Cases Of Lobular Endocervical Glandular Hyperplasia Research Articles

Characteristic Cytological Findings of Lobular Endocervical Glandular Hyperplasia Associated with Adenocarcinoma of the Uterine Cervix

Objective: To investigate the cytological findings of lobular endocervical glandular hyperplasia (LEGH) associated with adenocarcinoma and to clarify its characteristics and the coexisting adenocarcinoma using histochemistry and immunohistochemistry. Methods: Eighteen surgical cases of LEGH of the uterine cervix were retrospectively reviewed and classified into 3 groups: pure (pure type), atypical (atypical type), and LEGH with adenocarcinoma (mixed type). The mixed type is defined as LEGH or atypical LEGH with in situ or invasive adenocarcinoma. Cytological findings of conventional endocervical smear specimens (Papanicolaou stain) were analyzed. Histochemistry (periodic acid-Schiff reaction) and immunohistochemistry (M-GGMC-1, Muc-6 glycoprotein, and Ki-67) were performed using tissue specimens. Results: Cytologically, the pure type (7 cases) is characterized by glandular cell clusters that tended to form monolayered sheets with uniformly small nuclei and contain golden-yellowish mucin, whereas atypical (5 cases) and mixed (6 cases) types are characterized by glandular cell clusters similar to those of the pure type, but with complex glandular structures and mucin localization on the surface of glandular cell clusters. Ki-67 labeling index was significantly higher in atypical and mixed types than that in the pure type. Gastric-type mucinous carcinoma (MC-G) was observed in 2 out of 6 cases with mixed type. Conclusions: LEGH is found to be associated with adenocarcinoma types other than MC-G. Complex glandular structures or mucin localization on the surface of glandular cell clusters may be useful cytological findings to detect atypical and mixed types of LEGH.

Total Laparoscopic Hysterectomy for Diagnosis and Treatment of Cervical Cystic Lesions: A Case Series

Objective: Cervical cystic lesions are often observed in gynecological clinical practice. Many are caused by benign diseases such as lobular endocervical glandular hyperplasia (LEGH), and it is important to differentiate these lesions from those due to malignant diseases such as minimal deviation adenocarcinoma (MDA). In cases in which fertility preservation is not a concern, the final pathology is often confirmed by hysterectomy. To investigate the feasibility and safety of laparoscopic surgery for cervical cystic lesions, we retrospectively examined cases in which total laparoscopic hysterectomy (TLH) was performed for diagnosis and treatment. Methods: The subjects were 28 women who underwent TLH from April 2012 to March 2017 at Keio University Hospital. The pre- and post-operative courses of these patients were examined. Results: The average age was 49.4 (range 39 - 65) years and the mean body mass index was 21.7 (16.8 - 30.5) kg/m2. The average operation time was 159 (101 - 314) min and the average bleeding volume was 106.8 (0 - 600) g. There were no severe perioperative complications. The average hospital stay was 8.4 (7 - 14) days. In postoperative pathological diagnosis, 13 cases had benign diseases such as Nabot cysts, there were 14 cases of LEGH, and one patient was diagnosed with MDA. In the MDA case, additional bilateral salpingo-oophorectomy and pelvic lymph node dissection were performed at a later date. No metastasis was observed in these excised specimens. Conclusions: Our results suggest that TLH for cervical cystic lesions can be performed safely. However, it is important to consider the TLH indication before surgery based on the possibility of malignant disease.

Whole-exome sequencing of lobular endocervical glandular hyperplasia.

Lobular endocervical glandular hyperplasia (LEGH) was first reported as a benign proliferative disorder of the uterine cervix. However, it currently remains unclear whether it has the biological characteristics of pyloric metaplasia or precursor of minimal deviation adenocarcinoma (MDA)/gastric-type mucinous cervical adenocarcinoma (GAS). Therefore, in the present study we performed whole-exome sequencing on three cases of LEGH collected by laser-microdissection from the frozen tissue sections of surgically removed uteri. Analysis of the results identified 50 somatic variants. After several filtering processes, we identified 13 functional variants, including 12 missense and one insertion-deletion variants. Of these mutations, keratinocyte proline-rich protein, olfactory receptor M4 and zinc finger protein 645 mutations were found in the Catalogue Of Somatic Mutations In Cancer but were not related to carcinogenic diseases. We did not detect any significant copy number alterations or signatures. Although this was a limited case series, we did not identify any variants relevant to the tumorigenesis of LEGH to MDA/GAS, suggesting a metaplastic aspect of LEGH.

