of office endometrial biopsy can be increased by
combining it with office hysteroscopy especially in small
lesions .
❖ Disadv-The success of the procedure is affected by many
factors like cervical stenosis, alteration of the endometrial
cavity by the submucous fibroids, and the size of the lesion
itself.
❖ False-negative rate -10 %

33. PAP SMEAR
❖ If clinical examination does not reveal any obvious
cause of postmenopausal bleeding, a Pap smear
should be taken before doing the bimanual
examination.
❖ Atypical glandular cells (AGC) reported on Pap
smear are known to be associated with
endocervical, endometrial, ovarian, or fallopian
tube cancers 3–17 % of the time.
❖ These women should undergo a fractional
curettage and pelvic imaging to rule out these
cancers

34. Transvaginal Ultrasound
❖ A normal TVUS decreases the pretest probability of endometrial cancer from 10
to 1 % post test among postmenopausal women with vaginal bleeding .
❖ Society of radiologists in ultrasound defines endometrial thickness of 5mm or
greater as being abnormal
❖ negative predictive value (99 %)
❖ positive predictive value (57 %)
❖ Endometrial thickness-diffuse or focal.
❖ Diffuse -endometrial hyperplasia or carcinoma - non-focal blind biopsy for
diagnosis
❖ focal -polyps(benign or malignanT)- requires hysteroscopic-guided biopsy.
❖ Disadv- limited in premenopausal women due to endometrial thickness
fluctuates depending on level of hormones
Normal thin endometrium
Thickened endometrium

35. ❖ Tumor spread within the uterus can be assessed by TVUS by the virtue of its
high resolution, but extrauterine spread and nodal involvement cannot be
assessed efficiently owing to its poor tissue penetration.
❖ high levels of accuracy in detecting deep myometrial invasion (99 %) and
cervical extension (96 %)
❖ intrauterine sonography using high-frequency micro-tip probe inserted
transcervically have improved accuracy in assessing depth of myometrial
invasion when compared to TVUS .

36. Sonohysterography
❖ TVUS when performed after installing sterile normal
saline into the endometrial cavity to enable better
visualization of lesions like endometrial polyps,
submucous fibroids, adhesions, and others.
❖ sensitivities of 89–98 %
❖ specificities of 46–88 %
❖ good negative predictive value for detecting malignancy.
❖ positive predictive value for cancer prediction is very
poor (16 %) which implies that it is very good at
detecting benign conditions.
Normal endometrium
Typical endometrium
cancer

37. Color Doppler
❖ Color Doppler used along with TVUS aids in the
diagnosis of endometrial malignancy.
❖ distinguish between malignant and benign conditions.
❖ Broad-based lesions with diffuse high level of
vascularity - malignant lesions
❖ single feeding vessel in the stalk of a focal lesion
with low vascularity -benign condition (polyps)
❖ Doppler Vs gray-scale TVUS -abnormal endometrial
thickness alone is a better predictor of endometrial
pathology than Doppler analysis

38. Hysteroscopy and Guided Biopsy
❖ Hysteroscopy enables visualization and guided biopsy
especially in small early lesions which can be easily
missed on routine office endometrial biopsy .
❖ To evaluate falsely thickened endometrium of women on
tamoxifen which is due to subendometrial edema .
❖ Good sensitivity -86 %
❖ Good specificity -99 %
❖ negative predictive value - 99 %
❖ positive predictive value - 72 %
Fig-Hysteroscopic image of
endometrial malignancy

39. Dilatation and Curettage
❖ Dilatation and curettage was the recommended diagnostic test for evaluation of abnormal
bleeding before office endometrial biopsy took over.
❖ indications for
❖ inability to perform office endometrial biopsy due to patient distress
❖ cervical stenosis
❖ anatomical factors like submucous fibroids.
❖ Day care procedure done under anesthesia( local (paracervical block) or general)
❖ Adv-Hysteroscopic visualization during the procedures enables sampling of smaller lesions.

40. Magnetic Resonance Imaging (MRI)
❖ MRI is the most important imaging investigation for pre-op staging of EC.
❖ The accuracy of MRI in determining myometrial invasion, cervical involvement, and extra-
uterine spread (better than that of CECT or TVUS)
❖ MRI is 90 % accurate in predicting myometrial invasion and 80 % accurate for cervical
involvement.
❖ For lymph node metastasis-
❖ Sensitivity- 43.5%
❖ Specificity- 95.5%
❖ Errors in assessing myometrial invasion can occur in women with fibroids and adenomyosis and
in women with distension of the endometrial cavity.
❖ contrast-enhanced MRI (gadolinium) performs better than plain MRI.
REF: PEREZ AND BRADY PRINCIPLE AND PRACTICE OF RADIATION ONCOLOGY 8 ED

42. CECT
❖ CECT has a limited role in evaluating patients with
early disease.
❖ Advantage of CECT –resolution is not
compromised by bowel or patient motion when
compared to MRI
❖ detect distant parenchymal metastases, peritoneal
implants, and malignant ascites

43. Accuracy of imaging in the workup of endometrial Ca
Imaging modality
Cervical stromal
involvement %
Myometrial invasion % Distant spread
USG (1) 69 68 POOR
MRI (2) 80 90 GOOD
CECT (3) 58 76 GOOD
REF: Current Concepts in Endometrial Cancer (2017, Springer Singapore)

44. PET-scan
❖ Positron emission tomography (PET) -not found to be useful in early endometrial
cancer because of its limited ability in detecting micro-metastases in normal-sized
nodes
❖ Sensitivity for nodal metastases of 63 %
❖ Specificity of 98 %
❖ However, when used along with CECT or MRI, FDG PET images performed better in
detecting extra-pelvic and nodal metastases
❖ currently research is ongoing regarding the role of fusion PET-CT scanning for pre-op
staging of endometrial Ca

45. PROGNOSTIC FACTORS:
❖FiGO stage
❖Age
❖Histological type and grade, nuclear grade, myometrial invasion
❖Cervical stromal invasion
❖Lymphovascular space invasion
❖Tumor size >2 cm
❖Positive peritoneal cytology
❖Hormone receptor status
❖DNA ploidy and other biological markers
However, nuclear grade, hormonal status, DNA ploidy, peritoneal wash cytology are not
independent prognostic factors.

46. Conclusion
❖ Diagnosis of endometrial carcinoma is easily accomplished by simple
modalities like transvaginal ultrasonography and endometrial biopsy.
❖ Advanced imaging techniques like MRI, CECT, and FDG PET have no role
in diagnosis but serve to stage the disease preoperatively to optimize
treatment.