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Histomorphological Pattern of Childhood CNS Tumor: An Experience at National Institute of Neurosciences & Hospital, Bangladesh


Histomorphological Pattern of Childhood CNS Tumor: An Experience at National Institute of Neurosciences & Hospital, Bangladesh

 *Huq N,1 Haque ME,2 Baqui MN,3 Yusuf A,4 Islam N5

Abstract

CNS tumors in childhood differ considerably from adult in term of geographic distribution, histological patterns, clinical and therapeutic aspects, prognosis and outcome. There is a paucity of study about the distribution pattern of CNS tumors in pediatric age group in Bangladesh. National Institute of Neurosciences & Hospital (NINS&H) is a tertiary health care hospital in Bangladesh dealing with the neurological diseases having a well developed Pediatric Neurosurgery department. The purpose of the present study was to see the histomorphological pattern of childhood CNS tumors and the frequency distribution in Bangladesh. We analyzed the data compiled from CNS lesions biopsied in Pediatric Neurosurgical department and reported from the Department of Neuropathology of NINS&H during the time period of June 2013 to April 2016. A total of 239 cases of pediatric CNS lesions were included in this study. 180 cases were CNS tumors and 59 were tumor like lesions which was not further analyzed. The mean age was 10.30±5.48 years. Most of the patients were in 10 to 15 years age group. A slight male predominance was seen. Out of 239 cases 140 were intracranial and 50 were spinal. There were (103, 43.5%) supratentorial lesions and (37, 15.6%) infratentorial lesions. Grade I tumor (39.3%) was most frequent followed by grade IV (14.6%). Within the grade I tumor, Pilocytic astrocytoma was the most common variant (33, 36.3%) followed by Craniopharyngioma. Medulloblastoma was the common tumor (13, 38.2%) in grade IV group followed by Central Primitive Neuroectodermal tumor (PNET). Supratentorial tumors were more common   than infratentorial. Pilocytic astrocytoma was the commonest pediatric CNS tumor. Craniopharyngioma, Ependymoma, Medulloblastoma and PNET were next in frequency.

[Journal of Histopathology and Cytopathology, 2018 Jul; 2 (2):92-98]

 Keywords: Childhood CNS tumor, pilocytic astrocytoma, medulloblastoma

 

  1. *Dr. Naila Huq, Associate Professor (Pathology), Department of Neuropathology, National Institute of Neurosciences & Hospital, Dhaka. nailahuqpopy@gmail.com
  2. Mohammed Enamul Haque, Junior Consultant, General Hospital, Munshigonj.
  3. Muhammad Nazmul Baqui, Senior lecturer, Unit of Pathology, Faculty of Medicine, AIMST University, Kedah, Malaysia
  4. Abdullah Yusuf, Assistant Professor, Microbiology, National Institute of Neurosciences & Hospital, Dhaka.
  5. Professor Nowfel Islam, Head of the Department, Department of Neuropathology, National Institute of Neurosciences & Hospital, Dhaka.

 

*For correspondence

 

Introduction

Primary CNS lesions are a varied group of lesions occurring in brain and spinal region. It includes a wide variety of diseases ranging from neoplastic lesions to infectious diseases as well as some cystic lesions common in CNS.1 Brain tumor in childhood differs considerably from adult in term of distribution, histological patterns, clinical and therapeutic aspects, prognosis and outcome.2,3,4 The incidence of childhood brain tumors varies greatly throughout the world depending on its type. National Institute of Neurosciences & Hospital is the one of the referral centre in Bangladesh dealing with the neurological diseases both for pediatric and adult patients. Reports on the pattern of childhood CNS tumors in Bangladesh are rare.  We analyzed the data compiled from CNS lesions biopsied in Neurosurgical Department and reported from the Department of Neuropathology of NINS&H during the time period of June 2013 to April 2016. Although exact incidence cannot be provided by a hospital based study, but the information derived from this study will be useful in showing pattern of childhood CNS tumors in our regions. It will have implications for future research, treatment and prognostic factors.  It will provide information about the extent of diseases, address the weight of the problem and finally it will help to design the human resources and fund needed to face the problem. The etiology of CNS tumors is mostly unknown. Some CNS tumors have proven associations with some genetic and environmental factors.3,4,5 So the study will be also helpful to decline the disease prevalence in our country by prenatal diagnosis and molecular treatment.  The objectives of this study are to determine the histomorphological pattern of CNS lesions and the frequency distribution.

