Endometrial cancer

1. Endometrial
Carcinoma

2. Introduction
• One of the commonest malignancy of the
female genital tract, especially in developed
countries
• India – 3rd (after cervical & ovarian
malignancies)
• Peak incidence – 6th & 7th decade of life
• Average – 60 years
• Post menopausal – upto 80%
• Below 40 years - 5%
• 5 year survival rate – Approximately 75%

3. Epidemiology
Two pathogenetic types –
• Type I – History of exposure to unopposed
estrogen
Hyperplastic endometrium
Carcinoma
- Better differentiated – more favourable
prognosis
- Younger age group
- 75% - 85%

4. • Type II – Without history of estrogenic
stimulation
–Usually occurs in the background of an
atrophic endometrium
–Older & thin women
–Less differentiated
–Poorer prognosis

5. Risk Factors
• Family history / Lynch II syndrome
– 40-60% lifetime risk
• Nulliparity
– 2 to 3 times higher risk
• Early menarche / Late menopause
– Before 12 years / After 52 years
• Unopposed estrogen therapy
– Increases risk 4-8 times

6. • Obesity
Androstenedione
Estrone
- SHBG Unbound biologically active hormone
- Insulin binding globulin insulin + IGF
- Adipose tissue secretes inflammatory factor adipokines
insulin resistance
- Adiponectin inhibits proliferative pathways; level is
inversely correlated with fat mass
(Aromatization in fat)

7. • Diabetes Mellitus
– Hyperinsulinemia / insulin resistance
• PCOS
– Obesity / Insulin resistance / anovulatory cycles
• Tamoxifen therapy
– Increases risk 2-3 times
– Anti estrogenic / modest estrogenic
• ?Hypertension
– Inhibition of apoptosis
– Not consistent as an independent risk factor
• Atypical endometrial hyperplasia

8. Endometrial Hyperplasia
• Represents a spectrum of morphologic and
biologic alterations of the endometrial glands
and stroma
• Protracted estrogen stimulation in the absence
of progesterone influence
• Important clinically because
– Abnormal uterine bleeding
– Associated with estrogen producing ovarian tumour
– Result from hormonal therapy
– Precede or occur simultaneously with endometrial
cancer

9. Type of Hyperplasia Progression
to cancer (%)
Without Atypia
- Simple (cystic without atypia) 1
- Complex (adenomatous without atypia) 3
With Atypia
- Simple (cystic with atypia) 8
- Complex (adenomatous with atypia) 29
WHO Classification (1994)
• Based on glandular complexity and nuclear atypia

10. Drawbacks
• Descriptive and their interpretation does not suggest
any specific management algorithms
• Diagnosis often overlap
• Resulting in hysterectomies performed for
hyperplasia without atypia or progestogen treatment
administered for atypical hyperplasia
• 25 – 43% atypical hyperplasia during endometrial
biopsy or curettage specimen will have well
differentiated endometrial carcinoma during
hysterectomy

11. WHO Classification (2014)
Type of Hyperplasia
Non-atypical endometrial hyperplasia (benign
hyperplasia)
Atypical endometrial hyperplasia or Endometrial
Intraepithelial Neoplasia (EIN) / well differentiated
carcinoma
• Non-atypical hyperplasia should generally be treated
conservatively
• Atypical hyperplasia/endometrioid intraepithelial
neoplasia should generally undergo total
hysterectomy

12. Treatment of Endometrial Hyperplasia
• NON-ATYPICAL ENDOMETRIAL HYPERPLASIA
– Risk of progression to cancer < 5% over 20 years
– Reversible risk factors should be identified and
addressed
– Observation alone with follow-up endometrial
biopsies
– Treatment with progestogens has a higher disease
regression rate
– Indicated in women who fail to regress following
observation alone and in symptomatic women
with abnormal uterine bleeding

13. • The LNG-IUS
– First-line medical treatment
– Has higher disease regression
– More favourable bleeding profile with fewer
adverse effects
• Continuous progestogens
– Women who decline the LNG-IUS
– Medroxyprogesterone 10–20 mg/day or
Norethisterone 10–15 mg/day
• Treatment duration - minimum of 6 months

14. Follow up
• Endometrial surveillance
– Minimum of 6-monthly intervals
– At least two consecutive 6-monthly negative
biopsies
• Recurrence of abnormal vaginal bleeding after
completion of treatment may indicate disease
relapse
• Higher risk of relapse – 6 monthly
endometrial biopsies are recommended. Once
2 consecutive negative biopsies long-term
follow-up annual endometrial biopsies

