UNIVERSITY OF MEDICINE AND PHARMACY “GR.T.POPA” IAŞI
FACULTY OF GENERAL MEDICINE
THE ABSTRACT OF DOCTORATE THESIS
ENDOMETRIAL CANCER. DIAGNOSIS,
TREATMENT AND PROGNOSTIC
FACTORS
SCIENTIFIC COORDINATOR
Prof. dr. Mihai Pricop
CANDIDATE
Dr. Mihalcea Dan- Nicolae
2010
CONTENTS
GENERAL PART
CAP. I . INRODUCTION ..............................................................................................1
CAP. II .DESCRIPTIVE EPIDEMIOLOGY..........................................................................2
II. 1. RISK FACTORS...............................................................................................2
II. 2. SCREENING ..................................................................................................5
CAP. III. DIAGNOSIS OF ENDOMETRIAL CANCER..........................................................7
III. 1. CLINICAL DIAGNOSTIC.................................................................................7
III. 2. PARACLINICAL DIAGNOSTIC.........................................................................8
III.2.1. HISTOLOGICAL DIAGNOSIS..........................................................................9
III.2.2.IMAGISTIC METHODS......................................................................................12
III.2.3. ENDOSCOPIC DIAGNOSIS................................................................................16
III.2.4. BIOCHEMICAL MARKERS................................................................................18
III.2.5. PREOPERATIVE ASSESMENT ...........................................................................21
III.2.6. ANATOMOPATHOLOGICAL DIAGNOSTIC.......................................................22
III.3. DIFFERENTIAL DIAGNOSIS.......................................................................... 27
III.4. STAGING.....................................................................................................28
CAP. IV. TREATMENT OF ENDOMETRIAL CANCER......................................................32
IV.1. SURGERY...................................................................................................................32
IV. 2. RADIOTHERAPY..........................................................................................................45
IV.3.CHEMOTHERAPY..........................................................................................................53
IV.4. HORMONAL THERAPY.................................................................................................59
IV. 5. POSTTHERAPEUTICAL SURVEILLANCE..........................................................................66
CAP. V. FACTORS OF PROGNOSTIC..............................................................................................67
EXPERIMENTAL PART
CAP. VI. PURPOSE AND OBJECTIVES OF RESEARCH ................................................................90
CAP. VII. MATERIAL ŞI METHOD............................................................................................91
CAP.VIII.
DIAGNOSIS
OF
ENDOMETRIAL
CANCERRESULTS
AND
DISCUSSION................................................................................................................................99
VIII. 1. RISK FACTORS...........................................................................................................108
VIII.1.1.AGE................................................................................................................................110
VIII.1.2.PARITATY......................................................................................................................112
VIII.1.3. OBESITY.......................................................................................................................114
VIII.1.4. CONTRACEPTION........................................................................................................118
VIII.1.5.TREATMENT WITH TAMOXIFEN...................................................................................119
VIII.1.6. ENDOMETRIAL HYPERPLASIA......................................................................................122
VIII.2. SIMPTOMS...........................................................................................................128
VIII.3. CLINICAL EXAM....................................................................................................135
VIII.4. PARACLINIC ASSESMENT.....................................................................................136
VIII.4.1. PAP SMEAR........................................................................................................... 136
VIII.4.2. ULTRASONOGRAPHY..............................................................................................138
VIII.4.3. HYSTEROSCOPY.......................................................................................................144
VIII.4.4. ENDOMETRIALBIOPSY..........................................................................................148
CAP.
IX.
TREATMENT
OF
ENDOMETRIAL
CANCERRESULTS
AND
DISCUSSION............................................................................................................................154
IX.1. SURGERY............................................................................................................154
IX.1.1. ANESTETHIC RISK................................................................................................ .155
IX.1.2. SURGICAL STAGING...............................................................................................158
IX.1.3. POSOPERATIVE CARE.............................................................................................178
IX.1.4. COMPLICATIONS..................................................................................................179
IX. 2. ADJUVANT THERAPU........................................................................................182
CAP. X. PROGNOSTIC FACTORS IN ENDOMETRIAL CANCER- RESULTS AND
DISCUSSION............................................................................................... ...........................187
X.1. AGE....................................................................................................................187
X.2. STAGE.................................................................................................................191
X.3. HISTOLOGICAL GRADE.........................................................................................195
X.4. HISTOLOGIC TYPE.................................................................................................200
X.5. MIOMETRIAL INVASION.......................................................................................209
X. 6. LYMPH NODE INVASION......................................................................................213
X.7. ISTHMIC INVASION...............................................................................................217
X.8. PERITONEAL CYTOLOGY........................................................................................219
X.9. HORMONE RECEPTOR STATUS..............................................................................221
X.10. LVSI....................................................................................................................228
X.11. Ki67 ...................................................................................................................231
CAP. XI. GENERAL CONCLUSIONS.............................................................................................237
SELECTIVE REFFERENCES..........................................................................................................239
GENERAL PURPOSE AND OBJECTIVES OF RESEARCH
Endometrial cancer is a common form of pathology, was third in frequency of female genital
cancers in Romania. The current study builds on the experience of the Gynecology Clinic Fourth of
Medicine "Gr.T. Popa ", led by Prof. Mihai Pricop, in collaboration with the Department of
Gynecology III.
