CLINICOPATHOLOGICAL STUDY OF POSTMENOPAUSAL BLEEDING

Dr. Vijaya Singh 1 , Dr. Sudhanshu Sekhar Nath 2 and Dr. Chintamani Mohanta 3 . 1. Junior Resident. 2. Senior Resident. 3. Assistant Professor. ...................................................................................................................... Manuscript Info Abstract ......................... ........................................................................ Manuscript History

Abnormal uterine bleeding is frequent in gynecological complaint and accounts approximately 5-10% of postmenopausal women. About 10% of women with postmenopausal bleeding have a primary or secondary malignancy. Common malignancies among them are endometrial cancer, cervical cancer or an ovarian cancer. The incidence of malignancy in postmenopausal period remains sufficiently high so it requires immediate investigation for early diagnosis, vigilant follow up and prompt treatment. Aims and Objectives: To ascertain etiological factors of postmenopausal bleeding and to investigate its clinical significance in terms of incidence of malignancy and histopathological evaluation. Materials and Method: A total 100 patients with postmenopausal bleeding per vaginum attending the outpatient department or admitted for evaluation under Obstetrics and Gynaecology Department, VSSIMSAR, Burla, Sambalpur, Odisha over a period of two years from November 2014 to October 2016 were selected and studied. Results: The average of PMB was 56.68 years with highest incidence of cases between 55-65 years (52%). The incidence of malignancy was 57% out of which carcinoma cervix was found to be the most common malignancy causing postmenopausal bleeding representing 46% of total cases and 81% of total malignancies. Carcinoma endometrium found in 12% cases among total malignancies, resulting in carcinoma endometrium : carcinoma cervix ratio to be 1:7. On histopathology, we found atrophic endometrium in 49% ,proliferative endometrium in 6% of cases and hyperplasia in 14% of cases. Conclusion: Carcinoma of genital tract is one of the most important cause of PMB, so early detection of the causes can be life saving. Endometrial sampling is a cost effective procedure to rule out endometrial carcinoma /detect in very early stage. .
Stage I endometrial carcinoma has a 5 year survival rate of 98%, so early discovery greatly improves the chances of cure. It is estimated that postmenopausal women with vaginal bleeding have a probability of endometrial carcinoma of approximately 10% 7 .
The chances of postmenopausal bleeding decreases with increasing age but the frequency of malignancy is increased with increased age and increased with increased interval between postmenopausal bleeding and menopause. 8 Transvaginal ultrasonography (TVS) is the recommended first line non invasive procedure for assessing the endometrium in women with PMB. Measurement of endometrial thickness by TVS having a cut off of >4mm yields 98% sensitivity for detection of endometrial carcinoma 9 . Hysteroscopy and biopsy (curettage) is the preferred diagnostic technique to detect polyps and other benign lesions and to obtain endometrioum for histopathological examination. Following such assessment reassurance can be given or further investigations or treatment can be discussed and rearranged 10 .
Etiology of postmenopausal bleeding in about 80-90% patients are benign like atrophic vaginitis, endometrial or cervical polyps, simple endometrial hyperplasia, infections,decubitus ulcer in cases of uterovaginal prolapse, neglected pessary and forgotten intrauterine contraceptive device.
Proper evaluation of PMB will isolate the benign conditions. Treatment of benign conditions with reassurance and early detection and treatment of malignant lesions will help a menopausal lady to lead a healthy life.
Aims and objective:- To ascertain etiological factors of postmenopausal bleeding  To investigate the clinical significance of postmenopausal bleeding in terms of incidence of malignancy and histopathological evaluation.

Source of data:-
The data was collected from patients with postmenopausal bleeding per vaginum attending the outpatient department or admitted for evaluation under Obstetrics and Gynaecology Department, VSSIMSAR, Burla, Sambalpur, Odisha over a period of two years from November 2014 to October 2016. A total of 100 cases who presented clinically with PMB varying from spotting per vaginum, scanty flow, moderate to profuse bleeding were included.

Study design :-
This study was a prospective study of the patients with postmenopausal bleeding attending the outpatient department or admitted for evaluation under Obstetrics and Gynecology Department, VSSIMSAR, Burla, Sambalpur.

