Indian Journal of Obstetrics and Gynecology Research

Print ISSN: 2394-2746

Online ISSN: 2394-2754

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Indian Journal of Obstetrics and Gynecology Research (IJOGR) open access, peer-reviewed quarterly journal publishing since 2014 and is published under auspices of the Innovative Education and Scientific Research Foundation (IESRF), aim to uplift researchers, scholars, academicians, and professionals in all academic and scientific disciplines. IESRF is dedicated to the transfer of technology and research by publishing scientific journals, research content, providing professional’s membership, more...


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Santoso, Tjokroprawiro, and Pradnyani: Characteristics of granulosa cell tumor at Dr. Soetomo general hospital from 2014 to 2019


Introduction

Granulosa cell tumor (GCT) is a rare type of tumor and only accounts for 2-8% of all ovarian malignancies.1, 2, 3, 4, 5, 6, 7, 8 Estimated incidence is estimated at 0.99/100,000 in the United States, whereas incidence for other developed countries ranges from 0.4 to 1.7/100,000.2, 4, 5, 6, 7, 9, 10 GCT is characterized by slow growth in a sluggish course, and recurrence is possible even after more than a decade. For this reason, prolonged follow-up is required. Although the prognosis is often favorable, tumors that recur or are in an advanced stage at diagnosis may have a poor prognosis.

The case of granulosa cell tumor which was treated at RSUD Dr. Soetomo for the period 2014 – 2019 was an average of 6 patients per year. Researchers will specifically review how the characteristics of granulosa cell tumors in RSUD Soetomo especially in terms of management, recurrence rate and survival rate. At the end of this review, readers can understand how to diagnose and how to properly treat this rare ovarian malignancy.

Materials and Methods

The researcher used a retrospective analytic review study. We identified GCT patients diagnosed between 2014 and 2019 at the Dr. Soetomo. Complete patient data used were secondary data obtained from the medical record and Electronic Medical Record (EMR) database of the oncology department. Surgical results, pathological findings and follow-up data were analyzed. Statistical analysis was performed using Fisher exact test and Kaplan-Meier survival curves with log-rank test as comparison. The results of statistical processing presented in this investigation are in the form of Frequency and Percentage Distribution Tabulations and graphs.

Results

The results of the study were 38 cases of granulosa cell tumors in the oncology division of the Department of Obstetrics and Gynecology dr. Soetomo, Surabaya is presented in the following table:

Table 1

Frequency distribution of patient characteristics of Granulose cell tumor operated on at Dr. Soetomo 2014 to 2019

Number of patients (N)

Percentage (%)

Age

≤40

14

37

>40

24

63

Menopausal status

Pre-menopause

27

71

Post-menopause

11

29

Parity

Nullipara

7

18

Primi/multipara

31

82

Referral from

Surabaya

11

29

Outside Surabaya

26

68

Outside East Java

1

3

Stage

I

29

76

II

1

3

III

5

13

Advanced

3

8

GCT’s type

Adult

37

97

Juvenile

1

3

Symptoms

No symptoms

0

0

Bleeding

6

16

Abdominal pain

14

37

Abdominal distention

10

26

Palpable mass

8

21

CA-125   

<35

18

47

≥35 U/mL

20

53

Surgery      

TAH-BSO

29

76

USO

6

16

Debulking/Biopsy

3

8

Tumor size   

<10 cm

4

11

≥10cm

34

89

Tumor rupture   

Yes

7

18

No

31

82

Residual tumor   

Yes

7

18

No

31

82

Of 38 patients with malignant granulosa cell tumors who underwent surgery, the youngest patient was 13 years old and the oldest was 72 years old. The most granulosa cell tumors were in the 41-60 year age group, namely 22 patients (57.9%), followed by the 21-40 year age group as many as 13 patients (34.2%), the 61-80 year age group as many as 2 patients (5.3%) and at least 1 patient (2.6%). Patients with granulosa cell tumors who underwent surgery at Dr. Hospital. Soetomo in 2014 to 2019 were mostly referrals from outside the city of Surabaya, but still covered the East Java area, namely 32 patients (85%), from within Surabaya as many as 11 patients (34%) and there were also referrals from outside East Java. As many as 1 patient (3%). Based on parity, granulosa cell tumor patients who underwent surgery were mostly primi/multiparous as many as 31 patients (82%) and the rest were nulliparous as many as 7 patients (18%). Based on menopausal status, most of the patients were not menopausal as many as 27 patients (71%) and the remaining 11 patients (29%) had menopause.