The purpose of this research is to study the current management of endometrial cancer in
three perspectives: diagnosis, treatment and prognostic factors. Progress in recent years in terms of
diagnostic methods have imposed the need for new algorithms in the diagnosis of this cancer. We
intend to asses the risk factors for endometrial cancer , and in particular treatment with tamoxifen
and endometrial hyperplasia. Another goal of this research is to appreciate the value of "gold
standard"diagnostic method of endometrial neoplasia, biopsy of the endometrium with dilation and
curettage, and to compare it with a modern method, which is emerging as refference diagnostic
method- hysteroscopy.
Another proposed goal is to determine whether the two types of
endometrial cancer in terms of precursor lesions, hyperplasia and atrophy, have an different
biological behavior and prognosis. Regarding the treatment, we try to sustain the concept of
surgical staging in endometrial cancer, introduced in 1999 by Creasman and to demonstrate the
superiority of this treatment compared with classic therapy- total abdominal hysterectomy with
bilateral anexectomy We intend to demonstrate the usefulness of new techniques for assessing
myiomterial invasion -intraoperative visual inspection and frozen section and that
lymphadenectomy should become a routine practice in endometrial cancer.
We want to study the prognostic factors to establish the importance of each factor and to
asses some new factors. By statistical analysis we propose to establish correlations between
prognostic factors and to study several prognostic factors less studied, such as hormonereceptor
status, Ki67 proliferation index or isthmic invasion in stage I. By studying the survival analysis and
disease-free interval for the study group we intend to demonstrate that, although considered a
benign neoplasia with good prognosis, there are a number of cases with particularly poor outcome.
OVERVIEW of the study group
MATERIAL
Personal study was conducted on a number of 714 patients investigated
Gynecology Clinic of University of Medicine and Pharmacy "Gr T. Popa ":
in 3-rd and 4-th
84 patients between 1, 1997 to August 31, 2008, of which 76 operated and eight cases, inoperable.
208 cases between May 1992-February 1997, under treatment with Tamoxifen.
78 cases treated in the Gynecology Clinic IV between 1997-1999, investigated by endometrial biopsy
for endometrial lesions induced by tamoxifen.
68 cases of endometrial hyperplasia operated in IV-th Gynecology Clinic between 01.01.2000 31.12.2006.
171 patients with postmenopausal metrorrhagia investigated by endometrial biopsy during 20052008 in the Gynecology Clinic IV .
56 patients investigated by hysteroscopy in 3-rd Gynecology Clinic between 2006-2007
49 patients undergoing hysterectomy-biopsy , performed in the Gynecology Clinic IV between 19972008
We used the data from observation sheets, operative books and morphopathological sheets.
For each case data were analyzed in three ways: diagnosis, treatment and prognostic factors.
ENDOMETRIAL CANCER DIAGNOSIS include:
Risk factors
Clinical diagnosis
Paraclinical diagnosis
RISK FACTORS
1. AGE
A Chronological age.
25
20
15
10
5
0
51-60
41-50 ani
ani
61-70
ani
>70
ani
<40
ani
1
2
3
4
5
Figure 1. Distribution of cases by age group
An interesting aspect is the occurrence of endometrial cancer at young age. Thus, we found that
between 1997-2008 , 11.84% of the patients were under 45 years; by comparison, between 19831988, the incidence was 9.3%. The youngest patient was 38; young age is a positive prognostic
factor.
B. Age at puberty.
varsta menarha
1
<12 ani
>16 ani
13-15 ani
3
2
1
2
3
Figure 2. Age at puberty
C. The age of menopause.
In our study was enroled 54 cases of postmenopausal women; in 24 cases menopause appeared
after 50 years, representing a significant percentage (44.44%).
2. Parity
II
P
30
20
I
P
10
19
10
28
> III P
19
0
1
2
3
4
Fig. No. 3. . Distribution of cases by parity
Distribution of cases in our study is depicted in Fig. No.3. It is noted that an important proportion is
represented by nulli/primipara (29 cases, 38.15% of cases respectively), which is consistent with
literature data.
3. OBESITY
Obesity is a major risk factor for endometrial cancer. Quantification in the study group was done
with body mass index (BMI, Body Mass Index) calculated by the formula: BMI = G (kg) / H2 (m2).
Distribution of cases is shown in Fig. no. 4:
30
N
25
supra
OBZ I
20
BMI
15
10
5
OBZ
II
sub
0
1
2
3
4
5
OBZ
III
6
Figure 4. Distribution of cases according to Body Mass Index
We notice a large number of patients with BMI above the normal (67%) and 33% of patients with
obesity grade I, II or III, which confirms that obesity is a risk factor for the occurrence of endometrial
adenocarcinoma.
4. Treatment with Tamoxifen
Between May 1992-February 1997 in IV-th Gynecology Clinic were surgically treated 350 cases with
breast cancer. Postmenopausal patients (208 cases, 56.6% respectively) received adjuvant therapy
with tamoxifen (20 mg / day, 5 years). Patients were instructed to report the occurrence of uterine
bleeding; there were four cases of uterine bleeding caused by treatment with tamoxifen. In the four
cases an endometrial biopsy was performed,: there was no case of cancer, the results were
consistent with endometrial hyperplasia and atrophic endometrium .
