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ABSTRACT: Endocervical adenocarcinomas of the usual type are etiologically related to infection with oncogenic human papillomaviruses (HPVs). These tumors are typically diffusely positive for p16 and carcinoembryonic antigen (CEA) immunostains. The goal of our study was to determine the HPV status and immunohistochemical profiles of unusual histologic subtypes of endocervical adenocarcinoma.
The study consisted of a total of 26 cases of unusual subtypes including clear cell carcinoma (CCC, n=9), gastric-type adenocarcinoma (GAS, n=11), minimal deviation adenocarcinoma (MDA, n=3), mesonephric adenocarcinoma (MSN, n=1), serous adenocarcinoma (SER, n=1), and malignant mixed Müllerian tumor (n=1). In addition, 5 cases of usual-type endocervical adenocarcinoma (UEA) were included in the study as a control group. The cases were tested for HPV using SPF-10 PCR and LiPA assays, and immunostained for p16, HIK1083, hepatocyte nuclear factor 1-β, p53, CEA, estrogen receptor (ER), and progesterone receptor (PR).
HPV DNA was not detected in any of the unusual adenocarcinoma subtypes, with the exception of a single case of SER in which HPV16 was detected. p16 positivity did not correlate with HPV status, as 42% of HPV-negative tumors showed patchy/diffuse p16 overexpression; however, p16 positivity was uncommon in GAS/MDA. HIK1083 positivity was limited to GAS and MDA, indicating relative specificity for tumors with gastric mucin expression. Hepatocyte nuclear factor 1-β was positive in the majority of CCCs and also in other tumor variants and in some UEA as well, indicating a lack of specificity for clear cell differentiation. CEA was consistently negative in CCCs and in a single MSN, but positive in GAS, MDA, SER, and UEA, suggesting that it may serve as a negative marker of clear cell differentiation. p53 was diffusely positive in almost half of the GAS cases, whereas UEA showed mostly negative staining and other variants showed focal staining. PR was negative in all variant cases and in all UEA. ER expression, although mostly negative, showed focal staining in a few variant cases and UEA.
Unusual variants of endocervical adenocarcinoma are not related to HPV infection, with only rare exceptions, and p16 overexpression in non-UEA does not correlate with HPV status. Negative staining for PR and ER may serve as a general marker of endocervical neoplasia. GAS/MDA may be differentiated from all other adenocarcinomas with either positive HIK1083 stain or negative/focal p16 stain. Positive CEA stain differentiates GAS/MDA from CCC and negative PR and ER stains differentiate GAS/MDA from benign endocervical glands. CCC may be distinguished from all other adenocarcinomas, except MSN, with a negative CEA stain. Strong and diffuse p53 positivity in SER may be useful in differentiation from UEA. MSN may be identified with negative CEA, ER, and PR stains.
The American journal of surgical pathology 05/2011; 35(5):633-46. · 4.06 Impact Factor
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ABSTRACT: The classification of anal intraepithelial neoplasia (AIN) in mucosal biopsies is subject to considerable interobserver variability. Previous studies have shown that Ki-67 and p16/CDKN2A immunostains aid detection of dysplasia in biopsy samples from the uterine cervix. The aim of this study was to determine whether Ki-67 and p16/CDKN2A immunolabeling enhanced diagnostic accuracy in the assessment of anal mucosal biopsies from patients with suspected human papillomavirus (HPV) infection. The study consisted of 75 cases that were originally interpreted to represent normal anal transitional zone (n=15), fibroepithelial polyp (n=10), condyloma accuminatum (n=10), low-grade AIN (AIN1, n=20), and high-grade AIN (n=20), including 10 cases each of AIN2 and AIN3. The histologic features of all cases were re-reviewed and categorized based upon consensus agreement, which resulted in reclassification of 16 cases. Thus, the final study group consisted of 17 samples of normal anal transition zone, 14 fibroepithelial polyps, 6 condylomata accuminata, and 38 cases of AIN (11 AIN1, 16 AIN2, and 11 AIN3). Each case was tested for the presence of HPV DNA by a SPF10 polymerase chain reaction and LiPA25 genotyping assay and immunostained for Ki-67 and p16/CDKN2A. A positive Ki-67 result was defined as the presence of a cluster of at least 2 strongly stained epithelial nuclei in the upper two-thirds of the epithelial thickness. A positive result for p16/CDKN2A was defined as diffuse moderate-to-strong cytoplasmic and nuclear staining. None of the anal transition zone samples or fibroepithelial polyps showed Ki-67 or p16/CDKN2A staining. All condylomata and samples of AIN contained HPV DNA and showed positive Ki-67 labeling. All cases of high-grade AIN showed positive p16/CDKN2A staining. We conclude that Ki-67 labeling detects anal HPV-related changes with a high degree of sensitivity and specificity, whereas increased p16/CDKN2A staining is strongly associated with high-grade squamous neoplasia. These results indicate that a combination of these markers may aid interpretation of anal mucosal biopsy samples.
