Gynecology: Neoplastic Diseases of the Uterus

Lecturer: Elizabeth Ahyong-Reyes, MD

Transcriber: Patrick Angelo R. Bautista January 2020

References and Legends Diagnostic Tools

• {💻} Powerpoint and {📕} FEU-NRMF Gynecology Manual • Endometrial Biopsy (histologic exam of the endometrium)
• {📖} Chapter 32, Comprehensive Gynecology 7th Ed. o with Endocervical Curettage (ECC) – if endometrial
• {EJG} EJG transcription carcinoma is found, ECC is done to rule out invasion to
Table of Contents
endocervix; determines if patient is good risk for surgery.
I. Neoplastic Diseases of the Uterus 1 o without ECC
o Endometrial Carcinoma 1 • Pap smear
§ Histologic Classification 1 o screens for cervical neoplasia
§ Types, Staging, Prognostic Factors, Grading 2 o detects endometrial cancer in only 50% of cases
§ Treatment 3 • Hysteroscopy, Fractional D&C
o Uterine Sarcoma 4 o if adequate outpatient evaluation cannot be obtained or if the
§ Leiomyosarcoma 5 diagnosis or cause of the abnormal bleeding is not clear from
§ Endometrial Stromal Sarcoma 5 the tissue obtained.
§ Carcinosarcoma 6 o the endocervix is first sampled to rule out cervical involvement
by endometrial Ca, hysteroscopy is done to visualize the
I. NEOPLASTIC DISEASES OF THE UTERUS endometrial cavity, then complete uterine curettage is done.

1. Endometrial Carcinoma Histologic Classification {📖}

• The most common (leading) gynecologic malignancy in the US 1. Typical endometrioid adenocarcinoma
• Whites > Blacks, Hispanics, Asians
• most common type
Philippines Statistics
2. Adenocarcinoma with squamous elements
• 3rd ranking gynecologic malignancy
• has been used with a description of the degree of differentiation
• 20th most common overall (1.0%)
of both the glandular and squamous components.
• 8th leading site among women (4.0%)
• Adenocanthoma – used to describe a well-differentiated tumor
• 2451 new cases, deaths (2015)
• Adenosquamous carcinoma – used to describe a poorly
• Incidence starts rising steeply at age 40
differentiated carcinoma with squamous elements
Risk Factors
3. Clear cell carcinoma
• less common (<5%)
• Histologically resembles clear-cell adenoCa of ovary, cervix, vagina.
• tend to develop in postmenopausal women
• Prognosis: much worse than typical endometrial adenoCa.
• Survival rates of 39-55% have been reported, much less than the
65% or better usually recorded for endometrial carcinoma.

4. Serous carcinoma
• Highly virulent and a less common histologic subtype of
endometrial carcinomas (5-10%).
• Histologically resemble papillary serous carcinomas of the ovary.
• high rate of extrauterine disease
o even in cases without myometrial invasion
• Recommendation: a thorough operative staging in all cases of
these tumors because of the high risk of extrauterine disease even
in cases admixed w/ other histologic types (endometrial, clear cell).
• Omentectomy is part of basic management for this type
• {EJG} Prognosis: poor
• {💻} (+) progestational stimulation & corpus luteum is frequently
detected in the ovary – good prognosis

Clinical Presentation 5. Secretory carcinoma

• Abnormal premenopausal and perimenopausal bleeding
• Postmenopausal bleeding 6. Mucinous carcinoma
• Abdominal enlargement (late sign) • extremely rare
• Presence of abnormal uterine bleeding in the pre- and post- • primarily in post-menopausal women
menopausal age group warrants evaluation through endometrial • confused with mucinous CAs of the ovary, cervix, or bowel
sampling, endometrial curettage, or hysteroscopy with • Prognosis: good
endometrial curettage
• Thickened Endometrium 7. Squamous carcinoma
o “an endometrial thickness of ≥5 mm in the post-menopausal
• usually in post-menopausal women
age group and ≥15 mm among pre-menopausal woman
• radiation, chemotherapy, surgery
warrants further investigation with sonohysterography,
• rule out cervical cancer
transvaginal color doppler and/or endometrial tissue sampling”