Since 1997, all cases of breast cancer treated with tamoxifen for at least one year within the regular
checks were investigated in terms of endometrial histology. A statistic in 1997-1999 on a number of
78 cases investigated by endometrial biopsy shows no malignant cells and following histological
aspects(Figure no. 5)
Histological Appearance
Number of cases
Endometrial atrophy
67
86 %
Chronic inflammation
5
6.4 %
Complex hyperplasia without 2
atypia
2.5 %
Endometrial polyps
5.1 %
4
Percentage
Figure no. 5. Histological aspects reported for patients treated with tamoxifen
In the study group during 1997-2008, from 76 patients diagnosed with endometrial cancer, one
case had a history of treatment with tamoxifen. Our study does not confirms an increased risk of
endometrial cancer after treatment with tamoxifen. In our conditions, we consider valuable to
recommend to the patients to report immediately in case of uterine bleeding.
5. Endometrial hyperplasia
Endometrial hyperplasia is considered a major risk factor for cancer of the endometrium. The study
shows some interesting aspects in terms of association endometrial hyperplasia - cancer. The
anatomic-pathologic examination of uterus after surgery show the presence of endometrial
hyperplasia in 16 cases (21%) as shown in Fig. no. 6:
complex
without atypia
9
10
8
mild
6
4
complex
with atypia
3
4
2
0
Figure no. 6. Types of endometrial hyperplasia associated with endometrial cancer
Another aspect is the endometrial cancer developed within an atrophic endometrium; it occurs
mainly in older women, are less differentiated, with increased invasion and with a poor prognosis
compared with cancer associated with hyperplasia. In our study, anatomo-pathological examination
showed an association between cancer and atrophy of the endometrium in 12 cases (15.78%). The
average age of cases was significantly higher than the cases associated with hyperplasia (66.5 years).
In terms of tumor differentiation, we find in these cases poorly differentiated cancers (G3 - 7 cases,
58.33% respectively).
CLINICAL DIAGNOSIS
Abnormal genital bleeding is the cardinal symptom of endometrial cancer, it can manifest as
premenopausal or postmenopausal abnormal bleeding. In our cohort in 54 cases (71.05%)
metrorrhagia occurred after menopause and in 21 cases in premenopausal patients(27.63%) (Fig.
no. 7).
60
50
54
40
30
20
21
10
0
postmenopausalmenometrorrhagia
bleeding
Figure 7. Distribution of patients depending upon installation of genital bleeding
Histopathological substrate of postmenopausal uterine bleeding was studied between 2005-2008
on a cohort of 171 patients hospitalized in the Clinic IV "Cuza Voda" Iasi, in which endometrial biopsy
was performed and pathological results are represented in Fig. no. 8.
1
8
20
2
51
3
19
14
23
21
15
4
5
6
7
8
Fig. no. 8. Postclimax-uterine pathological substrate
Legend: 1mild hypeplasia 2. complex hyperplasia 3. complex hyperplasiawith atypia, 4.atrofia, 5.
endometrial polyp 6. inconclusive 7.chronic endometritis 8. endometrial .cancer
Pelvic pain is a symptom less common than metrorrhagia, its presence usually indicates a later stage
of endometrial cancer or the association of the presence of lesions (fibroid, endometriosis, etc.).
3. Clinical exam
Vaginal examination with speculum shows uterine origin of bleeding ; digital vaginal exam provides
information about the uterus (volume, mobility, consistency), ovaries and vaginal cul de sac.
4. PARACLINIC EXAM
4.1. Babes-Papanicolaou smear
4.2.Ultrasonography
4.3.Histeroscopy
4.4. Endometrial biopsia
4.1. Citodiagnostic smear. Citodiagnostic smear was collected and interpreted in 50 cases (65.79%)
from 76 . Distribution of cases is depicted in Fig. No. 9
25
23
20
15
10
8
10
5
4
5
4
5
0
1
2
3
Fig. no. 9. Distribution of patients depending upon Pap smear class
4.2. Ultrasonography
Minimal endometrial thickness to consider a lesion as suspicious is 5 mm in postmenopausal
women and 10 mm in premenopausal or on hormone replacement therapy patient. Of the 76 cases
examined, in 36 cases (47%) we assesed endometrial thickness by endovaginal ultrasonography
(Figure 14).
Fig. no. 10. Endometrial cancer: thick endometrium with heterogeneous structure
( 4-th Gynecology Clinic collection)
Endometrial thickness for the 28 cases of postmenopausal patients is depicted in Fig. no. 11.
10
10
8
6
6
4
2
0
4
5
1
5 mm 6 mm 7 mm 8 mm 9 mm
2
≥10 mm
Fig. no. 11. Postmenopausal endometrial thickness
The average endometrial thickness in postmenopausal cases was 7.7 mm. It is noted that in all cases
endometrial thickness was beyound the cut-off of 5mm , indicated in literature as the limit of
suspicion for endometrial cancer.