Usefulness of a management protocol for patients with cervical multicystic lesions: A retrospective analysis of 94 cases and the significance of GNAS mutation.

AimThe proper preoperative diagnosis and management of cervical proliferative disorders presenting with multiple cysts, including minimal deviation adenocarcinoma (MDA), lobular endocervical glandular hyperplasia (LEGH), and nabothian cyst (NC), have not been fully established. We previously proposed a management protocol comprising a diagnostic approach using cytology, magnetic resonance imaging, and gastric‐type mucin and subsequent treatment. We herein evaluate the usefulness of this protocol and implications of GNAS mutations in LEGH.MethodsThe clinical courses of 94 patients with cervical multicystic lesions who visited our hospital between June 1995 and September 2014 were retrospectively analyzed. GNAS mutations were investigated in 10 LEGH, five LEGH with atypia, and two MDA cases.ResultsOf the 94 patients, the conditions of 10, 59, and 25 were clinically diagnosed as suspicious of MDA or carcinoma (S/O MDA‐Ca), suspicious of LEGH (S/O LEGH), and NC, respectively. Ten patients each with S/O MDA‐Ca and S/O LEGH underwent hysterectomy, and the correct ratio for diagnosis was 90% (18/20). Of the 42 S/O LEGH cases followed‐up for more than 12 months, three showed an increase in tumor size. After hysterectomy, two were LEGH with atypia while one was NC. The GNAS mutation was detected in two cases of LEGH with atypia, one of which showed an increase in tumor size during follow‐up.ConclusionThe management protocol we propose herein will be useful. An increase in tumor size is important to detect potentially malignant LEGH. GNAS mutations may be involved in the tumorigenesis of potentially malignant LEGH.

Clonality analysis suggests that STK11 gene mutations are involved in progression of lobular endocervical glandular hyperplasia (LEGH) to minimal deviation adenocarcinoma (MDA)

Lobular endocervical glandular hyperplasia (LEGH) is a benign proliferative disease of cervical glands. Although histological resemblance of minimal deviation adenocarcinoma (MDA) to LEGH and frequent association of LEGH with MDA have been reported, it still remains unclear whether LEGH is a precancerous lesion of MDA. The present study was undertaken to examine the pathogenetic relationship between LEGH and MDA using a clonality analysis and mutational analyses of the STK11 gene, of which mutations have been reported in MDA. Of nine cases of LEGH only, four were polyclonal and five were monoclonal in composition. Of six LEGH lesions associated with MDA or adenocarcinoma, two were polyclonal and four were monoclonal. In cases of MDA or adenocarcinoma coexisting with LEGH, the patterns of X chromosome inactivation in malignant lesions were identical to those in coexisting LEGH lesions. A mutation of STK11 was only identified in one MDA, but not in LEGH. These results indicate that a subset of LEGH may be a precursor to malignant tumors including MDA and that a mutation of STK11 may be involved in progression of LEGH to MDA.

Preoperative Differential Diagnosis of Minimal Deviation Adenocarcinoma and Lobular Endocervical Glandular Hyperplasia of the Uterine Cervix

To clarify the preoperative differential diagnosis and management of minimal deviation adenocarcinoma (MDA) and lobular endocervical glandular hyperplasia (LEGH), a multicenter study was performed. A total of 112 patients who underwent conization or a hysterectomy for suspected MDA were collected from 24 hospitals. The pathological diagnosis in each case was determined by a central pathological review board. The diagnostic significance of clinicopathologic findings including results of magnetic resonance imaging (MRI), Papanicolaou (Pap) smears, and testing for gastric mucin was analyzed. The central pathological review identified 37 cases of Nabothian cyst or tunnel cluster, 54 cases of LEGH, 6 cases of MDA, 11 cases of adenocarcinoma, and 4 cases of benign disease. Lobular endocervical glandular hyperplasia was often associated with adenocarcinoma in situ, MDA, and mucinous adenocarcinoma. Three MDA patients had a recurrence, whereas none of LEGH patients had a recurrence irrespective of the type of surgery. On MRI, LEGH appeared as a characteristic multicystic lesion with an inner solid component, whereas MDA showed a predominantly solid pattern. A Pap smear or gastric mucin alone had limited diagnostic power. However, a combination of these findings is useful; that is, a cystic structure with inner solid components on MRI associated with mild glandular atypia and gastric mucin strongly suggested LEGH (24/26, 92%). A solid structure with atypical glandular cells was indicative of MDA or adenocarcinoma (5/5, 100%). The combination of MRI, Pap smears, and gastric mucin will improve the accuracy of the preoperative diagnosis of MDA and LEGH. Patients suspected of having LEGH may need to be treated with less aggressive methods.