Based on the type of complaint, the most with complaints of abdominal pain as many as 14 patients (37%), enlarged abdomen in 10 patients (27%), palpable masses in 8 patients (21%) and the least bleeding in 6 patients (16%). There were no asymptomatic patients (0%). Based on CA-125 results, most patients had CA-125 values ​​> 35 as many as 20 patients (53%) and the rest had CA-125 values ​​< 35 as many as 19 patients (47%). Based on the type of granulosa cell tumor, the most common types were adults with 97 patients (97%) and adolescents with 1 patient (3%). Based on the type of surgery performed on the patient, the most TAH-BSO type surgery was performed, namely 29 patients (74%), followed by USO as many as 6 patients (16%), and the least type of surgery was debulking of tumor mass/biopsy as many as 3 patients. (8%). The histopathological results showed that the tumor size which was more than or equal to 10cm was 34 specimens (89%), while the tumor size smaller than 10cm was 4 specimens (11%). Based on the classification of the condition of the tumor during surgery, whether it was ruptured or not, 7 patients were found to have ruptured tumors, namely (18%), while those that did not rupture or were compressed before the tumor was removed from the abdominal cavity were 31 patients (82%). Based on the presence or absence of residual tumor after surgery, 7 patients (18%) had residual tumors of various sizes (cm) and 31 patients (82%) had no residual tumor.

From the results of the post-op parade, the most common staging of granulosa cell tumor patients was stage I, which was 29 patients (76%), followed by stage III with 5 patients (13%), advanced as many as 3 patients (8%) and at least stage II that is 1 patient (3%). The data showed that from 38 patients who underwent surgery, there were 8 patients (21%) who received post-op adjuvant chemotherapy and as many as 30 patients (79%). Of 38 patients with granulosa cell tumors who were operated on for the first time until a recurrence appeared in the form of a residif mass during patient follow-up, there were 2 patients (5%) relapsed and the remaining 36 patients (95%) did not show recurrence. Based on the last condition of the patients we followed up, from 38 granulosa cell tumor patients, 10 patients (26%) died, the remaining 28 patients (74%) were alive and well without any complaints.

Table 2

Overall Survival (OS) 5 years for patients with granulosa cell tumors who underwent surgery at Soetomo Hospital in 2014 to 2019

Stage

Total N

N of Events

N

Percentage (%)

Advanced

3

3

0

0.0%

Stage I

29

3

26

89.7%

Stage II

1

0

1

100.0%

Stage III

5

4

1

20.0%

Overall

38

10

28

73.7%

Until October 2020, from a total of 38 patients who were followed up, the Overall Survival (OS) for 5 years was 73.7% with an average patient survival of 29 months. Successively the survival rate for Stage I is 89.7%. Stage II is 100%, Stage III is 20% and from the advanced stage we did not get 1 patient (0%) who managed to survive.

Table 3

Distribution of clinical pathology in patients receiving adjuvant chemotherapy versus no treatment

Adjuvant therapy b

p value a

Number of patients (n = 38)

No

n (%)

Yes

n (%)

(n = 30)

(n = 8)   

Age

≤40

13(43,3)

1(12.5)

>40

17(56,7)

7(87,5)

0.114

Stage

I

26(86.7)

26(86.7)

II - advanced

4(13,3)

5(62,5)

0.010

Surgery

Complete

25(83,3)

7(87,5)

Fertility preserves

5(16,7)

1(12,5)   

0.628

Tumor size

<10 cm

2(6,66)

2(25)

≥10 cm

28(93,4)

6(75)

0.189

Tumor rupture

Yes

4(13,3)

3(37,5)

No

26(86,7)

5(62,5)   

0.146

Residual tumor

Yes

2(6,66)

5(62,5)

No

28(93,4)

3(37,5)

0.002

[i] aCalculated by Fisher's exact test for proportion.