15. • Indications of Hysterectomy
– Progression to atypical hyperplasia
– No histological regression of hyperplasia despite
12 months of treatment
– Relapse
– Persistence of bleeding symptoms
– Patient declines surveillance or comply with
medical treatment
• Endometrial ablation - not recommended as
complete and persistent endometrial destruction cannot
be ensured and intrauterine adhesion formation may
preclude future endometrial histological surveillance

16. • ATYPICAL ENDOMETRIAL HYPERPLASIA
– Total Hysterectomy with/without BSO
– Women wishing to retain their fertility should be
counselled
– Pre-treatment investigations to rule out invasive
endometrial cancer or co-existing ovarian cancer
– First line - LNG-IUS
– Second line - Oral progestogens
– Once fertility is no longer desired - hysterectomy

17. Follow up
• Routine endometrial surveillance
– Should include endometrial biopsy
– Review intervals every 3 months until two
consecutive negative biopsies
• Long-term follow-up with endometrial biopsy
every 6–12 months until a hysterectomy is
performed.

18. Screening & Surveillance
• Screening of all high risk individuals - not
advised
• Early diagnosis, if patient presents early results
in a high cure rate
• Work up of AUB even in women < 40 years
should include endometrial biopsy
• Pap smear – inadequate
• Endometrial cytology - insensitive

19. • Lynch II syndrome / HNPCC
– Defective mismatch repair (MMR) proteins
resulting in mutations that degrade the self repair
capability of DNA
– Inherited as autosomal dominant
– Annual pelvic examination, TVS, endometrial
biopsy beginning at 30 to 35 years
– Prophylactic hysterectomy with BSO is an
effective primary prevention strategy in females
with MSH6 mutations

20. Symptoms
• Abnormal bleeding
• Discharge PV
• Hematometra / pyometra
• Pressure symptoms
• Colicky pain – pyometra or metastatic spread
• < 5% are asymptomatic
Post menopausal pyometra – 50% risk of
malignancy

21. Signs
• Physical examination – usually unremarkable
• Associated constitutional factors – Obesity &
hypertension
• Peripheral lymph nodes & breast
• Abdominal examination – ascitis, lump in
hepatic or omental metastasis
• Bimanual recto-vaginal examination – size and
mobility of uterus, adnexa for masses,
parametria for induration, POD for nodularity

22. Diagnosis
“A case of post menopausal bleeding should
be considered as endometrial carcinoma
unless proven otherwise”
• History & clinical examination
• Blood test – CBC, RBS, TSH
• TVS / Colour doppler study
– Endometrial thickness > 4 mm
– Polypoidal endometrial mass
– Hyperechoic endometrium with irregular lining
– Vascularity with vascular resistance
– Intra-cavitary fluid

23. • Outpatient endometrial aspiration biopsy
– Pipelle curette
– Diagnostic accuracy 90% - 98%
– Less pain
– Inexpensive
• Pap smear
– Only 30% - 50% have abnormal pap results
• Ca-125
– Raised in late stages / metastatic disease

24. • D & C
– Cervical stenosis
– Patient tolerance does not allow aspiration biopsy
– Bleeding recurs after a negative aspiration biopsy
– Inadequate specimen
• Hysteroscopy
- Identifying polyps and submucous myomas
- Biopsy can be taken under direct vision
• Chest X-Ray

25. • Further investigations
– CT Scan
– MRI
– PET Scan

26. Histologic classification
• Endometrioid Adenocarcinoma
- Accounts for about 80 %
- Usually well differentiated with good prognosis
- Variants
1) Squamous differentiation – 15-25%
2) Villoglandular or papillary – 2%
3) Secretory - 1%

27. • Mucinous Carcinoma
– About 5%
– More than half of the tumour is composed of cells
with intracytoplasmic mucin
– Well differrentiated with good prognosis
• Serous Carcinoma
– Also referred to as uterine papillary serous
carcinoma
– About 3% - 4%
– High risk lesion with high risk of recurrence
– Often associated with lymphovascular space and
deep myometrial invasion

28. • Clear Cell carcinoma
– Less than 5%
– Characteristically occur in older women
– Prognosis is poor, overall survival rate vary
between 33% - 64%
– Complete surgical staging is important as 52% of
patients with stage I have metastatic disease

29. • Squamous Carcinoma
– Rare
– Often associated with cervical stenosis, chronic
inflammation and pyometra
– Prognosis is poor
– Estimated survival rate in patients with clinical
stage I disease is 36%

30. FIGO Definition for Grading of
Endometrial Carcinoma
Grade 1 5% or less of the tumour shows a solid
growth pattern
Grade 2 6-50% of the tumour shows a solid growth
pattern
Grade 3 > 50% of the tumour shows a solid growth
pattern
• Applicable to all endometroid carcinomas and its
variants, and to mucinous carcinoma
• Serous, Clear cell and Squamous cell carcinomas –
nuclear grading takes precedence