The American journal of surgical pathology 10/2010; 34(10):1449-55. · 4.06 Impact Factor
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ABSTRACT: The objective of the study was to compare the distribution of HPV genotypes and HPV16 variants in glandular and squamous cervical neoplasia.
Cases of endocervical adenocarcinoma in-situ (AIS, n=33) invasive adenocarcinoma (ADCA, n=55), cervical intraepithelial neoplasia-3 (CIN3, n=130) and squamous cell carcinoma (SCC, n=60) were collected at the New York Hospital and tested for HPV using SPF(10)PCR-LIPA(25) (version 1) assays and for HPV16 variants using a multiplex PCR and reverse hybridization assay.
There was a difference between the spectrum of HPV genotypes detected in glandular and squamous neoplasia: 13 different HPV genotypes were detected in CIN3 as single infections and 11 in SCC, while only 4 single genotypes were detected in AIS and 3 in ADCA. The most common single HPV types in CIN3 were HPV16, 31, and 52 (56.9%, 10%, 8.4%, respectively). In SCC the most common were HPV16, 18 and 31 (70%, 6.5%, 4.9%). In AIS, HPV16, 18, 45 and 35 accounted for 69.7%, 27.2%, 3%, 3% of cases. The three single types in ADCA were HPV16 (43.6%), HPV18 (41.8%) and HPV45 (10.9%). European variants of HPV16 were the most common in CIN3 (83.8%), SCC (71.4%) and AIS (73.9%). In ADCA the Asian American (AA) variant was the most common (41.7%) followed by European variants (33.3%). AA variant was also detected in 17.4%, 4.1%, and 2.4% of HPV16 positive AIS, CIN3 and SCC, respectively.
Asian American variant of HPV16, HPV18 and HPV45 are preferentially associated with cervical adenocarcinoma as compared to squamous cell carcinoma.
Gynecologic Oncology 03/2010; 117(2):297-301. · 3.89 Impact Factor
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ABSTRACT: Chlamydia trachomatis (Ct) has been implicated as a co-factor in cervical carcinogenesis. The goal of the current study was to investigate if Ct may play a role in pathogenesis of cervical adenocarcinoma and, specifically, if there is a co-infection between Ct and Human Papillomavirus (HPV) in cervical adenocarcinomas. The second goal of the study was to determine the distribution of HPV genotypes in most recent cases of in-situ and invasive cervical adenocarcinomas.
Biopsies of 71 cervical adenocarcinomas (31 in-situ and 40 invasive) were tested for the presence of Ct using two novel PCR assays. In addition, all cases were tested for HPV using SPF10-PCR assay and genotyped using LIPA(25) test.
None of the cases was found to be positive for Ct using two independent PCR assays. All lesions, however, were positive for HPV with the exception of a case of minimal deviation adenocarcinoma. Overall, 94.2% of cases were positive for either HPV16 (n=44, 62.8%) or HPV18 (n=20, 28.5%), or both (n=2, 2.8%). Other single HPV types included HPV45 (n=3, 4.2%) and HPV35 (n=1, 1.4%).
The study demonstrated lack of co-infection between Human Papillomavirus and C. trachomatis in in-situ and invasive adenocarcinoma of the uterine cervix. The role of Ct as a carcinogenetic co-factor may be restricted to cervical squamous cell carcinomas. Accounting for type cross-protection, currently available HPV vaccines are likely to prevent close to 100% of HPV-positive cervical adenocarcinomas.