[ii] bCalculated on the data available

The results showed that most adjuvant chemotherapy was given on the basis of stage and presence of tumor residues. Patients diagnosed with stage 1 (86.7%) did not receive adjuvant therapy, while patients with stage II and above were 62.5% (p 0.010) receiving adjuvant therapy. Post-op patients with residual tumor who received adjuvant therapy were 62.5% (p 0.002)

Table 4

Distribution ofclinico-pathological parameters as prognostic factors for recurrence

Recurrenceb

p value a

Number of patients (n = 38)

No

n (%)

Yes

n (%)

(n = 36)

(n = 2)   

Age

≤40

13(36,1)

1(50)

>40

23(63,8)

1(50)

0,607

Stage

I

28(77,8)

1(50)

II - advanced

8(22,2)

1(50)

0,422

Tumor size

<10 cm

4(11,1)

0

≥10 cm

32(88,9)

2(100)

0,618

Tumor rupture

Yes

6(16,7)

1(50)

No

30(83,3)

1(50)

0,339

Residual tumor

Yes

6(16,7)

1(50)

No

30(83,3)

1(50)

0,339

Adjuvant

Yes

7(19,4)

1(50)

No

29 (80,6)

1(50)

0,833

Surgery

Complete

31(86,1)

1(50)

Fertility preserves

5(13,9)

1(50)

0,294

[i] aCalculated by Fisher's exact test for proportion.

[ii] bCalculated on the data available

The results showed that none of these factors had significant significance (p value > 0.05) on the incidence of recurrence of granulosa cell tumors.

Table 5

Clinical characteristics of the 2 cases of GCT recurrence

Mrs. J

Mrs. C

Age

37 years old

45 years old

Referral

Outside of Surabaya (Situbondo)

Outside of Surabaya (Bangil)

Chief complaint

Abdominal distended

Abdominal pain

Ca-125 U/mL

243,6

3,9

Primary surgery

SOS + PFC (3/2014)

Debulk Sin + Omentectomy (3/2017)

FIGO Stage

IC3

IIIB

Histopathology

AGCT PFC atypical cell (malignant)

AGCT; tumor confined inside capsule; No tumor found in omentum

Tumor size

≥10cm (21x20x5)

>10cm (13x9x8)

Tumor rupture

Yes

No

Residual tumor

-

Yes (4x4cm)

Chemotherapy

BEP 3series (2014)

-

Recurrent

Residif mass 4,7x2,9x5,4 (2/2016)

Residif mass 7,5 x5 x 5 (9/2017)

DFS

23 months

6 months

Recurrent therapy

Loss of ff up

Optimalization surgery TAH + Salpingectomy bilat + debulking mass tumor Sin (9/2017) BEP (-) Lost of follow up

Last follow up

3/2016

8/2018

Death

6/2016

9/2018

Discussion

Based on secondary data obtained in 2014-2019 from medical records, this tumor can be present at any age, 80% of the more common forms of Adult GCT appear in women older than 40 years, most often in perimenopausal or postmenopausal women between 50 years and 54 years.2, 4, 5, 6, 7, 9, 10, 11, 12, 13 Half of Juvenile GCTs are diagnosed in girls younger than 10 years, with studies showing a median age at diagnosis of 8 to 13 years.14, 15 Some case report also describe juvenile GCT found in infants.16 However, during the period 2014 to 2019, we did not find any cases of granulosa cells in infants. Patients with granulosa cell tumors who underwent surgery at Dr. Hospital. Soetomo in 2014 to 2019 were mostly referrals from outside the city of Surabaya. The same thing was found in the study of Wei K, et al. that the incidence and mortality of ovarian cancer was higher in urban areas than in rural areas.

Based on parity, the majority of granulosa cell tumor patients who underwent surgery at RSUD Soetomo were primi/multiparous, based on several case studies that have been reviewed previously explained that parity does not seem to affect the risk of GCT.1, 2 71% of granulosa cell tumor patients who had not yet menopause and 29% who had menopause were found. This is not in accordance with the results of previous studies which stated that almost 60% of adult GCT occurred after menopause.17, 18, 19, 20 Menopause does not cause granulosa cell tumors, but the risk of granulosa cell tumors increases with age. When a woman has gone through menopause, the risk of granulosa cell tumors increases due to old age. Based on several case studies that have been reviewed previously explained that menopausal status does not seem to affect the risk of GCT.1, 2