31. Pre-treatment Evaluation
• History & Physical examination
- Enlarged or suspicious lymph nodes, abdominal
masses, possible areas of cancer spread
• Chest X-Ray
• ECG, CBC, LFT, RFT, Electrolytes, RBS
• TSH

32. • Optional –
- CT
- MRI & USG
- CA 125
- Cystoscopy
- Colonoscopy
- IVU
- Barium enema
if clinically indicated

33. FIGO Staging of Endometrial Carcinoma
Stage I Tumour confined to uterine corpus
IA No or less than half myometrial invasion
IB Invasion equal to or more than half of the myometrium
Stage II Tumour invades cervical stroma, but does not extend beyond the uterus
Stage III Local and/or regional spread of the tumour
IIIA Tumour invades the serosa of the corpus uteri and/or adnexae
IIIB Vaginal and/or parametrial involvement
IIIC Metastases to pelvic and/or para-aortic lymph nodes
IIIC1 Positive pelvic lymph nodes
IIIC2 Positive para-aortic lymph nodes with or without positive pelvic lymph
nodes
Stage IV Tumour invades bladder and/or bowel mucosa, and/or distant
metastases
IVA Tumour invasion of bladder and/or bowel mucosa
IVB Distant metastases, including intra-abdominal metastases and/or inguinal
lymph nodes

34. Spread
• In general, spread from the uterine cavity is slow,
probably because lymphatics of the functional layer
are small and sparsely distributed
• Local spread
– Slow invasion of the myometrium is the
commonest spread
– May produce considerable uterine enlargement
– May involve the vaginal vault

35. • Lymphatic spread
– Most important prognostic factor in early stage
disease
– 6 fold higher chance of developing recurrent
cancer
– Stage I – about 10% will have pelvic and 6% will
have para-aortic lymph node metastasis
– 5 year disease free survival rate for patients with
lymph node metastasis is 54%, compared with
90% for patients without lymph node metastasis

36. • Venous spread
– Not a common feature
– Might account for the occasional appearance of
low vaginal metastasis
• Tubal spread
– May account for isolated ovarian metastasis
– Malignant cells can pass along the tube in the
same way as peritoneal spill can occur during
menstruation

37. Prognostic Variables
• Age
- Better prognosis in younger patients
- Increased risk for recurrence in older patients
• Histologic type
- Non endometroid carry increased risk for
recurrence and distant spread
• Histologic grade
- Increasing tumour anaplasiais associated with deep
myometrial invasion, cervical extension, lymph node
metastasis, local recurrence and distant metastasis

38. • Tumour size
- Significant factor for lymph node metastasis and
survival
• Hormone receptor status
- Tumour positive for one or both receptor – longer
survival time
• DNA Ploidy and Proliferative Index
- Proportion of nondiploid tumours increases with
stage, lack of tumour differentiation and depth of
myometrial invasion

39. • Myometrial invasion
- Increasing depth of invasion is associated with
increasing likelihood of extrauterine spread and
recurrence
• Lymphovascular space invasion
- Independent risk factor for recurrence and death
• Isthmus & Cervical extension
- Associated with an increased risk for extrauterine
disease, lymph node metastasis and recurrence
• Peritoneal Cytology
- Seems to have an adverse effect on survival only if
the endometrial cancer has spread to the adnexa,
peritoneum or lymph nodes

40. • Stage IIIA
- Adnexal or uterine serosal involvement – other
poor prognostic factors that place them at high risk
for recurrence
• Lymph node metastasis
- Most important prognostic factor in clinical early
stage disease
• Intraperitoneal metastasis
- Gross intraperitoneal spread is highly corellated
with lymph node metastasis

41. OPTIONS FOR THERAPY
• Surgical
• Radiotherapy
• Chemotherapy
• No therapy

42. PREOPERATIVE ASSESSMENT &
PREPARATION
• Thorough history & physical examination
• Previous medical history
• Symptoms of metastatic disease
– Abdominal or pelvic pain
– Bowel or bladder dysfunction
– Lower extremity pain or swelling
– Shortness of breath or cough

43. Surgical Treatment
• Peritoneal cytology
• Hysterectomy
• Bilateral salpingoopherectomy
• Staging
• Omentectomy + appendectomy + peritoneal
biopsy – nonendometroid cancer
• Lymphadenectomy

44. • Indications of Lymphadenectomy based on
– Type
– Grade
– Tumour size
– Extent of myometrial invasion
– Presence of extra uterine disease