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Patterns of Spread Grading
• Direct Peritoneal Spread Grade Differentiation Solid Components
o through the uterine wall G1 Well differentiated <5%
o lumen of the fallopian tube G2 Moderately differentiated 6-50%
• Four major channels of lymphatic drainage from the uterus that G3 Poorly differentiated >50%
serve as sites for extrauterine spread of tumor:
1. a small lymphatic branch along the round ligament that runs Types of Endometrial Cancer
to the inguinal femoral nodes
Type 1 Type 2
2. branches from the fallopian tubes
Prototype Endometrioid Ca Serous Papillary
3. ovarian pedicles (infundibulopelvic ligaments), which are
large lymphatics that drain into the paraaortic nodes Typical Patient Peri- or Early Late Post
4. broad ligament lymphatics that drain to the pelvic nodes.
Menopause Menopause
Background Hyperplastic Atrophic
o The pelvic and paraaortic node drainage sites (2, 3, 4) are
Endometrium
the most important clinically.
Grade Low High
o Frequency of nodal involvement becomes greater with higher-
Estrogen Dependence Dependent Non-Dependent
grade tumors and with greater depth of myometrial invasion.
Estrogen Receptors Usually (+) Usually (-)
Prognosis Better Poorer

Prognostic Factors {📖}

Clinical Factors:
• Survival: White > Black
o White patients have a higher survival rate than black patients, a
finding partially explained by higher-stage and higher-grade
tumors among black women.
• Stage and Grade: Older > Young
o Older patients have tumors of a higher stage and grade when
compared to younger patients.
Pathologic Factors:
• Tumor Stage
o well-recognized prognostic factor for endometrial carcinoma
o Fortunately, most cases are diagnosed in stage I, which provides
a favorable prognosis.
• Histologic Type – Type 1: better | Type 2: poorer
o Best prognosis:
§ Typical Adenocarcinoma
§ Secretory Carcinoma
§ Better Differentiated with/without squamous elements
o Poor prognosis:
§ Papillary Serous Carcinoma
§ Clear Cell Carcinoma
§ Poorly Differentiated Type Carcinoma
FIGO Staging • Histologic Grade
o major determinant of prognosis
o Endometrial carcinomas are divided into three grades:
§ grade 1: well differentiated
§ grade 2: intermediate differentiation
§ grade 3: poorly differentiated.
o worsening of prognosis with advancing grade
o Grade 1 better than Grade 3
• Myometrial Invasion
• The degree of myometrial invasion correlates with the risk of
tumor spread outside the uterus, but the higher grade and higher
stage tumors in general are more likely to have deep myometrial
penetration.
• Peritoneal Cytology
• studied as a prognostic factor but results are conflicting.