Methods

The present study is based on the data collected from the Neuropathology department of NINS &H. The study is a retrospective analytical study. The study included all the patients up to eighteen years of age having CNS lesions and has biopsy proven diagnosis during the period of June 2013 to April, 2016. Skin, soft tissue, bony tumors and tumor like lesions were excluded from the study. All the samples were stained by routine Hematoxyline & Eosin stain. Beside H& E stain, immunohistochemistry was performed in only selective cases where there was diagnostic dilemma. Histological diagnosis and grading of the tumor was based on the, “WHO classification of the tumor of the CNS” and other reference books of histopathology.6,7,8,9

 Result

A total of 239 cases of pediatric CNS lesions biopsied in the Neurosurgical department of NINS&H were included in the study. The mean age at diagnosis was 10.30±5.48   years with age range of 3 months to 18 years. Children were stratified into four age groups: Group I (0-5); group 2 (5-10); group III (10-15); group IV (15-18) years. Most of the patients were in 10 to 15 years age group and least number of patients in 5 to 10 years.

Table I: Age distribution among the study population

 

Age Group Frequency Percent
Less Than 5 Years 60 25.1
5 to 10 Years 48 20.1
10 to 15 Years 82 34.3
More Than 15 Years 49 20.5
Total 239 100.0
Mean±SD (Range) 10.30±5.488 (1-18)

 

The study shows a slight male predominance with a male to female ratio of 1.4:1.

 Anatomical location of the lesions

In this study out of 239 cases 140 were intracranial and 50 were spinal.  Exact site was not mentioned in 49 cases.  There were (103, 43.5%) supratentorial lesions and (37, 15.6%) infratentorial lesions. Among the supratentorial location sellar lesions (28, 28%) were most common and in case of infratentorial site posterior fossa (24, 63.2%) lesions were commonest.

 Histological types of the lesions

The tumors were sub grouped into grade I to IV according to WHO grading system. The most commonly encountered group was grade I tumor (39.3%) followed by grade IV (14.6%) and grade II(16.7%) There was only 4.4% of grade III tumor. In 7.2% cases tumor grade cannot be determined due to inadequate biopsy material, technical error, type of tumor and some other causes.

Pilocytic astrocytoma was the most common variant (33, 36.3%) followed by Craniopharyngioma(19,7.9%) and  Ependymoma (17,7.1%). Medulloblastoma (13, 38.2%) and PNET (11,4.6%) was next in frequency which was grade IV tumor . Fibrillary astrocytoma(8,3.3%), Gemistocytic astrocytoma, Nerve sheath tumor, Meningioma, Hemangioma and other tumors were also found in pediatric age groups in different frequency. Even Glioblastoma(4,1.7%) was not uncommon in this age .

Table II: Distribution of Different Grades of Tumor

 

Grade of Tumour Frequency Percent
Grade I 94 52.2
Grade II 30 16.7
Grade III 8 4.4
Grade IV 35 19.4
Undetermined Grade 13 7.2
Total 180 100.0

 

Table III: Distribution of Different Tumors according to frequency

 

TYPES Frequency Percentage
Pilocytic astrocytoma 33 13.8%
Craniopharyngioma 19 7.9%
Ependymoma 17 7.1%
Medulloblastoma 13 5.4%
PNET 11 4.6%

 

A B

 

Fig 1A. Photomicrograph showing pilocytes and Rosenthal fibres in a case of Pilocytic astrocytoma.
1B. MRI showing hyperintense mural nodule with a large cyst

 

 
A B

 

Fig 2A. Photomicrograph showing nests of squamous epithelial cells with peripheral palisading by columnar cells  in a case of Craniopharyngioma.

2B. MRI showing cyst with hyperintense contrast enhancement in solid area.

 

 

A B

Fig 3A. Photomicrograph showing nodules of undifferentiated ells with zones of  reduced cellularity in a case of Medulloblastoma.

3B. MRI showing homogenous enhancement in posterior fossa

 

A B

 

Fig 4A. Photomicrograph showing sheets of poorly differentiated cells.

4B. Immunohistochemistry showing positive reaction for Synaptophysin

 Discussion

The present study was designed to determine the spectrum of childhood CNS tumors, their  site, grade and morphological pattern. In many of the cases tumor like lesions cannot be differentiated preoperatively by clinical and radiological evaluation. We excluded these cases from our study. There have a paucity of publications regarding CNS lesions in Bangladesh.

Slight male predominance is found in this study (1.4:1). Other study of Asian region also found a high male to female ratio.2,4, 10

Present study revealed most cases in 10 to 15 years age group with a mean age of   10.30±5.48 years which is higher than other studies. The variation may be due to difference in sample size and selection of cases. This study defines pediatric age group up to 18 years of age whereas most of the study includes 14 or 15 years of age.2,3,4 In this study most of the tumors were supratentorial (43.5%) and only (15.6%) were infratentorial. But other study showed that infratentorial tumors are most common in childhood.11 As it is a hospital based study and NINS & H is a referral and research oriented hospital there are some selection bias. Some national and international workshop occurs in NINS&H regarding newer technological approach addressing tumor of some special site. This may be the cause of high sellar lesion in this study.  However Pollack, 1999 found higher supratentorial tumor then infratentorial. Among the sellar lesion Craniopharyngioma was commonest.