Measurement of endometrial thickness in premenopausal patients in the eight patients showed the
following results (Fig No 12)
2
1,5
1
0,5
0
8mm 11mm 12mm 13mm 1 5mm
Fig. no. 12. Endometrial thickness in premenopausal patients
The average endometrial thickness in premenopausal cases is 12.8 mm; we note that one case had
endometrial thickness below the cut-off of 10 mm, considered at risk for endometrial cancer.
4. 3. Hysteroscopy. Hysteroscopy is a very useful method for diagnosis of endometrial cancer,
because it allows direct inspection of the uterine cavity, highlighting suspicious lesions and allows
targeted biopsy .
Lack of hysteroscopy kit in 4-th Gynecology Clinic did not allowed us to investigate all cases by
hysteroscopy. To assess the value of hysteroscopy for endometrial cancer diagnosis, we studied a
group of 56 patients treated in the Clinic III "Elena Doamna" investigated by histeroscopic method.In
35 cases biopsy was perform by histeroscopic way and in 21 cases by curettage. Of the 35 cases in
which biopsy was performed under visual control during hysteroscopy, 32 cases were positive for
malignancy; in three cases the lesions were interpreted as complex hyperplasia with atypia.
Accuracy of the hysteroscopy was 91.4%.
Fig. no. 13. Endometrial cancer – hysteroscopic aspects (3-rd Gynecology Clinic Collection)
4.4. Endometrial biopsy
In the study group endometrial tissue sampling was done by dilation and curettage ( D&C). The main
indication for endometrial biopsy was abnormal uterine bleeding before of after menopause.
Endometrial biopsy was widely practiced at patients treated with tamoxifen, without vaginal
bleeding, in order to assess the risk of endometrial cancer.
Biopsy by curretage had a good diagnostic accuracy: the procedure aprreciated histological grade in
55 cases ( 88.7%);in six cases histological grade was underestimated by biopsy (9.67%) and in one
case, overestimated (1.61%). .
Cervical invasion could be assessed in 54 cases in which curettage was performed divided; in 16
cases we found that tumor has invaded the glands or cervical stroma.
Endometrial cancer-TREATMENT RESULTS AND DISCUSSIONS
Surgery
Until 1998 we used the clinical staging of endometrial cancer; from 1998, FIGO recommends the
surgical staging, which incorporates several elements that can be obtained only by surgical
treatment:
-peritoneal cytology
-miometrial invasion
-adnexal Invasion
- cervical invasion
-Invasion of pelvic organs / distant metastases
- lymph node-status
This work focuses on surgical treatment performed in the4-th Gynecology Clinic and highlights
some innovations introduced in recent years .
1.2. SURGICAL STAGING
Fig. no. 14. Surgical staging endometrial cancer (personal collection)
Anesthesia was in all cases general anestesia with intubation , which provides a proper analgesia,
good muscle relaxation and a better control of vital functions during surgery. No major anesthetic
complications were recorded.
Skin incision was in all cases pubo-subombilical median incision, which offers an optimal exposure of
the abdominal cavity required for surgical staging , and could be extended if necessary to the
xiphoid .
After exposure of peritoneal cavity and application of Gosset and Dartigues autostatic valves a
careful pelvic inspection was carried out, identifying internal genitalia. When free intraperitoneal
fluid was found, it was harvested using a sterile syringe and cytological examination was performed
to identify malignant cells. When intraperitoneal fluid was absent, we performed peritoneal cavity
lavage with 20 ml of warm saline, which was drawn by syringe microscopically examined.
Fig. no. 15. Endometrial cancer, intraperitoneal fluid (personal collection). Microscopic
examination showed the presence of malignant cells.
Peritoneal cavity inspection was carried out to identify any tumoral spread .The types of surgery is
listed in Fig. no. 16 and 17.
1
2
Fig. No. 16.Type of iIntervention: 1 subtotal hysterectomy, 2. total hysterectomy 2
Figure No. 17. Total hysterectomy: Intraoperative aspect / uterus with adnexae
(4-th Gynecology Clinic collection)
In the study group we performed total abdominal
hysterectomy with selective pelvic
lymphadenectomy in 39 cases; the number of lymph nodes removed was between 1-7 with an
average of 3. Of the 39 patients undergoing selective pelvic lymphadenectomy only in 2 cases we
found nodal invasion.
Bilateral oophorectomy was performed in 74 cases, becuase of the risk of metastases in the
adnexae or synchronous tumors of the endometrium and ovary.
Partial omentectomy was carried out as part of surgical staging in 21 cases (27.6%). In two cases,
pathological examination showed the presence of metastases at this level (9.5% of cases); the cases
was associated with adnexal invasion and positive peritoneal cytology (Fig. no. 30.31). Based on
these findings we conclude that omentectomy may be practiced in the surgical treatment of
endometrial cancer, being a simple procedure, which provides useful information for prognosis.
Fig. no. 18. Partial omentectomy
(Personal collection)
Fig. no. 19. Epiploic metastasis : microscopic
aspect
Peritoneal cytology is an element used in surgical staging of endometrial cancer. In our study we
found in 4 cases a variable amount of intraperitoneal fluid , up to 500 ml. Cytological examination
showed the presence of malignant cells in three cases (75%) ; in one case it was a synchronous
endometrial cancer with a bilateral ovarian cancer, malignant cells being probably exfoliated from
the surface of ovary. In the other two cases, positive peritoneal cytology was associated with
adnexal invasion , invasion of cervix and deep miometrial invasion (> 50%).