Stratify low risk, intermediate risk, high risk

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 Treatment Selective Estrogen Receptor Modulators:
Standard Treatment (Surgical) • Tamoxifen – G1 and 2 more likely to respond
• Extrafascial Hysterectomy (EH)
• Bilateral Salpingo-oophorectomy (BSO) Aromatase Inhibitors
• Peritoneal Fluid Cytology (PFC) • Anastrozole – an oral non-steroidal aromatase inhibitor
• Lymph Node Evaluation (LNE) • Response Rate:
o Unselected population: 9%
Lymph Node Evaluation o Endometrioid G1, G2: 30%
• definition of adequate lymphadenectomy needs further investigation
• 21 to 25 LNs (pelvic and paraaortic) – significantly increases the Guidelines:
probability of detecting at least 1 positive LN in endometrioid • Lymph Node Dissection may be omitted (Level 2B)
uterine cancer o low risk corpus cancer
• Level 2B o surface dimension ≤2 cm
• Routine Omentectomy is NOT recommended
Indications for Aortic Node Sampling o as part of surgical staging
1. suspicious para-aortic or common iliac nodes o for seemingly early stage endometrioid type adenocarcinoma
2. grossly positive adnexa • Adjuvant Treatment for adenoCa with squamous differentiation
3. grossly positive pelvic nodes o depend on the histological grade of the glandular component
4. high grade tumors G3 • Results of PORTEC 2 (Phase III RCT) study
5. clear cell or papillary serous or carcinosarcoma o vaginal brachytherapy vs pelvic EBRT alone
6. lower uterine segment involvement o vaginal brachytherapy provides a better result than pelvic
7. cervical involvement EBRT in terms of QOL (initial)
8. LVSI • Lower Uterine Segment Involvement
9. ≥50% myometrial invasion o predictive of NODAL SPREAD for endometrioid histologic type
tumors (odds ratio: 5)
Radiology: o prognostic significance, however, remains unknown
• given as primary treatment in poor surgical risk patients or as an • Positive LVSI (regardless of stage and grade)
adjuvant treatment o strong predictor of distant and lymphatic recurrence
• Either EBRT, EFRT, and/or Brachytherapy o warrants adjuvant therapy
• Adjuvant therapy is given for cases of poorly differentiated tumor o associated with a 2-fold risk of death
(grade 3) and for cases with myometrial invasion of >50%. o Adjuvant therapy chemotherapy (doxorubicin-based) or pelvic
radiotherapy
Chemotherapy:
• as adjuvant treatment for stage III, IV followed by RT Stage I: Confined to the Corpus
Surgery: EHBSO, PFC, LNE
TAP Regimen Every 3 weeks for a maximum of 7
cycles or until disease progression
Adjuvant: Radiation (not for low risk patients)
(Cisplatin-Doxorubicin-Paclitaxel
with Filgrastim support) or unacceptable toxicity occurs. No Surgico-Pathologic Stage Management (Surgery + Adjuvant)
dose reduction is required even if IA G1, G2 No Adjuvant
there is previous RT. G3 Vaginal Brachytherapy or Pelvic EBRT
AP Regimen Every 3 weeks for a maximum of IB G1, G2, G3 Vaginal Brachytherapy or Pelvic EBRT
(Doxorubicin-Cisplatin) Doxorubicin 500 mg/m2 or until
disease progression or
Stage II: Tumor extension to the cervix (Occult / Microscopic)
unacceptable toxicity occurs.
Occult stage II is defined as (+) ECC with histologic continuity but
Carboplatin-Paclitaxel regimen Every 4 weeks for 6 cycles
with no gross evidence of cervical involvement
Cisplatin-Paclitaxel regimen with RT
Surgico-Pathologic Stage Management (Surgery + Adjuvant)
Steroid Hormone Receptors in Endometria Ca II RHBSO, PFC, LNE
• The steroid receptor level in endometrial carcinoma is lower than No Adjuvant
in normal endometrium. EHBSO, PFC, LNE
• Highest levels of estrogen and progesterone receptors in tumors Pelvic EBRT
have been found in well-differentiated (grade 1) tumors and lowest There is no apparent benefit for
in grade 3 tumors. additional brachytherapy
• Survival rate is better for women with receptor rich tumors.
Stage II: Tumor extension to the cervix (Grossly confirmed)
Hormonal Treatment: Surgico-Pathologic Stage Management (Surgery + Adjuvant)
• Progestational Agents (Oral/IM Medroxyprogesterone Acetate II (RHBSO, PFC, LND)
Good surgical
and Megestrol Acetate)
risk (G1,2,3) No Adjuvant
o Used for recurrent cancer of the endometrium and with co-
Poor surgical Pre-operative pelvic EBRT and
morbidities because it is well tolerated, with low toxicity and
risk (G1,2,3) vaginal brachytherapy followed by
with moderate efficacy.
PFC & EHBSO with LNE
o Patients receiving the low dose regimen (200 mg/day) had a
higher response to therapy than those receiving the high-dose
Stage II: Tumor extended to the endocervix
regimen (1000 mg/day)
• Patients who underwent RHBSO
o poorly differentiated tumors or hormone-receptor-negative
o lines of resection are negative
tumors have significantly lower response rates.
o brachytherapy is NOT necessary
o should be considered in px with recurrent endometrial cancer
• Presence of any of the ff. after RH warrants adjuvant therapy
o Response rates: 30-50%
o with > 50% myometrial invasion
o Side effects: weight gain, edema, thrombophlebitis,
o grade 3 tumors
headache, and occasional hypertension
o cervical involvement
o (+) LVSI

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Stage IIIA: Serosal invasion and/or fallopian tubes/ovaries 2. Uterine Sarcoma
Stage IIIB: Involvement of vagina and/or parametria
• account for <5% of uterine malignancies and are much less
Stage IIIC: Metastasis to the pelvic or para-aortic LNs
frequent than endometrial carcinomas
Surgery: EHBSO, PFC, LNE, Debulking
• Risk Factors:
Adjuvant: Chemotherapy followed by RT
o estrogens, obesity – increases the risk
Surgico-Pathologic Stage Management (Surgery + Adjuvant) o oral contraceptive – decreases the risk
IIIB Chemotherapy followed by: • No uniformly defined staging criteria exist for these tumors, and
Pelvic EBRT the most widely used definitions are similar to those for
Vaginal Brachytherapy endometrial carcinoma:
IIIC Chemotherapy followed by: o stage I: confined to the corpus.
EFRT o stage II: corpus and cervix involved.
Vaginal Brachytherapy o stage III: spread outside the uterus but confined to the pelvis
or retroperitoneal lymph nodes.
Stage IV: invades bladder and/or bowel mucosa, (+/-) distant mets o stage IV: spread outside the true pelvis or into the mucosa of
Surgery: EHBSO, Tumor Debulking the bladder or rectum.
Adjuvant: Chemotherapy followed by EFRT, Vaginal Brachytherapy • Similar to endometrial adenocarcinoma:
o operative stage is the most important predictor of survival.
Poor Histologic Types: Uterine Papillary Serous/ Clear Cell Ca
Surgery: EHBSO, PFC, BLND, Para-aortic LN Sampling (PALS),
Infracolic Omentectomy (IO), Random Peritoneal Biopsy (RPB)
[Extended Surgical Staging]
Surgico-Pathologic Stage Management (Surgery + Adjuvant)
IA Observation
IA with myometrial Chemotherapy followed by
invasion and all others Abdominopelvic RT