Pattern of primary brain tumor in children differs significantly from adult. In this study tumors are further subdivided according to WHO grading system into 4 grades. However there are some tumors in which cases grade cannot be determined as Pituitary adenoma. We found that grade I tumor is more common in this age group (52.2%) followed by grade IV (19.4%). Among the grade I tumor Pilocytic astrocytoma (33, 13.8%) is the commonest tumor having better prognosis followed by Craniopharyngioma (19, 7.9%). In case of grade-II tumors, Ependymoma is (17, 7.1%) common in childhood. Medulloblastoma have a high frequency (13, 5.4%) followed by Central PNET (11, 4.6%) among the grade IV tumors. Jahan et al.4 also found Medulloblastoma as the commonest childhood CNS tumor followed by Ependymoma in Bangladesh. That study was done with a small sample size in comparison to the present study. On the other hand other publications noted Astrocytoma  as the commonest childhood CNS tumor.10,12,13

 Conclusion

The study reflects supratentorial region as the commonest site and Pilocytic astrocytoma as the commonest pediatric CNS tumor. Craniophayngioma, Ependymoma, Medulloblastoma, PNET are next in frequency. The current study is a single institutional study. A population based study including a larger sample size and long study period is required to determine the tumor burden and histopathological pattern of childhood CNS tumor in Bangladesh.

References

  1. Adnan HA, Kambhoh UA, Majeed S et al. Frequency of CNS Lesions In A Tertiary Care Hospital-A 5 Year Study. Biomedica, 2017;33(1): 4-8.
  2. Nasir S, Jamila B, Khaleeq S. A Retrospective Study of Primary Brain Tumors in Children under 14 Years of Age at PIMS, Islamabad. Asian Pacific J Cancer Prev, 2010;11:1225-1227.
  3. Elhaj N, Osman A, Alobeid et al. Pattern of Brain Tumors Among Children in Central Sudan . Sudanese journal of paediatrics and childhealth. 2010; 10:32-34.
  4. Jahan F, Kamal M, Sultana S. Pattern of Paediatric Brain Tumors Evaluated In BSMMU, Dhaka, Bangladesh. Bangladesh J Child Health 2013; 37(3): 154-157 .
  5. Ghadirian P, Fathie K, Thouez J P. Epidemiology of Brain/Nervous System Tumors in Children . The American Academy of Neurological and Orthopaedic Surgeons. 2014; Mar. 1-4.
  6. Louis DN, Ohgaki H,Wiestler OD,Cavenee WK, In: WHO Classification of Tumors of the Central Nervous System. 4th Ed, International Agency for Research on Cancer, Lyon, 2007; pp 8-11.
  7. Rosenblum MK.Central nervous system. In: Rosai J. Ed. Rosai and Ackermanss Surgical Pathology 10th St Louis, Mo. Elsevier. 2010.Vol-2, pp23
  8. Frosch MP, Anthony DC, Girolami UD. The Central Nervous System in: Robbins and Cotran pathologic Basis of Disease. 8th Elsevier.2012, pp 1279-1342.
  9. Burger PC and Scheithauer BW, Tumours of the central nervous system.In: Rosai J, ed.Atlas of Tumor Pathology,3rd series, Fascicle 10.Armed Forces Institute of Pathology, Washington DC. 1994; 25-952.
  10. Deopujan CE, Kumar A, Karmakar VS et al. Paediatric suprasellar lesions. J Pediatr Neurosci. 2011; 6(Suppl1): S46–S55.
  11. Katchy KC, Alexander S, Al-Nashmi N M et al. Epidemiology of primary brain tumors in childhood and adolescence in Kuwait. Pp 1-8.
  12. Siqueira EB, Rahm B, Kanaan I, and Jallu A. Brain tumors in pediatric patients at king faisal specialist hospital and research centre. Surgical neurology 1993; 39(6): 443-450.
  13. Mckinney P. A, Parslow R.C, Lane. S. A et al. Epidemiology of childhood brain tumors in     Yorkshire, UK, 1974-95: geographical distribution and changing patterns of occurrence.  Br J Cancer. 1998; 78(7): 974-979.
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Study of ER, PR and Ki-67 Expression in Different Histopathological Pattern of Endometrial Hyperplasia



Study of ER, PR and Ki-67 Expression in Different Histopathological Pattern of Endometrial Hyperplasia

*Fardousi F,1Sultana SS,2 Kaizer N,3 Dewan RK,4 Jinnah MS,5 Jeba R,6 Haque WS,7 Alam SM.8 Hussain M9

