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Premalignant lesions of Uterus

  1. Endometrial HyperplasiaIt represents a spectrum of morphological and biological alteration of endometrium (both in glands? and stroma), ranging from an exaggerated physiological state to carcinoma in situ. They are clinically important because:
  • They cause abnormal bleeding.?
  • Either preceede or occur simultaneously with endometrial carcinoma.

Types of Endometrial Hyperplasia




It results from circumstance in which there is prolonged, increased oestrogen production:

i. Follicular cysts of ovaryO

ii. PCODo

iii. Granulosa and Theca cell tumours of ovary?

iv. HRTo


In perimenopausal age they are associated with glucose intolerance.



 Glands are large, cystic with increased glands! stromal ratio?

 Scanty mitosis?

 Glands lined by columnar? epithelium

 Stroma is sparsely cellular

 Less obviously connected with increased estrogen

 Mostly, cause is unknown

 Can be associated with :


- Glucose Intolerance?





 Glands number is increased, size is increased and Glands are thrown into folds (overcrowding of glands)

 Numerous mitosis?

 Glands are lined by stratified squamous epithelium?

 Stroma is densely cellular?


Chances of Progression to Carcinoma


Type of hyperplasia

Progression to cancer

 Simple without atypia


 Complex without atypia


 Simple with atypia


 Complex with atypia


The four main types of endometrial hyperplasia are:

  • Simple hyperplasia without atypical cells.
  • Complex hyperplasia without atypical cells
  • Simple hyperplasia with atypical cells
  • Complex hyperplasia with atypical cells

Characteristics of Atypical cells

  • Large in size
  • Loss of polarity
  • Irregular shape
  • Hyperchromatic nucleus and prominent nudeoli?
  • Altered nucleus cytoplasmic ratio

Management of Endometrial Hyperplasia


Depends on the patient's age and the presence or absence of cytological atypia.

Non Atypical Hyperplasia


Since the chances of malignancy in this category are less (1 % for simple hyperplasia and 3% for complex), hence they are managed medically:

  • Premenopausal women: Progesterone therapy-
    Options: - Medroxyprogesterone acetate for 21 days a month daily for 3 months.
    - Progesterone containing IUCD.
  • Post-menopausal women:
    Simple hyperplasia without atypia-generally followed without therapy.
    Complex hyperplasia without atypia-cyclical/ continous progesterone therapy.
    These patients should be followed annually by endometrial biopsy.

Atypical Hyperplasia


In this category chances of malignancy are high (simple-8%, complex-30%, hence they are managed surgically).

  • Ideal treatment is-Hysterectomy
  • Premenopausal women willing to preserve fertility: High dose progesterone therapy after full information of risk of a undiagnosed cancer or progression to cancer. In these cases periodic TVS and endometrial biopsy is necessary.

Endometrial Carcinoma



  • Most common gynecological malignancy in developed countries and the 4th most common cancer in women
  • 20% of women develop endometrial carcinoma in lifetime
  • Mean age of presentation is 60 years: peak incidence occurs from 55 to 70 years
  • Majority are diagnosed early
  • 5 year survival for stage I disease is more than 90%
  • OverallS year survival for all stages is 60-70%

Risk Factor


Endometrial cancer occurs as a result of unopposed estrogen exposure in body.


Family Has OLD AUNTI


Family history






Late menopause/Early menarche




Atypical endometrial hyperplasia


Unopposed estrogen or increased estrogen in body as in : HRT, Fibroid,

PCOD and Feminizing ovarian tumours




Therapy: Tamoxifen Therapy and Radiation Therapy


H/O infertility/menstrual irregularity

Approximately 5% of endometrial cancer is hereditary, with majority of these presenting as a part of the Lynch II or Hereditary Non Polyposis Colorectal Cancer (HNPCq syndrome. Besides endometrial cancer, individuals in this family are at increased risk of colorectal cancer, ovarian, urinary, biliary, gastric and small intestinal cancer. Abnormal bleeding at any age should be evaluated by tissue biopsy in women of HNPCC families. Routine survillance may consist of yearly USG and endometrial biopsy commencing at the age of 30-35.

Minimum chances of progres- sion to carcinoma are with simple hyperplasia without atypia (also called as cystic glandular hyper- plasia) and maximum chances of carcinoma are with complex hyperplasia with atypia?