Extrafascial (Simple) vs. Radical Hysterectomy

• Extrafascial / Simple – removal of uterus and cervix
• Radical – removal of uterus, cervix, parametria, upper vagina

Other Treatment Options

• Laparoscopy Hysteroscopy with BLND
• Vaginal Hysterectomy

Persistence of Recurrent Disease – Treatment Options:

• should be individualized
• Depends on the site, extent of disease, and receptor status
• May give irradiation – for localized recurrences (pelvic and para-
aortic LN) or distant metastasis
• May give chemotherapy – for stage 3 or 4

Final Histopathology Report of Endometrial Ca Specimens

1. Histologic Type
2. Histologic Grade
3. Lymphovascular Space Involvement (LVSI)
4. Depth of myometrial invasion
5. Type of cervical involvement
6. Adnexal involvement Classification
7. Parametria
Homologous types of Sarcoma
8. Vaginal rim/cuff
• sarcomatous elements resemble mesenchymal tissue normally
9. Lymph node (location and number)
found in the uterus.
10. Peritoneal fluid
• include: leiomyosarcoma, endometrial stromal sarcoma (ESS),
11. Tumor size
and, rarely, angiosarcoma.
Follow-Up Heterologous types of Sarcoma
every 3-4 months for the first 2 years, then every 6 months for the • sarcomatous elements resemble tissues foreign to the uterus
next 3 years, then yearly thereafter. • include: rhabdomyosarcoma, chondrosarcoma, osteosarcoma,
and liposarcoma.
Pap Smear At least yearly
MRI / CT Scan Annual for the 1st 3 years Carcinosarcoma (malignant mixed müllerian tumor)
UTZ +/- Color Doppler Optional • sarcomas admixed with epithelial adenocarcinoma
Annual Chest X-ray Does not contribute to early detection of
recurrences
Isolated Vaginal Vault Curable up to 87% of cases in patients not
Recurrences previously exposed to radiation
CA-125 Monitoring Recommended in cases with advanced
surgical stage (Stage 3-4)
High risk histologic subtypes every 6
months on the 1st year
Annually thereafter up to 5 years