Gynecologic Oncology 07/2009; 114(3):390-4. · 3.89 Impact Factor
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ABSTRACT: A 43-year-old woman (gravida 2, para 1011) with a history of uterine leiomyomata and a Barnett colonic reservoir underwent a supracervical hysterectomy. Final pathology revealed Enterobius vermicularis within the myometrium and adnexal vasculature. Infection may have occurred through a modified mode given the presence of a Barnett colonic reservoir and absence of an anus.
American journal of obstetrics and gynecology 04/2009; 200(6):e6-7. · 3.28 Impact Factor
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ABSTRACT: Two independent pathways of vulvar carcinogenesis have currently been identified, one related to infection with mucosal human papillomaviruses (HPVs) and a second related to chronic inflammatory or autoimmune processes. The goal of the study was to examine a possible role of cutaneous HPVs from the beta genus in vulvar carcinogenesis and to evaluate the distribution of intratypic variants of HPV 16 in HPV 16-positive vulvar cancer. Consecutive cases of vulvar carcinoma were retrieved from the files and included the following histologic subtypes: keratinizing (n=21), basaloid (n=7), warty (n=1), mixed basaloid-warty (n=4), verrucous (n=4), keratoacanthoma (n=1), basal cell carcinoma (n=1). All tumors were microdissected and tested for 25 beta HPV types and 25 mucosal HPV types. Cases identified as positive for HPV 16 were further tested for intratypic variants. All cases were immunostained for p16INK4a. Beta HPVs were not detected in any of the tumor cases. Mucosal HPVs were detected in all but one basaloid/warty carcinomas; of these, nine cases (82%) were positive for HPV 16, including five European subtypes, one African subtype, one North American subtype and two indeterminate subtypes. Two of four verrucous carcinomas were positive for HPV 6. Mucosal HPVs were not detected in keratinizing carcinomas, keratoacanthoma and basal cell carcinoma. All cases of basaloid/warty carcinomas, but none of the remaining tumors, overexpressed p16INK4a protein. Our data do not support a role of beta HPVs in the pathogenesis of vulvar carcinoma. The study reaffirms the role of mucosal HPVs, in particular that of HPV 16, in the pathogenesis of basaloid and warty tumor subtypes. The HPV 16 intratypic variation showed correlation with patients' ethnic background. P16INK4a immunostaining seems to be a sensitive and specific marker of vulvar carcinomas positive for oncogenic mucosal HPVs.
Modern Pathology 04/2008; 21(3):334-44. · 4.79 Impact Factor
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ABSTRACT: The majority of low-grade squamous intraepithelial lesions (LSILs) of the cervix regress spontaneously; however, a small proportion of LSILs progress to high-grade squamous intraepithelial lesion (HSIL) if the lesion is not excised. The guidelines for which patients with LSIL should be treated and which may be followed safely are not well established. The goal of this study was to identify a subgroup of patients with LSIL who may require surgical treatment. We hypothesized that patients with LSILs with marked cytological atypia (LSIL-MA) may be at higher risk for subsequent HSIL. In addition, we were interested in whether LSIL-MA was associated with specific human papillomavirus genotypes. Consecutive patients with biopsy diagnosis of LSIL (n = 30) and LSIL-MA (n = 30) were identified. Marked atypia was defined as 5 or more cells with nuclear enlargement of at least 5 times the size of an intermediate cell nucleus or multinucleation with 5 or more nuclei. Patient follow-up was recorded for up to 24 months. Human papillomavirus genotyping was performed using SPF10 PCR and line probe assay. High-grade squamous intraepithelial lesion on follow-up was significantly more common in patients with LSIL-MA (36%) than in patients with LSIL (7%), and negative follow-up was significantly more common in patients with LSIL (50%) than LSIL-MA (23%). Cases of LSIL and LSIL-MA showed similar spectrum of human papillomavirus genotypes. Marked cytological atypia in LSILs identifies a subset of patients with a high rate of HSIL on follow-up. In such patients, an excisional cone biopsy should be strongly considered.