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A total of 100 cases who presented clinically with postmenopausal bleeding were selected. Written and informed consent was taken. They were evaluated by history, clinical examination and investigations like abdominal/transvaginal sonography, endometrial biopsy, fractional curettage, Papanicolau smear and hysteroscopic guided biopsy if required was done for all subjects and the specimens collected was sent to the department of pathology for examination and reporting. Depending on the reports obtained, the data was recorded and analysed by descriptive statistics using percentages.   Rural 78 78 78% of total cases came from rural areas, whereas 22% of cases were from urban areas.  Grand multiparous 29 29 411 61% of the patients were multipara and 29% of patients were grand multipara (parity ≥ 5). Whereas only 5% of cases were nullipara and primipara each. Benign 43 43 57% of cases were of malignant origin and rest 43% of the cases were benign. 1 Carcinoma cervix is most common 55-64years of age (57%) and is most common among multiparous and grand multiparous women accounting for almost 98% in total. Carcinoma endometrium is also most common in 55-64 years of age and is more commonly seen in nulliparous women (43%).
Carcinoma vagina has maximum incidence in 55-64 years (67%) and is more commonly seen in grand multiparous women (67%). Whereas carcinoma ovary seen in multiparous women and in 45-54 years of age. Vaginal discharge was the next most common complain after postmenopausal bleeding. Foul smelling, mucoid, watery or blood stained discharge were important clinical presentation of carcinoma cervix (72%). All cases of carcinoma ovary presented with mass and pain in abdomen.
412 Most commonly benign cases were seen between 45-64 years of age 81% and maximum cases were seen in multiparous women constituting 70% and grand multiparous 19%.
Atrophic endometrium (42%) was the most common histological finding associated with CIN and cervicitis in some cases. Endometrial Hyperplasia was seen in 14% of cases and leiomyoma & adenomyosis was seen in 16% of cases. Polyps seen in 9% of cases. After abnormal uterine bleeding, the second most common associated clinical presentation in benign cases was vaginal discharge, whitish, watery or mucoid in nature seen in 14% of cases followed by pain in abdomen seen in 9% of cases. ≥ 75 2 2 (100%) Malignancy was found in 64% in the age groups of 55-64 years followed by 51% in 45-54years and 45% in 65-75 years of age. However no malignant cases found less than 45years of age and in 100% of cases above 75years. Among benign cases 100% were found in age group of 40-44 years followed by 48% in 45-54 years age group, 36% in 55-64 years group and 55% in 65-75 years of age. No benign cases were found after the age of 75years. Ca Vulva --Carcinoma cervix was found to be the most common cancer amongst the patients presenting with postmenopausal bleeding in this study accounting 81% of the total causes. Carcinoma endometrium was seen in 12% of cases followed by carcinoma vagina (5%) and carcinoma ovary (2%). SCC Keratinisng 1 14 Adenocarcinoma of the endometrium (72%) was the most common histological type seen followed by epithelial and squamous cell kaertinising 14% each.  Insufficient tissue 6 11.7 Total 51 100 In 51 cases endometrial sampling was done. Atrophic endometrium was the most common finding seen in 49% of cases followed by Ca endmoetrium in 11.7% of cases. Insufficient tissue was obtained in 11.7% of cases on curettage, indicating inactive endometrium. However some of these cases were associated with other uterine pathology like leiomyoma. Adenomatous hyperplasia was found in 2% of cases.  Duration of bleeding ranged from one day to 5 years. Incidence of malignancy was found maximum 94% in patients who consulted at hospital between 6-12 months of first appearance of postmenopausal bleeding. 80% of patients presented within first six months of appearance of postmenopausal bleeding among which 50% were malignant and 50% were benign.  >10 37 37 54% of patients had Hb levels between 8-10 gm% i.e. they were mildly anemic and only 1% of cases were severly anemic with Hb levels less than 6 gm%.  Adenosquamous 1 2% Squamous cell carcinoma of the cervix was the most common histological type found among carcinoma cervix cases (98%). Among SCC large cell was the most common type seen. Small cell SCC was seen in 4% of cases. Ovarian pathology 2 2 9 Others 5 5 10 Inconclusive 2 2 Total 100 100 The most common cause of postmenopausal bleeding was found to be carcinoma cervix (46%) followed by atrophic endometrium (18%). Carcinoma endometrium accounted for 7% of the total causes . Here, the other causes include HSIL, proliferative, secretory and anovulatory endometrium.

Discussion:-
Postmenopausal bleeding is generally regarded as ominous and serious symptom. It is an alarming sign of genital malignancy.
The primary aim is to identify and exclude atypical hyperplasia and endometrial carcinoma. The risk of endometrial carcinoma in women with postmenopausal bleeding rises with age from 1% at the age of 50 years to approximately 25% at the age of 80 years.11 By conducting this study in Department of Obstetrics and Gynaecology, VSS IMSAR Burla Sambalpur we have made an attempt to find out the common causes of postmenopausal bleeding in the western part of Odisha and the incidence of malignancy among them attending gynecology department both indoor as well as OPD from November 2014 to October 2016.
The age of patients ranged from 44-80 years with an average of 56.68 years (SD-6.73). The highest incidence of cases was between 55-65 years (52%) followed by 45-54 years. (Table no 13.The lower mean age in our study group may be due to higher incidence of cervical carcinoma which has early age of presentation. In our study 78% of the patients were of rural areas (Table no. 2). Our hospital being the only tertiary centre in western Odisha, serves all the nearby rural areas.