The patients we treated at the Soetomo General Hospital had symptoms that were often non-specific as in common ovarian cancer. None of the patients we treated were asymptomatic. All patients were symptomatic and came with the most complaints of abdominal pain (37%), after which successively followed by complaints of enlarged abdomen, palpable mass and abnormal vaginal bleeding only (16%). This complaint of abdominal pain is a symptom related to the fact that GCTs are often large (10 to 15 cm) and hemorrhagic.6, 10, 21, 22 We did not find any patients with acute onset of pelvic pain due to torsion of the tumor mass or cases of spontaneous hemorrhagic rupture (hemoperitoneum). Bleeding in the granulosa cell tumor patients that we treated were not dominant and not in accordance with the developed theory, because there were only 6 patients who came with bleeding complaints. Abnormal uterine bleeding in 3 premenopausal patients and 3 postmenopausal patients.

All patients who underwent TAH-BSO, only 1 patient (3.5%) had nonatypical hyperplasia, this is not in accordance with the previous case study which stated that as many as 25% to 50% of the adult form of GCT is associated with the development of endometrial hyperplasia.2, 3, 4, 9, 23 In our patients USO (mean age 31 years) for fertility preservation was not routine for endometrial biopsy because the study results showed endometrial carcinoma/atypical hyperplasia was common in GCT patients >40 years; Based on this study, priority endometrial sampling was performed in symptomatic women with a minimum age of 40 years. In asymptomatic women < 40 years, endometrial sampling is not preferred.24 We did not find precocious pseudopuberty, because in one case of juvenile GCT our 13-year-old patient was a postmenarchal adolescent.

Preoperative CA-125 levels are routinely checked in all cases with suspected ovarian cancer, only to differentiate the case diagnosis that these 38 cases are not epithelial ovarian cancer, until proven yes. The ideal tumor marker examined in cases of granulosa cell tumors is inhibin, several other studies have confirmed this observation (Boggess JF et. al, 1997). However, the obstacle and this is the limitation of our study is the unavailability of this Inhibin tumor marker in Indonesia. Our patient diagnosed with this granulosa cell tumor had almost 53% CA-125 levels above 35 U/mL. And this does not conclude that granulosa cell tumor patients have high CA-125 levels, but it could be caused by other conditions. Because high levels of CA-125 can be caused by Endometriosis, PID, fibroids, impaired liver function, and others.

We found 97% of cases were adult type and 3% were juvenile type. From a total of 38 patients, we found one 13-year-old juvenile type patient. This is in accordance with the results of previous studies which stated that these granulosa cell tumors were of adult type (95%) and juvenile type (<20 years) (5%) based on histological findings. The mean size of the tumor as a result of histopathological measurements was 89% with a diameter of 10cm. This is in accordance with the results of studies that have been reviewed previously, namely that the average diameter size is 10-15cm.17, 19, 25 We found 18% of tumor ruptures, and the incidence of tumor rupture in 7 of our patients was caused by the evacuation process during surgery because the tumor was large, fragile with great adhesion. Based on tumor residuals, there were 18% of patients with post-op tumor residual. Residual tumors are caused by the attachment of the tumor mass to the peritoneal cavity organs such as the rectum or abdominal wall that is difficult to free.

Of the total 38 patients we treated, all of them received surgical treatment, either primary surgery, optimizing surgery due to recurrence, or optimizing surgery due to incomplete surgery from another referral hospital. The type of surgery that was performed the most was TAH-BSO 76% on the basis of the consideration that most of our patients did not want to maintain their fertility anymore. Our patients 82% were primi/multiparous with at least one live child. Meanwhile, 6 patients (18%) underwent USO (Unilateral Salpingo Oophorectomy without contralateral ovarian biopsy because the incidence of bilaterality was about 2–8%. This is consistent with previous studies, because in our patient who had both ovaries removed, we found 1 Bilateral tumor incidence (2.6%). Biopsies of the contralateral ovary are controversial and should be performed with caution to preserve fertility.4 In 3 cases (8%) we performed only suboptimal debulking or tumor mass biopsy only with death. The tumor residue on the basis of Durante Op's considerations, the tumor mass is so large with great adhesions that it is difficult to free it with profuse bleeding during the operation.