Miometrial invasion is a major prognostic factor, along with histological type, histological grade,
nodal invasion and stage.
We performed cutting and gross visual inspection of the uterus in 8 cases; in 6 cases (75%), depth of
invasion assessed by gross visual inspection was confirmed by paraffin exam, and in two cases
invasion was underestimated. We believe that the method is cheap, fast and can provide useful
information on miometrial invasion; we recommend that the procedure to be performed in the
presence of morphopathologists(Fig. no. 32).
Fig. No. 20. Gross visual inspection (personal collection)
An important part of surgical staging of endometrial cancer is lymphadenectomy, selective (biopsy)
or systematic pelvic lymph node dissection of pelvic and paraaortic lymph nodes.
Of the 76 cases analyzed, 39 received selective pelvic lymphadenectomy (51.31%). The right pelvic
lymphadenectomy was performed more frequently (32 cases and 82%), bilateral (three cases,
7.69%), left (one case, namely 2.56%) and lymphadenectomy with extemporaneous pathological
examination (three cases, namely 7.69%) (Fig. no. 33).
Fig. No. 21. Selective pelvic lymphadenectomy (4-th Gynecology Clinic collection)
Number of nodes obtained by sampling was between 1 and 7, with an average of three nodes. In our
study of 39 cases in which selective lymphadenectomy was performed in 2 cases (5.1%) malignant
adenopathy was identified: a case with serous papillary cancer with low differentiation (G3) and one
with adenoscuamos cancer , G1, both with deep miometrial invasion (> 50%).
1.4. Complications
Significant intraoperative complications occurred in three cases as follows:
-a lesion of urinary bladder, treated by suture and antibiotic therapy, with favorable evolution.
-a lesion of small intestine treated by suture, complicated in 3rd postoperative day by an intestinal
fistula, which necessitated transfer to a general surgery unic for repair, with further positive
developments .
-a lesion of the small intestine at the opening of peritoneal cavity due to entero-parietal adhesions,
treated by resection-anastomosis of intestine, which at 48 hours after surgery developed an
intestinal fistula, repaired by general surgeon.
The average duration of hospitalization was 10 days, with variations depending on patient age,
postoperative complications.
2. Adjuvant therapy
Of the 84 cases analyzed , eight cannot be surgically treated because of poor biological status or
advanced stage of disease.. Patients were reffered to oncology services and were treated as follows:
- 4 cases external radiotherapy
- 2 cases hormone therapy
-1 case chemotherapy
- 1 case of combined treatment, chemotherapy + radio.
The eight cases were gradually lost from surveillance..
Of the remaining 76 cases operated in 14 cases pathological examination showed no malignant
lesions; in these patients, considered with minimal risk of relapse, we reccomended surveillance
without adjuvant posttherapeutic treatment. Prognosis in these cases was favorable, with no
recurrence and 100% 5 years- survival.
Cases of high risk group undergone adjuvant therapy as follows:
-Radiotherapy 18 cases
-Radiotherapy + chemotherapy 9 cases
-Hormone therapy 3 cases
-Chemotherapy, 4 cases
-Absence of adjuvant therapy in 7 cases
3. The major goal of posttherapeutic surveillance is early detection of recurrence, followed by
appropriate treatment to increase survival and reduce morbidity related to relapses.
Patients experienced recurrence as follows:
-3 recurrences in the vaginal cuff
-a recurrence in the abdominal wall
-a pelvic recurrence.
As a conclusion, I propose the following therapeutic algorithm in endometrial cancer:
operable case
inoperable case
Surgical staging
RT / CHT / HT
Adjuvant therapy
depending on
prognostic factors
posttherapeutic surveillance
Prognostic factors of endometrial cancer, RESULTS AND DISCUSSIONS
1.Age.
2.Stage.
3. Histological grade.
4. Histologic type.
5. Miometrial invasion.
6. Invasion of lymph nodes.
7. Isthmic invasion.
8. Peritoneal cytology.
9. Hormone- receptor status.
10. Vascular-lymphatic space invasion.
11. Ki67.
1. AGE
Distribution of patients by age is depicted in Fig. no. 29; we note a number of 21 cases (27.6%) of
young women (age under 50), while 8 patients (10.5%) were with advanced age (over 70). To show
the relationship between age and other prognostic factors, we comparatively studied two age
groups: under 50 years versus over 70 years .
25
20
15
10
5
0
51-60
41-50
61-70
>70
<40
1
2
3
4
5
Fig. no 22 Age of patients
Analysis of eight patients over 70 years confirms the literature data : only one case (12%) of welldifferentiated tumor, the remaining of 88% being medium or low differentiated tumors (Fig. no. 30).
G3=25% G1=12%
G2= 63%
Fig. no. 23. Age> 70 years: histological grade
By comparison, from 21 patients under 5o years , at 7 of them microscopic examination of
operative specimen showed no malignant cells; excluding these cases, the 14 remaining cases have
the following distribution according to tumor grading (Fig. no. 31).
G2=29%G3=7%
1
2
G1=64%
3
Fig. no. 24. Age <50 years: degree of differentiation
We can see the high percentage of well differentiated tumors at young women.