International Journal of Gynecological Pathology 11/2007; 26(4):457-62. · 1.45 Impact Factor
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ABSTRACT: The purpose of this study is to determine the impact of the Bethesda System 2001 recommendation of reporting cytologically benign appearing endometrial cells (BEC) seen in Papanicolaou (Pap) tests of all women age 40 years and older, and to determine the significance of such finding.
Pap tests of women age 40 years and older containing BEC outside of the first half of menstrual cycle reported before and after the Bethesda System 2001 implementation were included. 300 postmenopausal women without BEC were included as control group. Clinical follow-up was reviewed and significant endometrial pathology was defined as simple hyperplasia or a higher diagnosis.
BEC reporting rate increased from 0.17% to 0.49% before and after the Bethesda System 2001 (P=0.0001), due to reporting in women with premenopausal status. Significant endometrial pathology was detected in 14 of 121 (11.6%) postmenopausal patients compared to 7 of 300 (2.3%) in the control group (P=0.0002, relative risk=4.96, 95% confidence interval 2.05-11.98), and in none of premenopausal patients. 12 of 14 women with significant endometrial pathology had either postmenopausal bleeding or hormone replacement therapy use.
The Bethesda System 2001 led to increased reporting of BEC only in premenopausal women, leading to biopsies performed solely for BEC in these women with no pathology detected. Presence of BEC in Pap tests of postmenopausal women warrants a thorough clinical review, and immediate biopsy is a valid consideration. Presence of hormone therapy or postmenopausal bleeding may be modifiers of risk.
Gynecologic Oncology 11/2007; 107(1):86-93. · 3.89 Impact Factor
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ABSTRACT: Atypical immature squamous metaplasia (AIM) of the cervix is a loosely defined entity characterized by immature metaplastic cells with mild cytologic atypia.
To examine whether a combination of immunostaining for p16 and Ki-67 could be used to stratify AIM cases into 3 categories: benign, cases with nondiagnostic atypia, and high-grade squamous intraepithelial lesion (HSIL).
The study consisted of 37 cases of AIM, 23 cases of benign cervical mucosa (NEG), and 36 cases of HSIL. All cases were tested for high-risk human papillomaviruses using SPF 10 polymerase chain reaction and immunostained for p16 and Ki-67.
All cases of HSIL were positive for both p16 and Ki-67. All but 2 benign control cases were negative for both p16 and Ki-67. Seven cases of AIM (19%) displayed a pattern of immunostaining identical to HSIL, and these most likely represent a spectrum of HSIL. A total of 54% of cases of AIM were negative for both p16 and Ki-67, consistent with benign reactive atypia. Two AIM cases (5%) were negative for p16 and positive for Ki-67 in the area adjacent to an ulcer, representing regeneration. Finally, 22% of AIM cases were positive for p16 and negative for Ki-67; such cases may represent a precursor of HSIL or, alternatively, a regressing HSIL.
The combination of immunostaining for p16 and Ki-67 is helpful in limiting of the number of cases with nondiagnostic atypia of the cervix.
Archives of pathology & laboratory medicine 10/2007; 131(9):1343-9. · 2.58 Impact Factor
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ABSTRACT: Identification of early invasion in vulvar intraepithelial neoplasia 3 (VIN 3) and cervical intraepithelial neoplasia 3 (CIN 3) may be difficult with the use of routine hematoxylin-eosin staining. Presence of obscuring inflammation and tangential tissue sectioning are the most common diagnostic pitfalls.
To examine the utility of double immunostaining for cytokeratin-collagen IV or cytokeratin-laminin in the detection of early invasion in VIN 3 and CIN 3.
The study group consisted of 10 cases of "VIN 3, suspicious for invasion" and 10 cases of "CIN 3, suspicious for invasion." The negative control group consisted of VIN 3 (n = 15) and CIN 3 (n = 10). The positive control group consisted of cases of invasive vulvar carcinoma (n = 11) and invasive cervical carcinoma (n = 25). All cases were double immunostained for cytokeratin and collagen IV and, in a separate reaction, for cytokeratin and laminin. The continuity of the basement membrane and the presence of stromal invasion were assessed in the stained sections.