Adjuvant chemotherapy is an additional postoperative therapy that is considered for patients who have a high risk of recurrence, such as stage IC and above, tumor rupture, large tumor size, and residual tumor. The main considerations in the patients we treated were the patient's stage (p 0.010) and the presence of residual tumor (p 0.002). Until now the recommended adjuvant chemotherapy is BEP (Bleomycin / Etoposide / Cisplatin) because it is well tolerated by Bjorkholm and Silfversward,9 reported that patients with clinical stage 1 disease whose tumor ruptured should be treated with BEP 3 series. Post-operative adjuvant chemotherapy was given to 8 patients (21%) namely in patients with stage IC to advanced stage who had a ruptured tumor/spillage durante op or with residual tumor. However, from the 8 patients there were 2 patients who received Pacli Carbo adjuvant therapy, 1 patient because they could not afford Etoposide (Etoposide was not covered by BPJS). Paclitaxel has been used in repeated GCT with dramatic response.26 The potential activity of paclitaxel has been confirmed by the study of Brown et al.27 Patients outside of stage IC to advanced patients were only followed up after surgery, this was because most of the stages we got were stage IA and did not require adjuvant therapy.3, 6, 9, 10, 12

From a total of 38 patients we treated, there were 2 adult GCT patients who had relapsed (5%), and we tried to relate it to various factors such as age, stage, tumor size, tumor rupture, residual tumor, adjuvant therapy and type of surgery. Of all the factors we tested, none of them gave any significance to the degree of recurrence (p > 0.05). Two relapsed patients were from the IC3 group of patients who received adjuvant and IIIB who did not receive adjuvant since primary surgery. And both patients died after experiencing a relapse.

From a total of 38 patients treated at RSUD Soetomo, the 5-year survival rate was 73.7% of all diagnosed stages. The 5-year survival rate of high granulosa cell tumors was caused by as many as 76% of patients being diagnosed as stage I. The 5-year survival rate of Stage I itself was 89.7%. This is in accordance with the survival rate according to tumor stage according to FIGO, where the 5-year survival rate Stage I is 90 to 100%.

Tumor stage is the most important prognostic factor.3, 5, 6, 9, 10, 12, 28 Tumor stage is closely related to the patient's survival rate. The relationship between survival rate and staging has been tested by researchers and is in accordance with the 5-year FIGO survival rate. The results of the linkage test can be concluded that the patients treated at RSUD Dr. Soetomo is diagnosed mostly at an early stage, and this provides a better prognostic and 5-year survival rate.

Conclusion

GCT is a rare low-grade malignant tumor, most patients are diagnosed at an early stage and generally have a good prognosis. Stage is not considered the most important prognostic factor. The role of adjuvant chemotherapy treatment is still debated because it has not been shown to reduce recurrence rates. Long-term surveillance including routine clinical follow-up and serial evaluation of tumor markers is mandatory to evaluate recurrence.

Source of Funding

None.

Conflict of Interest

The authors declare no conflict of interest.

References

1 

P Geetha K Nair Granulosa cell tumours of the ovaryAust N Z J Obstet Gynaecol20105021620

2 

ST Schumer Granulosa cell tumor of the ovaryJ Clin Oncol20032111809

3 

AT Evans TA Gaffey GD Malkasian JF Annegers Clinicopathologic review of 118 granulosa and 82 theca cell tumorsObstet Gynecol19805522318

4 

D Pectasides E Pectasides A Psyrri Granulosa cell tumor of the ovaryCancer Treat Rev200834112

5 

H Fox K Agrawal FA Langley A clinicopathologic study of 92 cases of granulosa cell tumor of the ovary with special reference to the factors influencing prognosisCancer19753523141

6 

JT Stenwig JT Hazekamp JB Beecham Granulosa cell tumors of the ovary. A clinicopathological study of 118 cases with long-term follow-upGynecol Oncol1979713652

7 

H Malmström T Högberg B Risberg E Simonsen Granulosa cell tumors of the ovary: prognostic factors and outcomeGynecol Oncol199452150510.1006/gyno.1994.1010

8 

C Rico MN Lague¨ P Lefèvre M Tsoi A Dodelet-Devillers V Kumar Pharmacological targeting of mammalian target of rapamycin inhibits ovarian granulosa cell tumor growthCarcinogenesis2012331122839210.1093/carcin/bgs263