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In our study 76% of the patients were illiterate (Table no 3). Lack of education led to ignorance of spotting or staining after the menopause with the result of presentation after long period with advanced stages of cancer. Uneducated, rural population made the major proportion of cancer patients with inoperable stages.
Being a government hospital our institution serves mainly the lower social classes. In our study all patients belong to either class III, IV or V of Prasad's scale (Table no.

4).
In present study 32% and 8% of patients were having hypertension and overweight, respectively. 5% of women were suffering from diabetes mellitus.We found diabetes mellitus, hypertension and obesity to be associated with endometrial hyperplasia and Carcinoma endometrium, however this is a very small sample size to draw any conclusions. Our observation is comparable to a study conducted by Kavitha78 (2013) et al in which hypertension was found in 36.6%, diabetes in 13.3% women & 43.3% of women were overweight.
In the present study we found the incidence of malignancy to be 57% (Table no. 6), which is in accordance with the studies mentioned, but in more recent studies this incidence is found to be lower.
While most of the earlier work showed an incidence of malignancy in patients presenting with postmenopausal bleeding ranging from 53% to 90%, figures greater than 50% are seldom found in the more recent literature, in fact most of the series state incidence lower than 35% as shown in following A decreasing trend in the incidence of malignancies is observed but in our study, we found a high incidence of malignancy especially of the cervical carcinoma. 57% incidence of malignancy found in our study is almost comparable to 63.6% incidence reported in 1977 study from India by Panda 11 et al & also comparable to 58.5% reported by Ruchita 12 (2014) and 52.86% reported by Arati (2013). These results reflect the lack of awareness leading to late presentation of the patients along with lack of facilities for early diagnosis of malignant diseases at rural and peripheral areas.
We found multiparity to be a high risk for postmenopausal bleeding. In the present study 56% of malignant cases were mutiparous and 33% were grand multipara.61% of cases with carcinoma cervix were mutiparous and 37% were grand mutipara (

Malignant causes of bleeding:-
In our study we found carcinoma cervix to be the most common malignancy causing postmenopausal bleeding representing 46% of total cases and 81% of total malignancies. Carcinoma endometrium found in 12% cases among total malignancies, resulting in carcinoma endometrium : carcinoma cervix ratio to be 1:7 which is in contrast to that found in other studies. The low incidence of cervical cancer in Western studies could be due to effective methods for screening and diagnosis of cervical carcinoma and its precursor lesions that has reduced the incidence of cervical carcinoma as a cause of postmenopausal bleeding in developed countries. On the other hand, in countries where effective cervical screening programme is not in place, especially in a developing country, cervical carcinoma still accounts for a majority of cases with postmenopausal bleeding.
In all studies carcinoma endometrium and carcinoma cervix were the commonest malignant causes. In postmenopausal women the anticipated ratio between endometrial and cervical carcinoma is 1:1. Most of the studies from other countries gave almost similar ratio. Norris 13 in 1935 noted that "after the menopause have been established the relative incidence of corpus carcinoma increases and practically parallels that of the cervix".
Pacheco & Kempers 14 (1964) found the ratio of 16:1 between endometrial carcinoma and cervical carcinoma in their study. They explained it by lowered incidence of advanced cancer of cervix through widespread and thorough use of cervical smear. Also they selected cases only after 2 years of menopause. They suggested that since the cervical cancer develops at an earlier age than does endometrial cancer, they found small number of cervical cancers.
Rai 15 (2001) reported the ratio of endometrial carcinoma to carcinoma cervix to be 1:10 in India. In 1977 by Panda 11 et al carcinoma cervix as a cause of postmenopausal bleeding in 53% of patients comparable to its incidence of 46% in our study. This high frequency is attributed to the high incidence of undiagnosed cancer of cervix in this underdeveloped country. Effective methods for screening and diagnosis of cervical neoplasia and its precursor lesion have effectively eliminated it as a significant cause of postmenopausal bleeding in developed countries, but we are still far from that situation. Recent study by Epstein (2006), calculated ratio of carcinoma cervix to carcinoma endometrium to be 2:1.
We found Ca endometrium in 7% of cases and Ca ovary in 1% of cases which is similar to observed by Arati et al(2013) Ca endometrium was 9.28% and Ca ovary 3.57%.
We found adenocarcinoma endometrium in 5% of cases and SCC & malignant epithelial carcinoma of endometrium each in 1% of cases. Lidor 16 et al (1986) found it in 7% and Gredmark 17 et al (1988) found it in 8% of the cases. Carcinoma cervix was most common in age group 55-64 years accounting for 56.5% cases among total carcinoma cervix cases.
Benign causes of postmenopausal bleeding:-Atrophic endometrium, leiomyomas/adenomysosis, endometrial hyperplasia and polyps were the most commonly found benign conditions, each constituting 18%, 6%, 7% and 4% respectively Atrophic endometrium was the most common benign cause in this study, associated with CIN and chronic cervicitis in some cases (Table no. 13).
In present study, Clear span, the period between cessation of periods and occurrence of postmenopausal bleeding, ranged from one to 25 years. Lee 18 et al (1995)

