|
Association of lymphovascular space invasion (LVSI) with histological tumor grade and myometrial invasion in endometrial carcinoma: A review study
Azita Rafiee1, Fereshteh Mohammadizadeh2
1 Pathologist, Iranian Medical and Pathology Laboratory, Zahedan, Iran
2 Department of Pathology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| Date of Submission | 12-Feb-2023 |
| Date of Acceptance | 18-Mar-2023 |
| Date of Web Publication | 28-Jun-2023 |
Correspondence Address:
Dr. Azita Rafiee
Pathologist, Iranian Medical and Pathology Laboratory, Zahedan
Iran
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/abr.abr_52_23
Endometrial carcinoma is one of the most frequent gynecological cancers in developed countries. Lymphovascular space invasion (LVSI), histological grade, and myometrial invasion (MMI) are important prognostic factors of endometrial carcinoma. LVSI is considered an independent poor prognostic factor in endometrial carcinoma. Based on the importance of LVSI, this study aimed to discuss the association of LVSI with tumor grade and MMI. A search of PubMed, EMBASE, Web of Science, Scopus, Google Scholar, and Cochrane Library was carried out to collect related studies. Consequently, most studies showed that LVSI is significantly associated with higher histologic grade and deep MMI.
Keywords: Endometrial neoplasms, lymphatic metastasis, myometrium, neoplasm grading, neoplasm invasiveness
How to cite this article:
Rafiee A, Mohammadizadeh F. Association of lymphovascular space invasion (LVSI) with histological tumor grade and myometrial invasion in endometrial carcinoma: A review study. Adv Biomed Res 2023;12:159 |
How to cite this URL:
Rafiee A, Mohammadizadeh F. Association of lymphovascular space invasion (LVSI) with histological tumor grade and myometrial invasion in endometrial carcinoma: A review study. Adv Biomed Res [serial online] 2023 [cited 2023 Sep 28];12:159. Available from: https://www.advbiores.net/text.asp?2023/12/1/159/379517 |
| Introduction | |  |
Endometrial carcinoma is the most common cancer of the female genital tract in developed countries[1],[2],[3],[4] with a generally good prognosis[1],[2],[3] and the sixth most frequent cancer in females with an increasing prevalence and mortality rate.[3] The American Cancer Society has assumed 66570 new cases and 12940 deaths in the United States in 2021.[5]
Principally, endometrial carcinoma involves postmenopausal females.[6] Early occurrence of symptoms and signs including spotting and postmenopausal hemorrhage results in early diagnosis, good prognosis, and up to 85% five-year survival rate.[7]
The most significant prognostic factors of endometrial carcinoma are tumor grade, International Federation of Gynecology and Obstetrics (FIGO) stage, histological subtype, depth of myometrial invasion (MMI), lymphovascular space invasion (LVSI), and age.[8]
LVSI is characterized by the tumor cells within endothelium-lined spaces around the main tumor[9],[10],[11] that are seen typically as “free-floating” cell clusters, which frequently fit the space shape.[9],[11]
The incidence of LVSI in the early stage of endometrial carcinoma is about 34%.[11] LVSI has been supposed as one of the initial events in the metastasis of endometrial carcinoma and a necessary step before lymphatic dissemination. LVSI has been meaningfully correlated with lymph node metastasis and a lower survival rate.[12],[13],[14],[15],[16],[17],[18],[19] LVSI usually is considered an independent unfavorable factor of recurrence and survival; even in some investigations, LVSI in patients without lymph node involvement has been shown as an independent prognostic factor of survival and recurrence.[20]
MMI is identified by the endometrial cancer cell invasion into the myometrial layer.[5]
Endometrial carcinoma is classified into two histopathological groups: low grade and high grade.[21]
Considering the significance of LVSI, depth of MMI, and grade in prognosis and survival of endometrial carcinoma, we conducted a study to evaluate the relationship between LVSI and two other important prognostic factors, including depth of MMI and grade of endometrial carcinoma.
| Materials and Methods | | |
The literature was investigated from Web of Science, PubMed, EMBASE, Scopus, Google Scholar, and Cochrane Library from April 1985 to November 2022. Only the studies published in English were included. The search terminologies consisted of “endometrial carcinoma,” “endometrial tumor,” “endometrial cancer,” “endometrial neoplasm,” “Lymphovascular Space Invasion,” “LVSI,” “myometrial invasion,” “grading,” and “classification.” One author independently reviewed the literature, and another author was consulted in disagreement.