Remember -Most common gynaecological cancer in developed countries is endometrial cancer.


Most common gynaeco- logical cancer in develop- ing countries like India is cervical cancer.

-Estrogen replacement without concomitant pro- gesterone carries a relative risk of 4.5 to 8 & persists for 10 years after treatment is stopped.


-BMI > 30 kg/m2 will triple the risk of endometrial cancer


-A woman taking Tamoxifen has an annual risk of 2 in 1000 of developing endometrial cancer and 40% of women will develop cancer more than 12 months after stopping therapy


-Women with HNPCC syn- drome have 39% risk of developing endometrial cancer by the age of 70 years.


OCP's decrease- endome- trial cancer risk by 40%, even u ptil 1 5 yea rs after discontinuation and the protection increases with the length of use.

  1. Cancer of Endometrium

Rick Factors for Endometrial CA (Estrogen-dependent tumor):



  1. Late menopause
  2. Obesity
  3. Diabetes mellitus and hypertension
  4. Unopposed estrogen therapy
  5. Tamoxifen therapy
  6. Atypical endometrial hyperplasia

Obesity, hypertension, and diabetes mellitus associated with CA endometrium = corpus CA syndrome


Type of Hyperplasia

Progression to CA (%)





Simple with atypia


Complex with atypia



Causes of postmenopausal uterine bleeding:


Cause of Bleeding


Endometrial atrophy


Hormone replacement therapy


Endometrial polyps


Endometrial hyperplasia


Endometrial CA


  • Adenocarcinoma is the MC variety of CA endometrium.
  • Papillary serous variety and clear cell variety have worst prognosis.
  • Among the two, clear cell variety has poorer prognosis.
  • Simpson's pain= colicky pain in patients of CA endometrium.

The diagnosis of Ca endometrium has to be by histopathological examination of endometrium obtained by D/C, fractional curettage, endometrial biopsy curette or hysteroscopy and biopsy.


However PAP smear can also detect 50--60% of endometrial carcinomas.


Endometrial cancerous cells present in the posterior vaginal fornix can be detected by PAP smear


FIGO Grading of Endometrial Carcinoma


Histopathologic degree of differentiation:


G1: s 5% nonsquamous or nonmorular growth pattern


G2: 6-50% nonsquamous or nonmorular growth pattern


G3: >50% nonsquamous or nonmorular growth pattern

Surgical Staging for Endometrial Cancer




la G12 3

No myometrial invasion

Ib G12 3

<Y2 Myometrial invasion

Ic G12 3

>Y2 Myometrial invasion

IIa G 123

Extension to endocervical glands

lIb G12 3

Cervical stromal invasion

IIIa G 1 23

Positive uterine serosa, adnexa, and.' or peritoneal cytology

IIIb G 1 23

Vaginal metastasis

IIIc G 123

Metastasis to pelvic and/ or para-aortic lymph nodes

IVa G 123

Tumor invasion of bladder and/ or bowel mucosa


Distant metastasis including intra-abdominal and/ or inguinal lymph nodes


Recent Advances



FIGO (2009) Staging for Ca Endometrium


Tumor confined to the uterus, no or <Y2 myometrial invasion


Tumor confined to the uterus, >Y2 myometrial invasion


Cervical stromal invasion, but not beyond uterus


Tumor invades serosa or adnexa


Vaginal and/ or parametrial involvement


Pelvic node involvement


Para-aortic involvement






Stage 1:


Surgery (total abdominal hysterectomy with bilateral salpingo-oophorectomy with lymph node sampling),
followed by radiotherapy


Stage 2:


Modified radical hysterectomy, bilateral salpingo-oophorectomy with lymph node dissection, followed by radiotherapy

Stages 3 and 4:


Debulking surgery followed by radiotherapy


Chemotherapy has no role in the management of CA endometrium


Only patients with stage 1 A, grade land 2 do not require postoperative radiotherapy.