Comparative analysis of two groups of cases let us stipulate that advanced age is an unfavorable
prognostic factor in endometrial cancer.
Stage
If this study, we obtained the following results of disease-free interval and survival at two, three
and five years:
stage
Ia
Ib
Ic
IIa
IIb
IIIa
IIIc
2 years
Diseasefree
interval
93.5
84.5
74.9
Survival
95.3
96.0
91.0
89.0
87.5
77.0
70.4
3 years
Diseasefree
interval
91.1
79.8
69.3
Survival
92.4
93.5
88.0
83.1
81.1
71.0
63.4
5 years
Diseasefree
interval
87.1
75.9
63.1
Survival
88.9
90.0
80.7
79.9
72.3
63.4
51.1
* A number of 19 patients were lost to follow-up at two years, 21 at 3 years and 25 at 5 years
Table no. 25. Disease free interval and survival at two, three and five years
Most patients in the study group showed no local recurrences or distant metastasis . Local
recurrences were detected during the first three years at the level of the vaginal stump in three
patients diagnosed with tumors in stage Ib, Ic, IIIc, an abdominal wall recurrence in a patient with
papillary serous carcinoma in stage Ic and a pelvic recurrence in a patient in stage IIIc.
Fig. no. 26. Endometrial cancer surgery: recurrence in the abdominal wall (4-th Gynecology Clinic)
Patients with recurrences at the vaginal stump received
treatment method, and for pelvic recurrence, chemotherapy.
external radiotherapy as adjuvant
Degree of differentiation
Degree of differentiation is an important prognostic factor for endometrial cancer, especially in
endometrioid carcinomas.
In our study, of the 62 cases in which paraffin exam identified malignant lesions, the degree of
histological differentiation is represented in Fig. no. 37
G3=13
cazuri
21%
G2=24
cazuri
39%
G1=25
cazuri
40%
Fig. no. 27. Histological grading.
Comparing the two groups of tumors with good (G1) and poorly differentiation (G3) we note that
the degree of differentiation is a predictor of miometrial invasion: only 16% of G1 tumors shows
deep miometrial invasion versus 69% of G3 tumors (Fig. no. 28).
deep invasion
16%
sup erficial invasion
84%
sup erficial invasion
31%
deep invasion
69%
Fig. no. 28. Miometrial invasion depending on tumoral grading
miometrial invasion -G1
-miometrial invasion – G3
We studied statistically the relationship between hormone receptor status and degree of
differentiation, knowing that expression of receptors for estrogen and progesterone is
characteristic of well differentiated tumors. We have demonstrated this correlation only for
estrogen-receptor: Chi-square method showed that estrogen-receptor positivity is significantly
associated with degree of tumor differentiation (Table no. 39)
Codes X
ER
Codes Y
GRD_DIF
GRD DIF
Chi-square
12.268
DF
6
Significance level
P = 0.0463
Contingency coefficient
0.637
Table no. 29- relation between estrogen receptors and degree of differentiation
In contrast, progesterone receptor status is’nt related to the degree of differentiation
Codes X
PR
Codes Y
GRD_DIF
GRD DIF
Chi-square
7.013
DF
8
Significance level
P = 0.5352
Contingency coefficient
0.529
(Table no. 30: relation between progesteron receptors and degree of differentiation
Histological type
After excluding the 14 cases in which microscopic exam shows no malignant lesions, the proportion
of each histological type is shown in Fig. no. 42:
3% 2%
8%
5%
6%
76%
1
2
3
4
5
6
Fig. no. 31. Histological types: 1. Endometrioid, 2. Viloglandular 3. Endometrioid with squamous
metaplasia, 4. Serous, 5. Clear cell, 6. Adenosquamos
Endometrioid type adenocarcinoma was found in 76% of all cases of endometrial adenocarcinoma,
similar to the incidence in the literature (80-90%).
Fig. no. 32. Endometrioid endometrial adenocarcinoma well differentiated type,
invasive(Laboratory of morphopathology, Cuza Vodă Hospital)
Analisys of the cases shows the predominance of well differentiated tumors ( G1=22 cases) and
intermediate( G2=17 cases), but also a significant number of cancers poorly differentiated( G3=8
cases)(fig.nr.45 ).
G3=17%)
G2=36%
G1=47%
Fig. no. 33. Endometrioid cancer: degree of differentiation
From the 13 cancers without miometrial invasion (stage IA), 12 had endometrioid histology (92.3%).
no invasion=26%
deep invasion=36%
superficial=38%
Fig. no. 34. Endometroid cancer: miometrial invasion
Ranked second in incidence in the studied group lies viloglandular cancer, a variant of endometrioid
adenocarcinoma with favorable prognosis (Fig. no. 47).
Fig. no. 35. Viloglandular carcinoma
Vodă Hospital)
, Col HE, ob x 20. (Laboratory of morphopathology, Cuza
In our study, two were well differentiated (G1) and two mild differentiated (G2) ; miometrial
invasion was absent in one case,in two cases was superficial and deep in one case.
Fig. no. 36. Endometrial adenocarcinoma , endometrioid type with squamous differentiation Col.