Inclusion and exclusion criteria
In this study, the following inclusion criteria were considered.
1) The studies in which the patients were only involved by endometrial carcinoma, 2) studies with adequate information on clinicopathological factors (LVSI, MMI, and tumor grading), 3) studies published exclusively in English, and 4) the types of studies consisted of cross-sectional, case–control, cohort, clinical trial, and review articles.
The following were the exclusion criteria:
1) Animal experiments, 2) unpublished studies, 3) incomplete studies, 4) case reports, and 5) studies that did not meet the expected design.
Definition, diagnosis, and grading of LVSI in endometrial carcinoma
LVSI is characterized by the collection of tumor cells in lymphatic and/or blood vessels, preferably adjacent to the vessel wall, around the main tumor.[22]
The existence of a proteinaceous substance helps in the diagnosis of a lymphatic vessel.[9],[10]
Furthermore, some histological findings, for example, vicinity to an arterial or venous blood vessel or perivascular lymphocytic infiltration, have been suggested to favor LVSI.[23] Some studies have reported that perivascular lymphocytic infiltration is associated with lymphovascular space invasion, but this histologic criterion, by itself, is not diagnostic for LVSI and true tumor emboli in vessels are necessary to confirm LVSI diagnosis,[9],[10] as Bosse et al.[24] reported perivascular lymphocytic infiltration in 32.7% of endometrial carcinomas, but only 26.4% of their cases with perivascular lymphocytic infiltration showed LVSI.
Before diagnosing LVSI, its mimickers must be excluded. The most common mimickers of LVSI include tumor cell displacement in myometrial clefts due to manipulation in surgery[25] or improper grossing[26] of a fragile, poorly fixed, or necrotic tumor. Other LVSI mimickers are stromal retraction surrounding the tumor and microcystic elongated and fragmented (MELF) pattern of invasion.[27]
In questionable cases, the immunohistochemistry (IHC) of CD31 can be used[11]; however, IHC has limited use in the diagnosis of LVSI.[28]
Because of some restrictions of the intraoperative frozen section, it is generally difficult to identify LVSI before the final pathology report.[5]
The presence or absence of LVSI must be reported in the pathology report. Moreover, it is suggested to report the location of LVSI (deep areas of myometrium, adnexa, cervix, parametrium, etc.).[28]
For scoring of LVSI in endometrial cancer, we searched the literature and found five scoring methods:
- Qualitative two-tiered system: Most publications identified LVSI as present or absent without any more details.[24]
- Semiquantitative three-tiered system: In 1999, Hachisuga et al.[22] graded LVSI as follows:
- None: no LVSI
- Mild: a single focus of LVSI surrounding the tumor
- Severe (diffuse or multifocal): >1 focus of LVSI surrounding the tumor.[22]
- Another semiquantitative three-tiered system was characterized by Bosse et al. in 2015[24] and the College of American Pathologists (CAP) in 2021[29]:
- Absent: no LVSI
- Focal or low: <3 involved vessels around the tumor
- Substantial or extensive (diffuse or multifocal): ≥ 3 involved vessels around the tumor
- Semiquantitative four-tiered system, classified by Fujimoto et al. in 2009[30]:
- No LVSI
- Minimal: a few vessels involved around the tumor
- Moderate: more vessels involved around the tumor
- Prominent: many vessels involved diffusely in the deeper areas of the myometrium
The four-tiered system for scoring LVSI did not show stronger prognostic significance compared with the three-tiered system designed by Hachisuga et al.[22] due to the absence of distinction between minimal and moderate LVSI. The three-tiered system designed by Hachisuga et al.[22] had a significantly increased hazard ratio (HR) compared with the two-tiered system, and its prognostic importance was strongest and most relevant to the clinical aspect. In this three-tiered system, mild LVSI is defined as a single focus of LVSI, but a survey of the number of involved vessels showed an average of two involved vessels and resulted in the creation of another three-tiered system classification by Bosse et al.[24] Substantial LVSI using the Bosse et al.'s[24] three-tiered system is defined as the strongest independent factor of prognosis for distant metastasis, pelvic recurrence, and overall survival.