Endometrial Histology:-
In our study we found atrophic endometrium in 49% of cases (Table no.  In our study we did not find even a single case of estrogen administration, but still proliferative endometrium was found in 6% of cases and hyperplasia found in 14% of cases. If no estrogens have been given, the possible involvement of a pathological ovarian process should be borne in mind. Adenomatous hyperplasia, with or without atypia, is considered to be a precursor of carcinoma (Caspi 26 et al,1977) and was found in about 1% of women in the present study. The relatively low incidence of hyperplasia as the cause of bleeding could be due both to the strict selection of postmenopausal women and to the fact that none had been treated with estrogen replacement therapy.
In present study 2 cases were diagnosed as cystic hyperplasia of endometrium on curettage finding, however, on histopathological examination of the specimen showed as one having Ca endometrium and the other one leiomyoma with atrophic endometrium.

Stage Of Cervical Cancers:-
At the time of presentation 2% of cases were in stage IA, 17% in I B, 26% in IIA and 55% were stage II B and above i.e. 55% of the total cases were inoperable at the time of presentation. This indicates an urgent need for widespread and thorough screening programme for cancer cervix in a developing country like India and especially in a peripheral set up like ours.

Causes Of Postmenopausal Bleeding:-
In the present study the most common cause of postmenopausal bleeding was carcinoma cervix (46%) to be followed by atrophic endometrium (18%) and carcinoma endometrium (Table no.  Majority of the patients were in the age group 55-64 years (52%) and were multipara (61%).
Most of the patients were illiterate (76%), belonging to rural areas (78%) and to low socioeconomic status (80%). Incidence of malignancy was 57% and benign lesions was 43%.
Carcinoma cervix was the most common cause of postmenopausal bleeding followed by atrophic endometrium and carcinoma endometrium.
Carcinoma cervix was the most commonly encountered malignancy and was more found in 45-64 years of age group (87%) and in multiparous (61%) and grand multipara (37%).

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Carcinoma vagina was more frequently found in 45-64 years of age (100%) and in grand multipara (67%). Carcinoma ovary was more frequently found in 45-64 years age group (100%) and multiparous women (100%). Abnormal uterine bleeding was found in all cases of carcinoma endometrium, carcinoma cervix, carcinoma vagina and carcinoma ovary.
Foul smelling, watery, whitish or mucoid vaginal discharge was the second most important clinical presentation of carcinoma cervix.
All cases of carcinoma ovary presented with mass abdomen. Benign lesions were most commonly seen in 45-64 years (84%) and in multiparous women (65%).
After abnormal uterine bleeding, the second most common associated clinical presentation was whitish, watery, mucoid or foul smelling discharge (14%).
Incidence of malignancy gradually increased, as the age advanced. Incidence of malignancy was found to be 51% in 45-54 years age group, 64% in 55-64 years age group, 45% in 65-74 years age group and 100% above 75 years of age.
The incidence of malignant lesion underlying the bleeding increased with the postmenopausal clear span with 33% of malignant cases in less than 6 years,55 % in 6-10 years, 68% in 11-15 years, 56% in 16-20 years and 100% in more than 20years.
Atrophic endometrium, leiomyoma of uterus, endometrial hyperplasia and polyps were the common benign pathology.

Conclusion:-
With increased life span the incidence of postmenopausal bleeding is on rise. Since the incidence of malignancy is quite high, any bleeding in that age group should be evaluated in the line of malignancy unless otherwise proved. Patient characteristics like nulliparity, hypertension , diabetes mellitus, obesity etc should be taken into account in the diagnostic workup along with increased endometrial thickness >4mm by transvaginal sonography (TVS) while considering further investigations like endometrial sampling.
High cervical cancer preponderance stresses on need for better patient education for screening and early diagnosis. Although routine Papanicolaou smears are easily available and widely encouraged, our system depends on opportunistic screening of women who seek medical care and misses out on many women, especially the elderly and those in high risk groups, who may not be aware of serious implication of postmenopausal bleeding and significance of routine Papanicolaou smears. Hence, there is need to intensify cytology screening programmes and to increase the awareness in general population about the value of periodic gynecological examination and adoption of healthy and hygienic practices.