Abstract
Endometrial hyperplasia is one of the major gynaecological problem in peri and postmenopausal women worldwide. It deserves special attention because of its relationship with endometrial carcinoma. To study the histopathological pattern of endometrial hyperplasia in peri and postmenopausal women and their association with ER, PR and Ki-67 expression by immunohistochemistry is essential for early diagnosis with effective treatment. Out of 70 endometrial hyperplasia cases, 53 cases were simple endometrial hyperplasia without atypia, 8 cases were simple endometrial hyperplasia with atypia, 6 cases were complex endometrial hyperplasia without atypia and 3 cases were complex endometrial hyperplasia with atypia. ER expression in majority (35) of the cases of endometrial hyperplasia was between 51-100%. All the cases (3) of complex endometrial hyperplasia with atypia express ER less than 10%. The PR expression in majority of the cases (37) of endometrial hyperplasia was between 51-100%. All the cases (3) of complex endometrial hyperplasia with atypia expressed PR less than 40%. Ki-67 expression in majority of the cases of all types of endometrial hyperplasia 32 (78%) was less than 35%. All the cases (24) of simple endometrial hyperplasia without atypia had less than 35% Ki-67 expression. Only 6 cases had Ki-67 expression of more than 35%. In this study, 5 cases had negative (0%) Ki-67 expression. It can be inferred that after evaluating the ER, PR and Ki-67 expression, conservative treatment with progestogen and GnRH-agonists can be effective in selected cases of simple endometrial hyperplasia without or with atypia and complex endometrial hyperplasia without atypia.

[Journal of Histopathology and Cytopathology, 2018 Jul; 2 (2):74-84]

 Key words: Endometrial hyperplasia, Gynecological problem, Peri and postmenopausal women, Histopathological pattern, Immunohistochemistry, ER, PR and Ki-67 expression

 

  1. *Dr. Farzana Fardousi, Lecturer, Department of Cytopathology, National Institute of Cancer Research and Hospital (NICRH), Mohakhali, Dhaka. farzanafardousi@yahoo.com.
  2. Sk Salowa Sultana, Assistant Professor, Department of Pathology, Ad Din Women’s Medical College. Dhaka.
  3. Nahid Kaizer, Associate Professor (CC), Department of Pathology, Shahabuddin Medical College.
  4. Professor Dr. Rezaul Karim Dewan, Head of the Department of Pathology, Dhaka Medical College.
  5. Mohammed Shahed Ali Jinnah, Associate Professor, Department of Pathology, Dhaka Medical College.
  6. Ruksana Jeba, Associate Professor, Department of Pathology, Dhaka Medical College.
  7. Lt Col (Dr) Wasim Selimul Haque. Classified spl in Pathology, Armed Forces Institute of Pathology.
  8. Prof Brig Gen Dr. SM. Mahbubul Alam, Ex Deputy Commandment, Armed Forces Institute of Pathology, Senior consultant- Histopathology, Apollo Hospitals Dhaka.
  9. Professor Dr. Maleeha Hussain, Ex Head of the Department of Pathology, Dhaka Medical College.

 

*For corespondence

 Introduction
Endometrial hyperplasia has a high risk for malignant transformation into endometrial carcinoma in peri and postmenopausal women.1,2 Eendometrial hyperplasia usually develops due to the continuous estrogen stimulation unopposed by progesterone. In the years before menopause, women may have numerous cycles without ovulation (anovulatory) during which there is sustained and unopposed estrogen activity. It is also likely that hormone replacement therapy (HRT) consisting of estrogen without progesterone may lead to endometrial hyperplasia.3 The postmenopausal endometrium which  despite being atrophic, retain a weak proliferative pattern for many years probably as a response to continuous low level of estrogenic stimulation. These are at a higher risk of progression to endometrial hyperplasia and subsequently to endometrial malignancy. Although the diagnosis of endometrial hyperplasia can be made by histopathological examination; the immunohistochemistry aids for the prognosis, in order to establish the best treatment.4

The receptor status for estrogen and progesterone in endometrial hyperplasia can be a prognostic indicator in the treatment. The expression of estrogen and progesterone receptors varies in different types of endometrial hyperplasia. Several studies have found that, all types of hyperplasia present a smaller number of receptors compared to the endometrium in proliferative phase, but higher compared with secretory endometrium and endometrial carcinoma.5 The proliferative activity of endometrial hyperplasia can be examined by using an antibody to Ki-67 antigen, a non-histone protein, a well established marker of proliferative activity. The expression of the human Ki-67 protein is strictly associated with cell proliferation.