- Recently, a cutoff criterion of ≥ 4 involved vessels in at least one hematoxylin- and eosin-stained section has been suggested to identify substantial or extensive LVSI.[31]
An easy prediction model for LVSI is defined as the LVSI risk index characterized by “TD×%MMI×tumor grade×cervical stromal involvement.” In this index, tumor diameter (TD) and percentage of myometrial invasion (% MMI) are computed as absolute numbers.[5]
Evaluation of the depth of MMI in endometrial carcinoma
For measurement of MMI, three parameters are used: %MMI, depth of MMI in millimeters, and tumor free diameter (TFD).[32],[33] Before improving a model for anticipating LVSI, it must be evaluated which of these three parameters best predicts LVSI. Kim et al.'s[5] study revealed %MMI as the most practical parameter among them.[5]
Ordinarily, %MMI is identified in hysterectomy specimens as less than or greater than 50% of myometrial thickness.[34]
FIGO grading system for endometrial carcinoma
Endometrial carcinoma is graded histopathologically into two main groups: low grade (FIGO G1–G2) and high grade (FIGO G3). These two grades have various biological behaviors.[2] The most common histological subtype of endometrial carcinoma is endometrioid adenocarcinoma.[35] FIGO grading system of endometrioid endometrial carcinoma is identified by the amount of solid, nonsquamous components. Grades 1, 2, and 3 are characterized by ≤5%, 6–50%, and >50% solid nonsquamous components, respectively.[35],[36]
Some subtypes of endometrial carcinoma are considered as high grade. These include serous carcinoma, clear cell carcinoma, dedifferentiated carcinoma, undifferentiated carcinoma, and carcinosarcoma.[8],[35]
Is there any relationship between LVSI with tumor grade and MMI?
Multiple studies have shown a positive relationship between the existence of LVSI with tumor grade and depth of MMI,[15],[37],[38] but the results of Motasim et al.[11] study are partly different. They studied LVSI in 32 patients with early-stage (stage 1), low-grade endometrioid endometrial carcinoma and observed that there is no association between LVSI and depth of MMI. This result is contrary to Tortorella et al.'s[39] study on 524 patients with early-stage, low-grade endometrial carcinoma that revealed a higher frequency of MMI among patients with LVSI. They reported that all patients with focal and substantial LVSI had MMI [Table 1].[39] However, regarding the association between LVSI and tumor grade, the results of the two studies by Motasim et al.[11] and Tortorella et al.[39] were in agreement with other studies. They showed a significant association between LVSI and tumor grade, as 82% of cases with LVSI were grade G2 in Motasim et al.'s study.[11] This proportion was higher in Tortorella et al.'s[39] study, which mentioned that 97.1% and 100% of patients with focal and substantial LVSI, respectively, had G2 grade carcinoma. | Table 1: Patients' characteristics according to lymphovascular space invasion
Click here to view |
The results of Kim et al.'s,[5] Watanabe et al.'s[40] and Dai et al.'s[41] studies demonstrated that LVSI-positive tumors were significantly associated with higher tumor grade (P-value <0.001) and deep MMI (MMI >50%) (P-value <0.001).
Hachisuga et al.[22] [Table 1], Bosse et al.,[24] Oliver-Perez et al.,[42] Veade et al.[43] [Table 1], and Cappozi et al.[44] analyzed endometrial carcinoma and identified that LVSI is more common in, or is more likely to be associated with, a higher grade and deep MMI.
More frequency of LVSI in tumors with deep MMI is quoted in other studies conducted by Wang et al.[45] and Dane and Bakir[46]
Important evidence of a higher rate of LVSI in higher-grade carcinomas of the endometrium is gained from the World Health Organization (WHO) classification that characterized serous carcinoma as a high-grade endometrial cancer that is associated with extensive LVSI.[35]
Also, Singh et al.[28] said that LVSI is an infrequent histologic finding in low-grade endometrial carcinoma.