The staining for collagen IV and laminin yielded identical results. A well-defined, continuous basement membrane was visualized in all cases of VIN 3 and CIN 3. A discontinuous or absent basement membrane was observed around the malignant cells on the invasive tumor front in all cases of vulvar and cervical carcinoma. In 2 of 10 cases of VIN 3, suspicious for invasion and in 4 of 10 cases of CIN 3, suspicious for invasion definitive foci of microinvasion were identified with the use of double immunostaining. A well-defined, continuous basement membrane was present in the remaining cases "suspicious for invasion."
Double immunostaining for cytokeratin- collagen IV or cytokeratin-laminin is useful for evaluation of early invasion in equivocal cases of VIN 3 and CIN 3.
Archives of pathology & laboratory medicine 07/2005; 129(6):747-53. · 2.58 Impact Factor
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ABSTRACT: The new Bethesda System 2001 (TBS 2001) minimized the subclassification of atypical squamous cells of undetermined significance (ASCUS).
The primary goal of this study was to determine the impact of the new subclassification on the accuracy of Papanicolaou (Pap) test diagnosis by examining the prevalence of human papillomavirus (HPV) DNA in different ASCUS subcategories, as defined by the new TBS 2001 versus the original TBS 1991. The second goal was to identify specific morphologic features of atypical squamous cells that are more frequently associated with HPV detection.
Consecutive cases of ThinPrep Pap tests were retrospectively reviewed by a panel of pathologists to obtain consensus diagnoses. The study group consisted of ASCUS cases; the positive control group consisted of low- and high-grade squamous intraepithelial lesions (LSILs and HSILs, respectively); and the negative control group consisted of cases "negative for intraepithelial lesion or malignancy." All ASCUS cases were subclassified according to TBS 1991 into the following categories: favor reactive (ASCUS-R), favor LSIL (ASCUS-L), favor HSIL (ASCUS-H), and not otherwise specified (ASCUS-NOS). In a separate review, ASCUS cases were subclassified according to TBS 2001 into the following categories: atypical squamous cells of undetermined significance (ASC-US) and atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H). Furthermore, morphologic ASCUS subtypes were recorded (atypical mature, immature, parakeratotic, and atrophic cells); in addition, individual morphologic features of atypical cells were recorded. Broad- spectrum HPV DNA amplification and genotyping was performed using short PCR fragment (SPF 10) polymerase chain reaction/Line Probe assays.
In cases classified according to TBS 1991, HPV was detected in 32% of negative, 49% of ASCUS, and 93% of LSIL/HSIL cases. On the second review, using the diagnostic categories of TBS 2001, which eliminated the ASCUS-;R category, the number of ASCUS cases decreased by 45%. The prevalence of HPV DNA in ASCUS cases downgraded to the negative category was 38%, which was not significantly different from HPV prevalence in negative cases as diagnosed under TBS 1991. Furthermore, HPV was detected in 56% of ASC-US and 71% of ASC-H cases. The prevalence of HPV in different morphologic subtypes of ASCUS was not significantly different, and none of the 8 individual morphologic features of atypical cells were more frequently associated with HPV detection.
Elimination of the ASCUS-R category in TBS 2001 resulted in a significant decrease in the number of ASCUS diagnoses. Downgraded cases had a relatively low prevalence of HPV DNA. It is expected that TBS 2001 will increase specificity of the Pap test without compromising its sensitivity.
Archives of pathology & laboratory medicine 06/2004; 128(5):527-32. · 2.58 Impact Factor
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ABSTRACT: Histologic criteria of low-grade vulvar/vaginal intraepithelial neoplasia (VIN1/VAIN1) are well established; however, a significant interobserver variability in diagnosing VIN1/VAIN1 has been reported. The goal of this study was to evaluate the utility of MIB-1 immunostaining as an adjunct test to increase the diagnostic accuracy in equivocal cases of VIN1/VAIN1. The second goal was to examine the distribution of low- and high-oncogenic risk human papillomaviruses (HPVs) in VIN1/VAIN1 lesions. Consecutive vulvar/vaginal biopsies originally diagnosed as VIN1/VAIN1 (n = 43) or benign (n = 20) were reviewed by two pathologists to obtain a consensus diagnosis. The diagnosis was further confirmed with HPV testing using Short PCR Fragment 10 and Line Probe Assay. MIB-1 immunostaining was performed, and positive staining was defined as a cluster of two or more stained nuclei in the upper two thirds of the epithelial thickness. After verification of the diagnosis using the consensus histologic review and HPV detection as an objective confirmatory test, 31% of cases originally diagnosed as VIN1/VAIN1 were identified as being overdiagnosed. The sensitivity and the specificity of MIB-1 staining for identifying VIN1/VAIN1 were 0.96 and 0.90, respectively. Seventy percent of VIN1 cases were associated with low-risk viral types. In contrast, the majority (84%) of VAIN1 cases were associated with high-risk HPVs. In conclusion, MIB-1 staining is sensitive and specific for identifying VIN1/VAIN1, helpful in verifying the diagnosis in equivocal cases.