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1. Leiomyosarcoma 2. Endometrial Stromal Sarcoma (ESS)
• represent 1-2% of uterine malignancies and approximately 1/3 of • approximately 10% of uterine sarcomas.
uterine sarcomas • all ESSs are considered low grade.
• exact cause is unknown; not thought to arise from benign o If high-grade elements are present, these tumors would be
leiomyomas. classified as undifferentiated high-grade sarcomas.
• Approximately 85% of women diagnosed with a leiomyosarcoma o Undifferentiated sarcomas have a greater degree of anaplasia
have clinical stage I or II disease (limited to the uterus and cervix). and lack the branching vasculature characteristic of ESSs.
• Poorer prognosis than adenomas/ endometrial carcinoma • Peak incidence: 5th decade of life (40-50 years)
• no association with previous radiation nor are risk factors of
Clinical Presentation endometrial carcinoma associated with the development of ESS
• enlarged pelvic mass, occasionally accompanied by pain or • Histologically, most resembles proliferative endometrial stroma.
vaginal bleeding.
• suspected if the uterus undergoes rapid enlargement, particularly Management
in patients in the perimenopausal or postmenopausal age group. • Surgery – primary treatment for all sarcomas
• Hormonal treatment
Histopathologic Features o these tumors contain estrogen and progestin steroid hormone
• The determination of malignancy is made in part by ascertaining: receptors and are often sensitive to hormone therapy.
o the number of mitoses in 10 hpf o Complete resolution has been reported with megestrol acetate
o presence of cytologic atypia (Megace), medroxyprogesterone (Provera), letrozole (Femara),
o abnormal mitotic figures tamoxifen, and 17α-hydroxyprogesterone caproate (Delalutin).
o nuclear pleomorphism • Radiation
• A finding of >5 mitoses per 10 hpf with cytologic atypia leads to o Reports of radiation in the treatment of pelvic recurrence, with
a diagnosis of leiomyosarcoma resolution of all residual tumors, but extensive experience with
o when there are ≤4 mitoses per 10 hpf, the tumors usually radiation therapy is not available.
have a more benign clinical course. • Systemic chemotherapy (in question)
• The presence of bizarre cells may not necessarily establish the o Systemic chemotherapy with cytotoxic agents has not been
diagnosis because they can occasionally be seen in benign reported to be effective, although good responses to doxorubicin
leiomyomas and in patients receiving progestational agents. (Adriamycin) have been reported.
• It is important to note that an ↑ in mitotic count in leiomyomas
occurs in pregnancy, as well as during oral contraceptive use. Leiomyosarcoma Staging
This can occasionally cause confusion in the histologic diagnosis. Stage 1: Tumor limited to the uterus
1A Limited to the endometrium/endocervix with no
Management myometrial invasion
• Surgery - primary treatment for all sarcomas; includes: 1B ≤50% of the myometrium
o Total hysterectomy 1C ≥50% of the myometrium
o Bilateral salpingo-oophorectomy Stage 2: Tumor extends to the pelvis
o Staging 2A Adnexal involvement (fallopian tube, ovaries)
• Limited information on adjuvant treatment either radiotherapy or 2B Tumor extends to the extrauterine pelvic tissues
chemotherapy whether early, advanced, recurrent disease. Stage 3: Tumor invades the abdominal tissues
(not just protruding into the abdomen)
Leiomyosarcoma Staging 3A 1 site
Stage 1: Tumor limited to the uterus 3B >1 site
1A <5 cm 3C Metastasis to the pelvic and/or para-aortic LNs
1B >5 cm Stage 4: Metastasis
Stage 2: Tumor extends to the pelvis 4A Tumor invades the bladder and rectum
2A Adnexal involvement (fallopian tube, ovaries) 4B Distant metastasis
2B Tumor extends to the extrauterine pelvic tissues
Stage 3: Tumor invades the abdominal tissues ESS Prognosis
(not just protruding into the abdomen) • Prognosis depends on the:
3A 1 site o extent of disease
3B >1 site o ability to remove the entire tumor at the time of surgery
3C Metastasis to the pelvic and/or para-aortic LNs • In general, ESSs are indolent, slowly progressing tumors.
Stage 4: Metastasis • Recurrent disease may be diagnosed as many as 30 years after
4A Tumor invades the bladder and rectum diagnosis.
4B Distant metastasis • ESS tends to recur locally in the pelvis or peritoneal cavity and
frequently spreads to the lungs.
No grading

Leiomyosarcoma Prognosis
• Despite the low incidence of high-stage disease, ~50% of
patients will have a recurrence within 2 years.
o The recurrence in most of these patients is outside the pelvis.
• Vascular invasion and extrauterine spread of tumor are
associated with worse prognoses.
• The prognosis worsens for tumors with >10 mitoses per 10 hpf.

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3. Carcinosarcoma (Malignant Mixed Müllerian Tumors)
• these tumors consist of both carcinoma and sarcoma elements
native to the uterus that may resemble the endometrial stroma of
smooth muscle (homologous) or of sarcomatous tissues foreign
to the uterus (heterologous).

Clinical Features
• those with carcinosarcoma tend to be older and primarily
postmenopausal, usually beyond the age of 62 years.
• Previous pelvic irradiation has been identified as an occasional
predisposing factor.
• Pattern of Spread: locally into the myometrium and pelvis, or
distally to the abdominal cavity, lungs, and pleura
o similar to the spread of endometrial carcinoma
• postmenopausal bleeding, enlarged uterus.
• tumor may appear to be a polypoid excrescence from the cervix

Diagnostic Aids
• Dilatation & Curettage
• Vaginal Ultrasound Examination

Management
• Surgery – primary treatment for all sarcomas
o Total abdominal hysterectomy and Bilateral Salpingo-
oophorectomy are completed with stage I tumors
o More extensive procedures are occasionally attempted for
stage II tumors as well as for those with early extrauterine
spread

Prognosis
• Best prognosis if confined to the uterus.
• extent of the tumor and the depth of myometrial invasion are
important prognostic factors.

Staging
• should be staged the same as endometrial carcinoma

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