Based on a significant and strong association between LVSI with higher tumor grade and deep MMI, these uterine factors (grade and depth of MMI) are used as indirect methods for anticipating the existence of LVSI.[5]
In summary, despite the significant association between LVSI with MMI and grade that is mentioned in many studies, it should be considered that the presence and absence of LVSI can be seen in G1 and G3 carcinomas, respectively. Also, LVSI can be present in patients with no MMI. In addition, in LVSI-negative cases, deep MMI can be present.
| Conclusion | | |
Our study showed that although scant LVSI-positive endometrial carcinomas may be associated with low-grade (G1) and superficial MMI, and also, few LVSI-negative cases may be accompanied by high tumor grade (G3) and deep MMI, in most patients with LVSI, there is a significant association between LVSI with higher histologic tumor grade and deep MMI. More evaluation is necessary regarding exceptions and different results. Moreover, considering the importance of LVSI as a prognostic factor in endometrial carcinoma, further investigations are needed to determine the role of various grades of LVSI in the selection of the type of treatment, requirement for adjuvant therapy, and the response to various treatment modalities of endometrial carcinoma.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | Genestie C, Leary A, Devouassoux M, Auguste A. Histological and molecular classification of endometrial carcinoma and therapeutical implications. Bull Cancer 2017;104:1001-12.  |
| 2. | Ries LAG, Melbert D, Krapcho M, Stinchcomb DG, Howlader N, Horner MJ, et al. SEER cancer statistics Review, 1975-2005. Bethesda, MD: National Cancer Institute; 2008. p. 907. |
| 3. | Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin 2019;69:7-34. |
| 4. | Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomatarm I, Jemal A, et al. Global cancer statistics 2020: GIOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer Clin 2021;71:209-49. |
| 5. | Kim SII, Yoon JH, Lee SJ, Song MJ, Kim JH, Lee HIN, et al. Prediction of lymphovascular space invasion in patients with endometrial cancer. Int J Med Sci 2021;18:2828-34. |
| 6. | Siegel RL, Miller KO, Jemal A. Cancer statistics, 2018. CA Cancer Clin 2018;68:7-30. |
| 7. | Kurman RJ, Carcangiu ML, Herrington CS, Young RH. WHO classification of tumors of female reproductive organs. WHO classification of tumors. 4 th ed. France: International Agency for Research on Cancer; 2014. p. 6. |
| 8. | Colombo N, Creutzberg C, Amant F, Bosse T, Gonzalez-Martin A, Ledermann J, et al. ESMO-ESGO-ESTRO Consensus Conference on endometrial cancer: Diagnosis, treatment and follow-up. Ann Oncol 2016;27:16-41. |
| 9. | Winer I, Ahmed QF, Mert I, Bandyopadhyay S, Cote M, Munkarah AR, et al. Significance of lymphovascular space invasion in uterine serous carcinoma: What matters more; Extent or presence? Int J Gynecol Pathol 2015;34:47-56. |
| 10. | Folkins AK, Nevadunsky NS, Saleemuddin A, Jarboe EA, Muto MG, Feltmate CM, et al. Evaluation of vascular space involvement in endometrial adenocarcinomas: Laparoscopic vs abdominal hysterectomies. Mod Pathol 2010;23:1073-9. |
| 11. | Motasim A, Hameed Z, AhmadI. Assessment of lymphovascular invasion in early stage endometrial carcinoma-A retrospective study. Surg Exp Pathol 2021;4:9. |
| 12. | Padillo-Iserte P, Lago V, Tauste C, Herves D, Domingo S. Impact of uterine manipulator on oncological outcome in endometrial cancer surgery. Am J Obstet Gynecol 2021;224:65.e1-11. |
| 13. | Ahmed M, Al-Khafaji JF, Class CA, Frumovitz M, Lyer RB. Can MRI help assess aggressiveness of endometrial cancer? Clin Radiol 2018;78:833.e11-8. |