The endometrium of reproductive-aged women undergoes cyclic developmental changes in response to the steroids – estrogen and progesterone. The highest score of estrogen and progesterone receptors are observed in the epithelial and stromal cells of the normal uterine endometrium at the early proliferative phase; then, throughout the secretory phase, the ER and PR scores decline. Again, the highest score of estrogen receptors and progesterone receptors are observed in non-atypical hyperplasia and lowest score of estrogen receptors and progesterone receptors are observed in atypical hyperplasia.6

Ferrandina et al. (2005)7 found that, ER and PR positive cases of endometrial hyperplasias had a statistically significant association with the clinicopathological parameters, which correlates with a more favorable prognosis. In addition, the hormone receptor status appears to correlate with the treatment response to the progesterone therapy. This finding may be of particular clinical importance, since almost all endometrial hyperplasia cases contain estrogen/ progesterone receptors and progesterone therapy could be beneficial in this cases.8

The expression of the human Ki-67 protein is strictly associated with cell proliferation. During interphase, the antigen can be exclusively detected within the nucleus, whereas in mitosis most of the protein is relocated to the surface of the chromosomes. The fact that the Ki-67 protein is present during all active phases of the cell cycle (G(1), S, G(2), and mitosis), but is absent from resting cells G(0), makes it an excellent marker for determining the so-called growth fraction of a given cell population. The highest score of Ki-67 expression is observed in atypical hyperplasia and lowest score of Ki-67 expression is observed in non-atypical hyperplasia. Scholzen and Gerdes, (2009)9 in their study showed that, cell proliferation is highly correlated with Ki67 expression.

Perez-Medina et al have observed that, ER, PR and Ki-67 expression rate, along with the histopathological features of endometrial hyperplasia are important prognostic factors.10 After evaluating the ER, PR and Ki-67 expression rate, they have shown that, for all cases of endometrial hyperplasia, the general treatment protocol i.e. hysterectomy is not rationally justified. Patients who want to complete their family or who have heart disease or surgical or anaesthetic risk history, if they have positive ER, PR expression and low Ki-67 expression; they can be selected for conservative treatment with progestogens and GnRH-agonists. These patients should be followed for 5 years by biopsies every 6 months.

Hysterectomy is usually recommended for cases with endometrial hyperplasia.2 Several studies have revealed that less than 5 % of simple and complex non-atypical hyperplasia cases undergo malignant transformation in the long term (20 years), whereas this percentage increases to 30 % when there is an atypical hyperplasia.11 So, the rationality of hysterectomy in the treatment of endometrial hyperplasia in general needs to be evaluated.

The evaluation of receptor status by markers for hormone receptors (estrogen and progesterone receptors) and proliferative activity by proliferative marker (Ki-67) in patients with endometrial hyperplasia can predict the treatment option in selected cases.12 -16

 Methods
This is a descriptive cross sectional study which was carried out at the Department of Pathology, Dhaka Medical College, and Dhaka during the period of January 2013 to December 2014. A total of 110 peri and postmenopausal women with dysfunctional uterine bleeding or postmenopausal bleeding who underwent D&C or hysterectomy were screened.  A total of seventy histopathologically diagnosed cases of endometrial hyperplasia who met the enrollment criteria (inclusion & exclusion criteria) were included in this study. Among 70 cases, endometrial curettage biopsy specimens were 45 and hysterectomy specimens were 25. Routine Hematoxylin and Eosin staining was done on all 70 samples. Out of these 70 cases, ER, PR and Ki-67 immunostaining was done on 41 cases. Ethical clearance was taken for this study from institutional ethical committee of Dhaka Medical College. Each patient was interviewed before collection of the specimen and relevant information was recorded in a prescribed clinical proforma. Detail history with particular attention to age, clinical features, age at menarche, parity, obesity, history of contraceptives, history of hormone replacement therapy, history of diabetes, history of hypertension, history of estrogen producing ovarian tumor, age at menopause were taken.

 Histopathological examination

The gross examination of specimens, routine tissue processing and Hematoxylin & Eosin staining were done at the Department of Pathology, Dhaka Medical College.

 Microscopic analysis

According to WHO classification endometrial hyperplasia is classified into simple endometrial hyperplasia without atypia, Simple endometrial hyperplasia with atypia, Complex endometrial hyperplasia without atypia, Complex endometrial hyperplasia with atypia.17

 Immunohistochemical examination

Immunostaining for ER, PR and Ki-67 was done at AFIP (Armed Forces Institute of Pathology, Dhaka). A total of 41 cases were selected for immunohistochemical examination for ER, PR and Ki-67 expression. For immunostain, 3cases of proliferative phase of endometrium, 3 cases of secretory phase of endometrium and 3 cases of well differentiated endometrial carcinoma were enrolled as control.

All the data were recorded in data sheet along with patient’s clinical findings. The main objectives of this study were to observe the histopathological pattern of endometrial hyperplasia in peri and postmenopausal women and their association with ER, PR and Ki-67 expression by immunohistochemical method.