HE, ob x 20. (Laboratory of morphopathology, Cuza Vodă Hospital)
In the study group we found two cases of serous type of adenocarcinoma . Microscopic tumor
architecture was papillar.
Fig. no. 37. Serous endometrial cancer (personal collection)
Fig. no. 38. Serous type of endometrial adenocarcinoma Col HE, ob x 20
(Laboratory of morphopathology, Cuza Vodă Hospital)
Serous cancer prognosis is more poorly than endometrioid form with survival at 5 years by 45% in
stage I and II and 11% in stages III and IV.
Clear cell adenocarcinoma
Of the 76 cases studied, clear cell cancer was identified in one case, which was associated with deep
miometrial invasion (> 50%), endocervical invasion (stage IIB) and degree of differentiation G1. The
prognosis is considered reserved because of miometrial and vascular invasion, survival at 5 years
being between 35% and 65%. For these reasons the patient received adjuvant radiotherapy
recommendation.
MIOMETRIAL INVASION
Miometrial invasion can be assesed preoperatively or postoperatively. The assessment is made by
preoperative imaging methods (endovaginal sonography and best by MRI).
Statistical analysis of cases (Kruskal-Walis test) showed a significant correlation between miometrial
invasion and aggressive histological types:
No table. 39. Kruskal-Wallis test for testing association between histological type, miometrial
invasion.
Data
TIP_HISTO
TIP HISTO
Factor codes
INV_MIOM
INV MIOM
Test statistic
5.9903
Corrected for ties Ht
8.6487
Degrees of Freedom (DF)
3
Significance level
P = 0.0343
Depth of miometrial invasion is correlated with patient age, advanced age being a marker for deep
miometrial invasion , young patients harbouring a lower risk (Student t test):
Variable
INV_MIOM
INV MIOM
Sample 2
Variable
VARSTA
Mean difference
57.6557
Standard deviation
9.8774
95% CI
55.1260 to 60.1855
Test statistic t
45.590
Degrees of Freedom (DF)
60
Two-tailed probability
P < 0.0001
Table no. 40. Relation between age and miometrial invasion
LIMPH NODE INVASION
Since selection of cases with low risk of nodal dissemination can not be done with enough accuracy,
we recommend the routine practice of limphadenectomy .
If this study we performed a total of 39 selective pelvic limphadenectomy , removing an average
number of three nodes (between 1-7). Of these, in two cases we found metastasis in lymph nodes.
Fig. no. 41. Lymph node metastases (Laboratory of morphopathology, Cuza Vodă Hospital)
Both in literature and in our study, patients with positive lymph nodes received adjuvant therapy
(radiotherapy on pelvic lymph node areas).
7. Isthmic invasion
In this study from the 35 tumor patients in stage I, 8 (22.85%) had isthmic extension.
We analyzed the relative distribution of patients in terms of classical prognostic factors - age,
histological grading, lymphovascular space invasion, depth of miometrial invasion - depending on
the presence / absence of isthmic extension and we obtained the following results (Table no. 58) :
Isthmic invasion
Age
Low grading
ISVL
Deep miometrial
invasion
57,12 ani
18,75%
31,25%
25%
No
isthmic
invasion
58,69 ani
10,53%
15,79%
21,05%
Total
P
57,71 ani
14,28%
22,86%
22,86%
insignificant
0,032
0,002
0,006
Table no. 42. Classical distribution of prognostic factors according to the presence of isthmic
invasion
We propose invasion of isthmus as prognostic factor in endometrial tumors in early stages.
8. Peritoneal cytology
The presence of positive peritoneal cytology was examined in patients with endometrial cancer but
there is no consensus on its prognostic value.
We found intraperitoneal fluid in four cases ; in 24 cases with absent fluid cavity lavage was
performed with warm saline, followed by cytologic examination. In three of the four patients with
ascites cytology was malignant, and in all 24 patients with lavage result was negative.
Fig. no. 43. Malignant peritoneal cytology
(Laboratory of morphopathology, Cuza Vodă Hospital)
9. Hormone receptor status
In the present investigation, immunohistochemical analysis of estrogen and progesterone receptor
was performed in a total of 18 patients. Immunohistochemical explorations were conducted in the
laboratory of immunology of University of Medicine adn Pharmacy Iaşi ; paraffin blocks were
obtained from the Pathology Laboratory of the hospital "Cuza Voda" Iasi.
From the 76 cases immunohistochemical analysis was performed for 18 cases:
pstmenopausal patirents and 5 before menopause.
13 were
Fig. No. 44. Steroid hormone receptor status - immunohistochemical analysis
(Laboratory of morphopathology, Cuza Vodă Hospital)
Analysis of immunohistochemical expression of ER and PR through Spearman correlation test
revealed a statistically significant positive association (p <0.001) .