45. • Bilateral pelvic & para aortic
lymphadenectomy
– Evidence of extra uterine disease
– FIGO Grade 3
– Non endometroid tumours
– Tumour invasion > 50% of the thickness of
myometrium
• Only bilateral pelvic lymphadenectomy
– Absence of above risk factors
– Tumour size > 2 cm
– Para aortic lymphadenectomy to be done only if
pelvic nodes were positive

46. • Lymphadenectomy not required
– Absence of above factors
– Tumour size < 2 cm
– Absence of cervical involvement

47. Vaginal Hysterectomy
• Indications
- Extremely obese
- Poor medical status
- Extensive utero-vaginal prolapse
• Vaginal hysterectomy + BSO may be
considered adequate
– Endometroid grade 1 or 2
– < 50% myometrial invasion
– Tumour size < 2 cm
Particularly suitable for patients who are at low risk
for extra uterine spread

48. • Laparoscopic management
• Robotic assisted surgery
• Thromboprophylaxis
Should be considered in patients > 40 years with
- h/o DVT or pulmonary embolism
- Varicose vein
- Obesity
- Estrogen therapy
- Prolonged surgery

49. Radiation therapy as primary
treatment
• 5 – 15% unsuitable for surgery due to medical
comorbidities
• Intracavitary radiation
• External beam radiation therapy

50. MODALITIES OF POSTOPERATIVE
TREATMENT
• Observation
- Grade 1, 2 lesions without myometrial invasion
• Vaginal Vault Radiation
- Grade 3 & lymphovascular space invasion in stage I
• External Pelvic Radiation
- Extrauterine pelvic disease – including adnexal
spread, parametrial involvement, pelvic lymph node
metastases

51. • Extended Field Radiation
- Histologically proven para aortic node metastases
and no other evidence of spread outside the pelvis
- Entire pelvis, common iliac lymph nodes, para
aortic lymph nodes
• Whole Abdomen Radiation
- Stage III & IV
- Uncommon as chemotherapy is superior to
radiotherapy in advanced disease

52. • Chemotherapy
- Standard treatment in advanced disease
- Superior to whole abdominal radiotherapy
- Doxorubicin, cisplatin, paclitaxel

53. • Clinical Stage II
- Incidence of pelvic lymph node metastases is about
36%
- Incidence of disease spread outside pelvis is higher
Two approaches
- Radical hysterectomy + BSO + pelvic & para aortic
lymphadenectomy
- Combined radiation and surgery (extra pelvic
radiation + intracavitary radiation followed in 6
weeks by TAH + BSO / initial surgical approach
followed by radiation

54. Summary of Stage I & II
• Grade 1,2
• No or minimal myoterial invasion
Observation only
• G2, superficial myometrial
invasion
• G3, no myometrial invasion
Vaginal radiation
• G3, any myometrial invasion
• Deep myometrial invasion
• Cervical spread
• Positive lymph nodes
Pelvic RT & Vaginal boost
(extended field if positive
para-aortic nodes)
• Adnexal spread
• Intraperitoneal disease
completely resected
Whole abdominal radiation
or Chemotherapy
• Positive peritoneal cytology Observe or Progentins

55. • Clinical Stage III
- 7-10%
- Goal of surgery in is eradication of all macroscopic
disease
- Debulking , peritoneal cytology, pelvic and para
aortic lymphadenectomy, biopsy or excision of any
suspicious areas, omentectomy, peritoneal biopsy
- TAH + BSO, except in bulky parametrial disease

56. • Clinical Stage IV
- 3%
- Combination of Surgery + RT + Hormonal /
Chemotherapy
- Objective of surgery is to provide palliative relief of
bleeding, discharge and complications involving the
bladder and rectum
- Pelvic exanteration

57. • Recurrent Disease
- About ¼ treated for early endometrial cancer
develop recurrent disease
- Multimodality approach – RT Radical Surgical
Resection intra-operative RT (IORT)
- Hormonal therapy – Progestins, Tamoxifen
- Chemotherapy – response rates 38% - 76%
- Doxorubicin + Cisplatin
- Cyclophosphamide + Doxorubicin + Cisplatin
- Paclitaxel + Cisplatin +/- Doxorubicin
- Carboplatin + Paclitaxel

58. • FIGO Annual Report 2001
• Overall 5 year survival rate – 76%
• Patients undergoing surgical staging had much
better survival rate than those staged clinically
(Stage I - 87% / 54%)
(Stage II - 76% / 41%)
(Stage IIII - 57% / 23%)
(Stage IV - 18% / 12%)
TREATMENT RESULTS

59. FOLLOW UP
• History & Physical examination
• First 2 years – every 3 to 4 months, then 6 months
thereafter
• Half of patients with recurrence have symptoms
• 75% -85% of recurrences are detected on physical
examination
• Chest X-Ray every 12 months