1) Primary antibody –Mouse monoclonal Anti-Human Estrogen Receptor, clone 1D5, code M7047(1:60 dilution), Mouse monoclonal Anti-Human Progesterone Receptor, clone PgR636(1:50 dilution) and Mouse monoclonal antibody against ki67 antigen(1:100 dilution)  were used as primary antibody.

2) Secondary antibody – Envision (ready to use, Dako), was used as secondary antibody.

3) Positive control –

  1. High grade breast carcinoma was taken as positive control for ER and PR.
  2. Follicular hyperplasia of lymph node was taken as positive control for Ki-67.

 Immunohistochemical analysis

For ER and PR expression in endometrial tissue: 18

Score for proportion staining Score for staining intensity
1. 0-25 % nuclei 1. Absent or weak staining
2. 26-75 % nuclei 2. Strong staining
3. ≥ 76 % nuclei 3. Very strong staining

 

Cat – I Total score 2 Immuno negative
Cat – II Total score 3-4 Immuno reactive
Cat – III Total score 5-6 Immuno reactive

For Ki-67 expression in endometrial tissue:

The patients are divided into two groups:

  1. Low Ki-67 expression (≤ 35 % cells are Ki-67 positive)
  2. High Ki-67 expression (> 35 % cells are Ki-67 positive)

(Nuclear staining in endometrial glandular epithelial cells are evaluated)

 Statistical analysis

Statistical analyses of the results were obtained by using window based computer software devised with Statistical Packages for Social Sciences (SPSS-16). Percentages were calculated to find out the proportion of the findings. The results are presented in Tables and Figures.

 Results
A total of 70 histopathologically diagnosed endometrial hyperplasia cases were included in this study.  Among 70 cases endometrial curettage biopsy specimens were 45 and hysterectomy specimens were 25. Out of all endometrial hyperplasia cases, 53 cases were simple endometrial hyperplasia without atypia, 8 cases were simple endometrial hyperplasia with atypia, 6 cases were complex endometrial hyperplasia without atypia and 3 cases were complex endometrial hyperplasia with atypia. Out of these all the 8 cases of simple endometrial hyperplasia with atypia, 6 cases of complex endometrial hyperplasia without atypia, 3 cases of complex endometrial hyperplasia with atypia and 24 cases of simple endometrial hyperplasia without atypia.

Table I: Distribution of the study patients by immunohistochemistry findings (ER %) (n=50)

 

Immunohisto-chemistry
findings (ER %)		 PP

(n=3)

 SP

(n=3)

 SEH without atypia

(n=24)

 SEH with atypia

(n=8)

 CEH without atypia

(n=6)

 CEH with atypia

(n=3)

 End. Ca. grade 1

(n=3)

 Total

(n=50)
n %
≤10 0 1 0 0 0 3 1 5 10.0
11-20 0 0 0 0 0 0 1 1 2.0
21-30 0 0 0 0 0 0 1 1 2.0
31-40 0 1 0 0 0 0 0 1 2.0
41-50 0 0 3 0 0 0 0 3 6.0
51-60 0 0 2 2 0 0 0 4 8.0
61-70 0 1 2 0 1 0 0 4 8.0
71-80 0 0 10 0 0 0 0 10 20.0
81-90 2 0 5 5 4 0 0 16 32.0
91-100 1 0 2 1 1 0 0 5 10.0
Total 3 3 24 8 6 3 3 50 100

(PP- Proliferative phase of endometrium, SP- Secretory phase of endometrium, SEH without atypia- Simple endometrial hyperplasia without atypia, SEH with atypia- Simple endometrial hyperplasia with atypia, CEH without atypia – Complex endometrial hyperplasia without atypia, CEH with atypia- Complex endometrial hyperplasia with atypia and End. Ca. grade 1- Endometrial carcinoma Grade-I)

 Distributions of the patients with PR expression (%). PR expression in majority of the cases (37) of endometrial hyperplasia is between 51-100%. All the cases (3) of complex endometrial hyperplasia with atypia express PR less than 40% (Table II).