Histological grading is inversely correlated with both ER expression (r =- 0.35) and PR (r =- 0.17) (Fig.
no. 45)
Scatterplot: Gradul de diferentiere vs. PR
(Casewise MD deletion)
PR
= 2.8627 - .2575 * Gradul de diferentiere
Correlation: r = -.1692
4.5
4.5
4.0
4.0
3.5
3.5
3.0
3.0
2.5
2.5
PR
ER
Scatterplot: Gradul de diferentiere vs. ER
(Casewise MD deletion)
ER
= 3.1159 - .4077 * Gradul de diferentiere
Correlation: r = -.3496
2.0
2.0
1.5
1.5
1.0
1.0
0.5
0.5
0.0
-0.5
0.8
0.0
1.0
1.2
1.4
1.6
1.8
2.0
2.2
Gradul de diferentiere
2.4
2.6
2.8
3.0
3.2
95% confidence
-0.5
0.8
1.0
1.2
1.4
1.6
1.8
2.0
2.2
Gradul de diferentiere
2.4
2.6
2.8
3.0
3.2
95% confidence
Fig. no. 45. Correlation between expression of ER, PR and histological grading
Fig. no. 46. Steroid receptor status - immunohistochemical analysis (PR 95% positive)
The data obtained allow us to assert that the tumors with intense expression of steroid receptors
are associated with better prognosis (good differentiation, early stages) and negativity for ER and PR
is associatewith low degree of differentiation and presence of deep miometrial invasion .
10. Invasion of lymph-vascular space ( LVSI)
In this study lymph-vascular space invasion was evaluated in 54 of the patients included in the study
group and was present in 28 of them (51%). We analyzed LVSI association with other recognized
prognostic factors and survival (immediate and remote). The mean age of patients who had LVSI was
63.25 years compared with 55.69 years for those without LVSI, the difference being statistically
significant (t test p = 0.001).
Lymphovascular space invasion was present especially in moderately or poorly differentiated
tumors; in contrast well differentiated tumors shows no LVSI(Fig. no. 71).
25
8
20
15
10
5
0
16
2
15
11
ISVL absentă
ISVL prezentă
2
G1
G2
G3
Fig. no. 47. Relation between LVSI and histological grading
From 28 patients with LVSI , 20 had deep miometrial invasion , compared with only three of the
patients without LVSI. All serous papillary carcinoma cases, clear cell carcinoma and positive lymph
nodes had LVSI.
Analysis of disease free interval at 1, 3 and 5 years using Kaplan-Meyer curves revealed a 20%
percent higher in three years and almost 40% higher at 5 years for patients without LVSI (Fig. no. 48
).
Fig. no. 48. Relation between LVSI and disease-free interval
11. Ki67
Ki67 antigen is a marker of cell cycle and cell proliferation coefficient used to estimate proliferation
in a cell population.
In this study, Ki67 antigen was determined in 18 patients, the degree of cell proliferation is shown in
the Figure. 49.
7
6
5
4
3
2
1
0
6
Redusă
7
5
Moderată
Intensă
Fig. no. 49. Relation between Ki67 and degree of cell proliferation
Fig. 50. Ki-67 positive 15% - reduced proliferation and KI-67 positive 35% - moderate proliferation
Regarding deep miometrial invasion, it was more common in cases with intense expression of Ki67
(Fig. no. 51)
40%
35%
30%
25%
20%
15%
10%
5%
0%
5,56%
27,78%
Invazie miometrială
>50%
16,67%
27,78%
11,11%
Intensă
Invazie miometrială
<50%
11,11%
Moderată
Redusă
Fig. no. 51. Expression of Ki67 according to miometrial invasion
Analysis of association between tumor grading and cellular proliferation category shows that poorly
differentiated tumors are accompanied by intense positivity for Ki67 (Fig. no. 52).
100%
1
80%
60%
3
6
0%
G3
2
G2
40%
20%
0
0
1
Intensă
2
Moderată
3
G1
Redusă
Fig. no. 52. Ki67 expression according to cytological grading
Of the 18 patients with analysis of Ki67,one has positive pelvic lymph nodes . The data obtained are
concordant with literature that states there is an association between Ki67 is a marker for
aggressive tumors.
CHAPTER XI
GENERAL CONCLUSIONS
Endometrial cancer is a disease of postmenopausal age, most of the patients in the study group
were between 51-60 years.
We found an increasing number of patients younger than 45 years, which requires endometrial
biopsy to check the uterine bleeding after 40 years of age.
Reason for presentation to the doctor was in most cases metrorrhagia; however only 7% of uterine
bleeding was from malign etiology .
Measurement of endometrial thickness by ultrasound is particularly useful at postmenopausal age,
a value less than 5 mm excluding the presence of malignancy .
Gold standard diagnostic method used in study was biopsy by uterine curettage : the method is
cheap , available in all services and provides valuable information about histological type, degree
of differentiation and cervical invasion.
Pap smear Babes has low diagnostic value; in our study, positive Pap smear was associated with
cervical invasion, and a later stage.
We recommend surgical staging, involving total hysterectomy with bilateral anexectomy, peritoneal
cytology, omentectomy and pelvic lymphadenectomy.
Lymphadenectomy can be omitted in cases with low risk of nodal spread : well differentiated
endometrioid adenocarcinoma with superficial miometrial invasion (<50%) ; we recommend MRI
assessment of miometrial invasion.
When MRI is not available we can practice frozen section exam for miometrial invasion.
The patient needs to be included in a risk group according to prognostic factors; high risk cases will
benefit from adjuvant therapy.
Main prognostic factors in endometrial cancer are histological type, the degree of differentiation,
miometrial invasion and stage ; less important are age , hormone-receptor status, nodal invasion
and index of proliferation.
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