Modern Pathology 09/2003; 16(8):735-41. · 4.79 Impact Factor
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ABSTRACT: There is considerable interobserver variation in the diagnosis of low-grade squamous intraepithelial lesion that involves mature squamous epithelium. Our aim was to evaluate the utility of MIB-1 immunostaining as an adjunct test to increase diagnostic accuracy. Consecutive cervical biopsies originally diagnosed as normal (n = 26) or low-grade squamous intraepithelial lesion (n = 23) were reviewed by three pathologists to obtain a consensus diagnosis. MIB-1 immunostaining was performed, and positive staining was defined as a cluster of at least two stained nuclei in the upper two thirds of the epithelial thickness. Human papillomavirus (HPV) DNA detection was performed using a polymerase chain reaction assay. All cases were subsequently reclassified as low-grade squamous intraepithelial lesion (LSIL) or normal (NL) when two or three of three gold standard criteria were satisfied (LSIL gold standard criteria = consensus diagnosis of LSIL, HPV+, MIB-1+; NL gold standard criteria = consensus diagnosis of NL, HPV-, MIB-1-). Using the gold standard diagnoses, we have identified that 14 normal cases (36%) were originally overdiagnosed as LSIL, and one LSIL case (10%) was originally underdiagnosed as normal. All MIB-1-positive cases were HPV+ and identified as LSIL in the consensus review. All MIB-1-negative cases were NL by gold standard criteria. The sensitivity (1.0) and the specificity (1.0) of MIB-1 staining for identifying LSIL were superior to the sensitivity (0.9) and the specificity (0.8) of HPV testing. In conclusion, MIB-1 is a highly sensitive and specific marker for identifying low-grade squamous intraepithelial lesion and is helpful in verifying the diagnosis of equivocal cases.
American Journal of Surgical Pathology 02/2002; 26(1):70-5. · 4.35 Impact Factor
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ABSTRACT: Recent studies have indicated that the use of the MIB-1 immunostaining may be useful in distinguishing endocervical neoplasia from benign nonneoplastic lesions. We sought to investigate this finding further with a specific emphasis on the common benign processes that may result in a nonspecific increase of MIB-1 staining. In this study we quantified the MIB-1 immunostaining in the mucinous endocervical epithelium (n=45) and in tubal metaplasia (n=28) during the proliferative and secretory phases (hormonal influence), in the mucinous endocervical epithelium in cases of cervicitis (inflammation) (n=10), in cases with a history of a recent biopsy (regeneration) (n=15), endocervical polyps (benign growth) (n=8), in the endocervical glands adjacent to a squamous intraepithelial lesion (human papilloma virus [HPV] infection) (n=63), and in in situ and invasive cervical adenocarcinomas (n=30). All cases with increased MIB-1 staining were subsequently tested for the presence of HPV DNA. The range of MIB-1 staining in the benign endocervical epithelium was from 0% to 48% and in the neoplastic epithelium from 25% to 84%. MIB-1 staining below 10% always reflected a benign process and MIB-1 staining higher than 50% was always associated with a neoplasia. Rare benign cases (tubal metaplasia during the proliferative phase, glands adjacent to squamous intraepithelial lesions, and cases with a history of a recent biopsy) had increased MIB-1 index, which overlapped with the neoplastic cases. In conclusion, MIB-1 is a useful marker of endocervical neoplasia, although in rare cases an overlap between benign and neoplastic cases may exist.
International Journal of Gynecological Pathology 02/2002; 21(1):22-6. · 1.45 Impact Factor