 Table II: Distribution of the study patients by immunohistochemistry findings (PR %) (n=50)

 

Immunohist-ochemistry
findings (PR %)		 PP

(n=3)

 SP

(n=3)

 SEH without atypia

(n=24)

 SEH with atypia

(n=8)

 CEH without atypia

(n=6)

 CEH with atypia

(n=3)

 End. Ca. grade 1

(n=3)

 Total

(n=50)
n %
≤10 1 0 0 0 0 0 0 1 2.0
11-20 0 0 0 0 0 2 1 3 6.0
21-30 0 0 0 0 0 0 0 0 0.0
31-40 0 0 1 0 0 1 0 2 4.0
41-50 0 0 0 0 0 0 0 0 0.0
51-60 0 0 3 0 0 0 0 3 6.0
61-70 0 0 2 0 0 0 1 3 6.0
71-80 0 0 6 0 0 0 0 6 12.0
81-90 2.0 1 6 5 1 0 1 16 32.0
91-100 0 2 6 3 5 0 0 16 32.0
Total 3 3 24 8 6 3 3 50 100

(PP- Proliferative phase of endometrium, SP- Secretory phase of endometrium, SEH without atypia- Simple endometrial hyperplasia without atypia, SEH with atypia- Simple endometrial hyperplasia with atypia, CEH without atypia – Complex endometrial hyperplasia without atypia, CEH with atypia- Complex endometrial hyperplasia with atypia and End. Ca. grade 1- Endometrial carcinoma Grade-I)

Table-III shows distributions of the patients with Ki-67 expression (%). Ki-67 expression in majority of the cases of all types of endometrial hyperplasia 32(78%) is less than 35%.

 Table III: Distribution of the study patients by immunohistochemistry findings (Ki-67%) (n=50)

 

Immunohisto
-chemistry
findings (KI-67%)		 PP

(n=3)

 SP

(n=3)

 SEH without atypia

(n=24)

 SEH with atypia

(n=8)

 CEH without atypia

(n=6)

 CEH with atypia

(n=3)

 End. Ca. grade 1

(n=3)

 Total

(n=50)
n %
0 0 0 4 0 1 0 0 5 10.0
1-10 0 2 10 1 1 0 0 14 28.0
11-20 0 1 1 2 2 0 0 6 12.0
21-30 0 0 3 0 1 0 0 4 8.0
31-35 0 0 6 3 0 0 1 12 24.0
36-50 0 0 0 0 1 2 0 1 2.0
51-60 1 0 0 2 0 1 1 5 10.0
61-70 0 0 0 0 0 0 0 0 0.0
71-80 1 0 0 0 0 0 0 1 2.0
81-90 1 0 0 0 0 0 0 1 2.0
91-100 0 0 0 0 0 0 1 1 2.0
Total 3 3 24 8 6 3 3 50 100

(PP- Proliferative phase of endometrium, SP- Secretory phase of endometrium, SEH without atypia- Simple endometrial hyperplasia without atypia, SEH with atypia- Simple endometrial hyperplasia with atypia, CEH without atypia – Complex endometrial hyperplasia without atypia, CEH with atypia- Complex endometrial hyperplasia with atypia and End. Ca. grade 1- Endometrial carcinoma Grade-I)

(SEH without atypia- Simple endometrial hyperplasia without atypia, SEH with atypia- Simple endometrial hyperplasia with atypia, CEH without atypia – Complex endometrial hyperplasia without atypia, CEH with atypia- Complex endometrial hyperplasia with atypia I)

 

Figure 1.  Pie chart showing distribution of the patients by diagnosis (n=70)

Pie chart showing the commonest diagnosis in 70 patients was SEH without atypia (75.7%) followed by SEH with atypia (11.4%) (Fig 1).

Discussion
Endometrial hyperplasia has a significant place in gynecological morbidity in women of reproductive age (10% to 18%).19 Endometrial hyperplasia is associated with menstrual irregularities and anaemia in women and poses a high risk for malignant transformation into endometrial cancer.20 World wide endometrial cancer is the most common gynecological cancer in peri and postmenopausal women.21,22 The incidence of endometrial adenocarcinoma not only has remained high but in recent years has tended to significantly increase in many countries, including Bangladesh.19,23-32

In this study, the commonest diagnosed lesion was simple endometrial hyperplasia without atypia which was 53(75.7%) followed by simple endometrial hyperplasia with atypia 8(11.4%), complex endometrial hyperplasia without atypia 6(8.6%) and then complex endometrial hyperplasia with atypia 3(4.3%).

From the present study it was observed that, in all types of endometrial hyperplasia except complex endometrial hyperplasia with atypia, the ER expression was lower than proliferative phase but higher than secretory phase of endometrium. However, the ER expression in complex endometrial hyperplasia with atypia was lower than any other type of endometrial hyperplasia or proliferative phase or secretory phase of endometrium. It was even lower than endometrial carcinoma. Similar study done by Ilie et al. (2011)33 also found that the ER expression in different types of endometrial hyperplasia and endometrial cancer is lower than proliferative phase but higher than secretory phase of endometrium.33 Found that, the expression of ER in different types of endometrial hyperplasia was much lower (41.5%) than the present study (75%) except that of complex endometrial hyperplasia with atypia. This variation may be due to inclusion of menopausal patients in their study.