| 14. | Lavaud P, Fedida B, Canlorbe G, Bendifallah S, Darai E, Thomassin-Naggara I. Preoperative MR imaging for ESMO-ESGO-ESTRO classification of endometrial cancer. Diagn Interv Imaging 2018;99:387-96. |
| 15. | Laufer J, Scasso S, Papadia A, Sosa C, Cirillo F, Raspagliesi F. Association between tumor diameter and lymphovascular space invasion among women with early-stage endometrial cancer. Int J Gynaecol Obstet 2013;123:142-5. |
| 16. | Gemer O, Gdalvich M, Voldarsky M, Barak F, Ben Arie A, Schneider D, et al. Lower uterine segment involvement is associated with adverse outcome in patients with stage I endometrioid endometrial cancer: Results of a multicenter study. Eur J Surg Oncol 2009;35:865-9. |
| 17. | Mariani A, Webb MJ, Keeney GL, Haddock MG, Calori G, Podratz KC. Low-risk corpus cancer: Is lymphadenectomy or radiotherapy necessary? Am J Obstet Gynecol 2000;182:1506-19. |
| 18. | Brown AK, Madom L, Moore R, Granai CO, DiSilvestro P. The prognostic significance of lower uterine segment involvement in surgically staged endometrial cancer patients with negative nodes. Gynecol Oncol 2007;55-8. |
| 19. | Querleu D, Morrow P. Classification of radical hysterectomy. Lancet Oncol 2008;9:297-303. |
| 20. | Cusano E, Myers V, Samant R, Sudai T, Keller A, Le T, et al. Prognostic significance of lymphovascular space invasion in the absence of lymph node metastasis in early-stage endometrial cancer. Int J Gynecol Cancer 2018;28:890-94. |
| 21. | Santor A, Angelico G, Travaglino A, Inzani F, Arciuolo D, Valente M, et al. New pathological and clinical insights in endometrial cancer in view of the updated ESGO/ESTRO/ESP guidelines. Cancers (Basel) 2021;13:2623. |
| 22. | Hachisuga T, Kaku T, Fukuda K, Eguchi F, Emoto M, Kamura T, et al. The grading of lymphovascular space invasion in endometrial carcinoma. Cancer 1999;86:2090-7. |
| 23. | Peters EEM, Bartosch C, Mccluggage WG, Genestie C, Lax SF, Nout R, et al. Reproducibility of lymphovascular space invasion (LVSI) assessment in endometrial cancer. Histopathology 2019;75:128-36. |
| 24. | Bosse T, Peters EEM, Creutzberg CL, Jurgenliemk-Schulz IM, Jobsen JJ, Mens JW, et al. Substantial lymph-vascular space invasion (LVSI) is a significant risk factor for recurrence in endometrial Cancer -A pooled analysis of PORTEC 1 and 2 trials. Eur J Cancer 2015;51:1742-50. |
| 25. | Logani S, Herdman A, Little JV, Moller KA. Vascular “pseudo invasion” in laparoscopic hysterectomy specimens: Adiagnostic pitfall. Am J Surg Pathol 2008;32:560-5. |
| 26. | Kitahara S, Walsh C, Frumovitz M, Malpica A, Silva EG. Vascular pseudoinvasion in laparoscopic hysterectomy specimens for endometrial carcinoma: A grossing artifact? Am J Surg Pathol 2009;33:298-303. |
| 27. | Murray SK, Young RH, Scully RE. Unusual epithelial and stromal changes in myoinvasive endometrioid adenocarcinoma: A study of their frequency, associated diagnostic problems, and prognostic significance. Int J Gynecol Pathol 2003;22:324-33. |
| 28. | Singh N, Hirschowitz L, Zaino R, Alvarado-Cabrero I, Duggan MA, Ali-Fehmi R, et al. Pathologic prognostic factors in endometrial carcinoma (other than tumor type and grade). Int J Gynecol Pathol 2019;38:S93-113. |
| 29. | Krishnamurti UG, Crothers BA. Protocol for the Examination of Specimens from Patients with Carcinoma and Carcinosarcoma of the Endometrium. College of American Pathologists. United States of America: Bob McGonnagle; 2021. p. 8. |
| 30. | Fujimoto T, Nanjyo H, Fukuda J, Nakamura A, Mizunuma H, Yaegashi N, et al. Endometrioid uterine cancer: Histopathological risk factors oflocal and distant recurrence. Gynecol Oncol 2009;112:342-7. |