9 

E Björkholm C Silfverswärd Prognostic factors in granulosacell tumorsGynecol Oncol19811132617410.1016/0090-8258(81)90040-8

10 

G Ohel H Kaneti JG Schenker Granulosa cell tumors in Israel: a study of 172 casesGynecol Oncol1983152786

11 

RH Young GR Dickersin RE Scully Juvenile granulosa cell tumor of the ovary. A clinicopathological analysis of 125 casesAm J Surg Pathol1984857596

12 

BE Miller BA Barron JY Wan Prognostic factors in adult granulosa cell tumor of the ovaryCancer19977919515

13 

E Pankratz DA Boyes GW White BW Galliford, RN Fairey JL Benedet Granulosa cell tumors. A clinical review of 61 casesObstet Gynecol197852671823

14 

G Vassal F Flamant JM Caillaud F Demeocq C Nihoul-Fekete J Lemerle Juvenile granulosa cell tumor of the ovary in children: a clinical study of 15 casesJ Clin Oncol198869905

15 

CV Biscotti WR Hart Juvenile granulosa cell tumors of the ovaryArch Pathol Lab Med1989113406

16 

KAP Schultz SF Sencer Y Messinger JP Neglia ME Steiner Pediatr Blood Cancer Pediatric ovarian tumors: a review of 67 casesPediatr Blood Cancer20054421677310.1002/pbc.20233

17 

MT Deavers E Olivia MR Nucci Sex Cord-Stromal Tumors of The OvaryGynecologic PathologyChurchill ElsevierLivingstone200946073

18 

RC Isabelle Ovarian Tumors of Sex Cord-Stromal Origin. (Cited on 2011 October 23)http://www.orpha.net/data/patho/GB/uk-STROMA.pdf

19 

FA Tavassoli E Mooney Gersell Sex Cord-Stromal Tumours. In : World Health Organization Classification of Tumours. Pathology & Genetics Tumours of the Breast and Female Genital Organs. WHO IARC Press20021469

20 

CM Michener Granulosa-Theca Cell Tumors Clinical Presentation. (Cited on 2011 October 23)http://emedicine.medscape.com/article/254489-clinical

21 

HS Cronje I Niemand RH Bam Review of the granulosa-theca cell tumors of the Emil Novak ovarian tumor registryAm J Obstet Gynecol19991803237

22 

Case records of the Massachusetts General Hospital: Weekly clinicopathological exercises-Case 10-1995, a 56-year-old woman with abdominal pain, anemia, and a pelvic massN Engl J Med199533287681

23 

SB Gusberg P Kardon Proliferative endometrial response to thecagranulosa cell tumorsAm J Obstet Gynecol197111163343

24 

J Ottolina G Ferrandina A Gadducci P Scollo D Lorusso G Giorda Is the endometrial evaluation routinely required in patients with adult granulosa cell tumors of the ovary? Gynecol Oncol20151362230410.1016/j.ygyno.2014.12.016

25 

N Weidner DJ Dabbs M Peterson Granulosa Cell TumoursOvaries : Sex Cord-Stromal Tumors. In : Modern Surgical PathologyVolume 1Saunders ElsevierPhiladelphia2009137981

26 

D Tresukosol AP Kudelka CL Edwards C Charnsangavej N Narboni JJ Kavanagh Recurrent ovarian granulosa cell tumor: a case report of a dramatic response to TaxolInt J Gynecol Oncol1995521569

27 

J Brown HS Shvartsman MT Deavers LM Ramondetta MF Burke MF Munsell The activity of taxanes compared with bleomycin, etoposide and cisplatin in the treatment of sex cord-stromal ovarian tumorsGynecol Oncol20039748996

28 

FF Lauszus AC Peterson J Greisen A Jakobsen Granulosa cell tumor of the ovary: a population-based study of 37 women with stage I diseaseGynecol Oncol20018145660



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© This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Article type

Case Report


Article page

585-591


Authors Details

Eko Santoso, Brahmana Askandar Tjokroprawiro*, Ni Nyoman Ratih Pradnyani


Article History

Received : 24-08-2021

Accepted : 31-08-2021

Available online : 26-11-2021


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