In this study it was observed that, the mean ER expression was 75±15.1% in simple endometrial hyperplasia without atypia. Similar observations was found by Goncharenko et al. (2013)20 they have found 75.6% ER expression in simple endometrial hyperplasia without atypia. This may be due to inclusion of perimenopausal women in their study like present study. It was also observed that the mean ER expression was 10±0% in complex endometrial hyperplasia with atypia in the current study. These findings differed from Goncharenko et al. (2013)20 they found 65.2% ER expression in complex endometrial hyperplasia with atypia. This variation may be due to inclusion of many patients in their study at their reproductive age.

From the present study it was observed that, the  PR expression  in all types of endometrial hyperplasia except complex endometrial hyperplasia with atypia, was higher than proliferative phase of normal endometrium and endometrial carcinoma ,but they were lower than secretory phase of normal endometrium. However, the PR expression was lowest in complex endometrial hyperplasia with atypia.  In the study done by Ilie et al. (2011)33 found that, the PR expression in different types of endometrial hyperplasia was lower than proliferative phase but higher than secretory phase of endometrium and endometrial carcinoma. This variation may be due to inclusion of only menopausal women in their study. In this current study it was observed that, the mean PR expression was 80.8±16.4% in simple endometrial hyperplasia without atypia. This finding was nearly similar to the observations found by Goncharenko et al. (2013).20 They have found 69.3% PR expression in simple endometrial hyperplasia without atypia as they also included perimenopausal patients in their study.

It was observed in our study that the mean PR expression was 25±8.7% in complex endometrial hyperplasia with atypia. These findings differed from Goncharenko et al. (2013)20 they found 44.3% PR expression in complex endometrial hyperplasia with atypia. This may be due to inclusion of many patients in their study at their reproductive age. This result is in concordance with that of, Uchikawa  et al. (2003)5 in which it was found that, the expression of ER and PR decreased in endometrial hyperplasia compared with normal proliferative endometrium.

In present study, the expression of Ki-67 was compared with proliferative phase (73.3±12.6%) and secretory phase (12.3±5.8 %) of normal endometrium and with endometrial carcinoma, grade I (66.7±30.5%). We found that, the presence of mitotic activity in normal endometrium was observed more in the proliferative phase than the secretory phase. Mitotic activity in neoplastic and hyperplasic endometrium was low compared with proliferative phase of normal endometrium, but more than the endometrium in secretory phase.This findings are similar to the study done by Ilie et al. (2011).33

In the present study, the mean Ki-67 expression was 36.3±18.5% in simple endometrial hyperplasia with atypia. This finding are nearly similar to the study done by Goncharenko et al. (2013)20 who found upto 50% Ki-67 expression in simple endometrial hyperplasia with atypia. This may be due to inclusion of perimenopausal patients like our study. The present study result is in concordance with that of Uchikawa et al. (2003)5 in which they found that, ki-67 expression was more in atypical hyperplasia (50%) than non-atypical hyperplasia (10%).

In patients with simple endometrial hyperplasia with atypia and complex endometrial hyperplasia without atypia, Ki-67 expression can predict the treatment protocol. The patients with low Ki-67 expression can be selected for conservative treatment with hormone therapy and with high Ki-67 expression should undergo hysterectomy.  In complex endometrial hyperplasia with atypia, they should preferably be treated by hysterectomy operation. If, patients who want to complete their family and have low Ki-67 expression, they can be temporarily treated by conservative treatment. After delivery, they must undergo surgical intervention.16

The treatment response with hormone therapy depends on expression of ER & PR. So, before hormonal intervention, ER & PR should be evaluated, because in few cases, where expressions are low, have the chance of poor response to treatment. 10

 Limitation of the study

The study population was selected from the department of Pathology of Dhaka Medical College Hospital. But there are many patients with endometrial hyperplasia who are attending other hospitals than DMCH. Therefore, the sample lacks representation of the population. Thus, the study place was selected purposively and the respondents, those are interviewed, were attended a particular department of a specific hospital.

 Conclusion

The study revealed that highest ER & PR expression were observed in complex endometrial hyperplasia without atypia and lowest ER & PR expression were observed in complex endometrial hyperplasia with atypia. Again, highest Ki-67 expression was observed in complex endometrial hyperplasia with atypia and lowest Ki-67 expression was observed in simple endometrial hyperplasia without atypia. In complex endometrial hyperplasia with atypia, if patient desires to complete the family, after evaluation of ER, PR and Ki-67 expression, conservative treatment can be given and allowed to conceive. After delivery, if Ki-67 expression remains high, then hysterectomy must be done.

 Recommendations

A large follow–up study is recommended for patients of endometrial hyperplasia selected for conservative treatment with progestogen and GnRH-agonists. Monitoring should be done by observing the Ki-67 expression in these patients. If the Ki-67 expression increases, they should be treated by surgical intervention.

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