| 31. | Peters EEM, Leon-Castillo A, Smit VTHBM, Boennelycke M, Hogdall E, Hogdall C, et al. Defining substantial lymphovascular space invasion in endometrial cancer. Int J Gynecol Pathol 2022;41:220-6. |
| 32. | Doghri R, Chaabouni S, Houcine Y, Charli L, Boujelbene N, Driss M, et al. Evaluation oftumor-free distance and depth of myometrial invasion as prognostic factors in endometrial cancer. Mol Clin Oncol 2018;9:87-91. |
| 33. | Oge T, Comert DK, Cakmak Y, Arik D. Is tumor-free distance an independent prognostic factor for early-stage endometrioid endometrial cancer? J Oncol 2020;2020:2934291. |
| 34. | Blake P, Swart AM, Orton J, Kitchener H, Whelan T, Lukka H, et al. Adjuvant external beam radiotherapy in the treatment of endometrial cancer (MRC ASTEC and NCIC CTG EN.5 randomised trials): Pooled trial results, systemic review, and meta-analysis. Lancet 2009;373:137-46. |
| 35. | Herrington CS. WHO classification of tumors editorial board. Female Genital Tumors. 5 th ed. France: International Agency for Research on Cancer; 2020. |
| 36. | Soslow RA, Tornos C, Park KJ, Malpica A, Matias-Guiu X, Oliva E, et al. Endometrial carcinoma diagnosis: Use of FIGO grading and Genomic subcategories in clinical practice: Recommendation of the international society of gynecological pathologist. Int J Gynecol Pathol 2019;38:S64-74. |
| 37. | Hanson MB, Van Nagell JR Jr, Powel DE, Donaldson ES, Gallion H, Merhige M, et al. The prognostic significance of lymph-vascular space invasion in stage I endometrial cancer. Cancer 1985;55:1753-7. |
| 38. | Alexander-Sefre F, Nibbs R, Rafferty T, Aghan A, Singh N, Jacobs I. Clinical value of immunohistochemically detected lymphatic and vascular invasion in clinically staged endometrioid endometrial cancer. Int J Gynecol Cancer 2009;19:1074-9. |
| 39. | Tortorella L, Restaino S, Zannoni GF, Vizzielli G, Chiantera V, Cappuccio S, et al. Substantial lymph-vascular space invasion (LVSI) as predictor of distant relapse and poor prognosis in low-risk early-stage endometrial cancer. J Gynecol Oncol 2021;32:e11. |
| 40. | Watanabe T, Honma R, Kojima M, Nomura S, Furukawa S, Soeda S, et al. Prediction of lymphovascular space invasion in endometrial cancer using the 55-gene signature selected by DNA microarray analysis. PLoS One 2019;14:e0223178. |
| 41. | Dai Y, Dong Y, Cheng Y, Hou H, Wang J, Wang Z, et al. Prognostic significance of lymphovascular space invasion in patients with endometrioid endometrial cancer: A retrospective study from a single center. J Gynecol Oncol 2021;31:e27. |
| 42. | Oliver-Perez MR, Magrina J, Villalain-Gonzalez C, Jimenez-Lopez JS, Lopez-Gonzalez G, Barcena C, et al. Lymphovascular space invasion in endometrial carcinoma: Tumor size and location matter. Surg Oncol 2021;37:101541. |
| 43. | Veade AE, Foote J, Ehrisman J, Broadwater G, Davidson BA, Lee PS, et al. Association between lymphovascular space invasion, nodal recurrence and survival in patients with surgical stage I endometrioid endometrial adenocarcinoma. World J Surg Oncol 2019;17:80. |
| 44. | Cappozi VA, Sozzi G, Uccella S, Ceni V, Cianciolo A, Gambino G, et al. Novel preoperative predictive score to evaluate lymphovascular space involvement in endometrial Cancer: An aid to the sentinel lymph node algorithm. Int J Gynecol Cancer 2020;30:806-12. |
| 45. | Wang Y, Xu P, Yang X, Yu Q, Xu X, Zou G, et al. Association of myometrial invasion with lymphovascular space invasion, lymph node metastasis, recurrence, and overall survival in endometrial cancer: A meta-analysis of 79 studies with 68870 patients. Front Oncol 2021;11:762329. |
| 46. | Dane C, Bakir S. The effect of myometrial invasion on prognostic factors and survival analysis in endometrial carcinoma. Afr Health Sci 2019;19:3235-41. |
[Table 1]
|
Search Pubmed for