Gestational Trophoblastic Neoplasia

  1. Gestational trophoblastic neoplasia almost always develops with or follows some form of pregnancy.
  2. Among all the cases of choriocarcinoma:
    • 50% develop following a hydatidiform mole'
    • 25% develop following an abortion
    • 20% develop following a full-term pregnancy and 5% develop following an ectopic pregnancy
  3. Beta-hCG is the tumor marker. The diagnosis of gestational trophoblastic neoplasia is made primarily by persistently elevated serum hCG levels.
  4. An important diagnostic feature of choriocarcinoma, in contrast to hydatidiform mole or invasive mole, is absence of villus pattern.
  5. Factors involved in malignant transformation of the chorion are unknown. In choriocarcinoma, the predisposition of normal trophoblast to invasive growth and erosion of blood vessels is greatly exaggerated.
  6. Metastases often develop early and are generally blood borne because of the affinity of trophoblastic cells for blood vessels. -
  7. The MC sites of metastasis are the lungs (75-80% cases) followed by vagina in about 30-50%.
  8. In vagina, the classical lesion is bluISh purple nodule located in suburethral region.
  9. The chest X-ray findings in case of metastasis to the lungs are:
    • Cannonball metastasis
    • Snowstorm appearance
    • Pleural effusion


  • "Snowstorm" on USG = vesicular mole
  • "Snowstorm" on chest X-ray = pulmonary metastasis of choriocarcinoma

Staging of Gestational Trophoblastic tumors


Stage I

Disease confined to uterus

Stage IA

Disease confined to uterus with no risk factors

Stage IB

Disease confined to uterus with one risk factor

Stage IC

Disease confined to uterus with two risk factors

Stage II


Gestational trophoblastic tumor extending outside uterus but limited to genital structures (adnexa, vagina, and broad ligament)

Stage IIA


Gestational trophoblastic tumor extending outside uterus but limited to genital structures without risk factors

Stage IIB


Gestational trophoblastic tumor extending outside uterus but limited to genital structures with one risk factor

Stage IIC


Gestational trophoblastic tumor extending outside uterus but limited to genital structures with two risk factors

Stage III


Gestational trophoblastic disease extending to lungs with or without known genital tract

Stage IIIA


Gestational trophoblastic tumor extending to lungs with or without genital tract involvement and with no risk factors

Stage IIIB


Gestational trophoblastic tumor extending to lungs with or without genital tract involvement and with one risk factor

Stage IIIC


Gestational trophoblastic tumors extending to lungs with or without genital tract involvement and with two risk factors

Stage IV

All other metastatic sites (liver /brain)

Stage IVA

All other metastatic sites without risk factors

Stage IVB

All other metastatic sites with one risk factor

Stage IVC

All other metastatic sites with two risk factors

Scoring System Based on Prognostic Factors












Age (years)





Antecedent pregnancy










Interval between end of antecedent pregnancy





and start of chemotherapy (months)





Human chorionic gonadotropin (ill /L)





ABO groups





Largest tumor, including uterine (em)





Site of metastases








tract, liver


Number of metastases










Prior chemotherapy



1 drug

≥ 2 drugs

Score <4, low risk; ≥8, high risk.





A GTN belongs to a high-risk category if it develops after a full-term pregnancy (postmolar pregnancy; a GT can be a repeat molar pregnancy or a choriocarcinoma, but a GTN that develops after a full-term pregnancy is always a choriocarcinoma).



  • Chemotherapy is the treatment of choice.
  • Methotrexate is the drug of choice.
  • If the patient has jaundice then actinomycin D should be given.
  • High-risk patients and patients with stage 4 are to be treated with combination chemotherapy (EMACO regimen):
    1. E = etoposide
    2. M = methotrexate
    3. A = actinomycin D
    4. C = cyclophosphamide
    5. 0 = vincristine (Oncovin)
  • EMA-CO regimen results in response rates of about 90% and survival rates of 80-100%.
  • The recent overall cure rate for gestational trophoblastic neoplasia of all severities is about 90%.
  • Women with nonmetastatic tumors or low-risk gestational trophoblastic neoplasia are cured virtually 100% of the time if single-agent chemotherapy (methotrexate) is started as soon as persistent disease is identified.


  • Weekly measurement of hCG until they are normal for 3 consecutive weeks
  • Monthly measurement of hCG until they are normal for 12 consecutive months for stages 1-3
  • Monthly measurement of hCG until they are normal for 24 consecutive months for stage 4
    Placental Site Trophoblastic Tumor
  • It is an uncommon variant of Cc.
  • It consists predominantly of intermediate trophoblasts.
  • Human placental lactogen (hPL) is the tumor marker.
  • They are insensitive to chemotherapy.
  • Hysterectomy is the most efficacious treatment for confirmed placental site trophoblastic tumor.

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