Expression of the insulin-like growth factor-II mRNA-binding protein 3 (IMP3) and carcinoembryonic antigen (CEA) in mucinous minimal deviation adenocarcinoma

Mucinous minimal deviation adenocarcinoma (MDA) is a rare highly differentiated mucinous adenocarcinoma of the uterine cervix, which always remains a diagnostic dilemma. Lobular endocervical glandular hyperplasia (LEGH), a rare benign lesion of the uterine cervix, is identified as precursor of mucinous MDA. The insulin-like growth factor-II mRNA-binding protein 3 (IMP3) is expressed in a number of cancers and is associated with progression of the tumors. The purpose of this study was to evaluate the expression of the IMP3, carcinoembryonic antigen (CEA), and cyclin-dependent kinase inhibitor p16 INK4a in mucinous MDA and LEGH, and to estimate the possible role of these biomarkers in the diagnosis of mucinous MDA. Twelve samples of MDA, eight samples of lobular endocervical glandular hyperplasia (LEGH), and 20 normal control cases were included in this study. Typical lesions and less well-differentiated lesions coexisted in 11/12 mucinous MDA samples. Positive cytoplasmic expression for IMP3 and CEA was found in less well-differentiated lesions of all 11 mucinous MDA samples, primarily with strong to intermediate staining intensity. The typical well-differentiated lesions of all 12 MDA cases and 8 cases of LEGH showed negativity for both IMP3 and CEA. No exact p16 INK4a positivity was observed in 12 mucinous MDA and 8 LEGH. The significant expression of IMP3 and CEA in less well-differentiated foci of mucinous MDA may be helpful in the diagnosis of mucinous MDA to some extent, particularly in small specimens from cervical biopsy. More cases and in-depth researches are needed to elucidate the potential different mechanisms between typical and less well-differentiated lesions of mucinous MDA.

Clinical Impact of Preoperative Screening for Gastric Mucin Secretion in Cervical Discharge by HIK1083-Labeled Latex Agglutination Test

The present study evaluated the clinical impact of preoperative screening for gastric mucin in cervical discharge, using a latex agglutination test with HIK1083, a monoclonal antibody against gastric mucin. HIK1083-labeled latex agglutination tests were performed preoperatively using cervical secretions from 44 patients (group 1) with profuse watery vaginal discharge, multiple cervical cysts on vaginal ultrasonography, or yellowish mucin on a Papanicolaou smear and from 31 patients (group 2) with none of these clinical signs. The results were positive in 26 patients in group 1 and in no patients in group 2. Glandular lesions with a gastric phenotype were identified histologically in all 26 cases positive for the HIK1083 latex test, such as minimal deviation adenocarcinoma, lobular endocervical glandular hyperplasia (LEGH), and pyloric gland metaplasia, but not in negative cases. In 2 cases of LEGH, adenocarcinoma in situ was identified. Screening of gastric mucin in cervical discharge may facilitate preoperative detection of some early cervical adenocarcinoma.

Intranuclear cytoplasmic inclusion is a significant diagnostic feature for the differentiation of lobular endocervical glandular hyperplasia from minimal deviation adenocarcinoma of the cervix

Lobular endocervical glandular hyperplasia (LEGH) is a cervical lesion with pyloric gland metaplasia. Minimal deviation adenocarcinoma (MDA) is an extremely well differentiated form of endocervical adenocarcinoma (AC). To date, it is difficult to differentiate LEGH from MDA because they share similar clinical, radiological, and immunohistochemical features. Furthermore, the cytological features of LEGH and MDA have not been well defined. In the present study, we describe the cytological features of LEGH and MDA. We reviewed 24 cases of LEGH (18 pure and six mixed forms) and four MDA cases of the cervix. A total of 40 cytologic smears from 28 patients were reviewed. Abundant yellow mucin was frequently present in both LEGH and MDA; however, an INCI was found in 22 of the 24 LEGH cases and it was not found in either MDA or adenocarcinoma cells associated with LEGH. Neither cell atypia nor architectural distortion was observed in LEGH. In MDA, slight cellular atypia, three dimensional, irregular cell clustering, and prominent nucleoli were observed. The presence of an INCI is a good parameter for the diagnosis of LEGH. Cytology is an effective aid in the differentiation of LEGH from MDA.

P16INK4a Overexpression Independent of Human Papillomavirus Infection in Lobular Endocervical Glandular Hyperplasia

A high rate of human papillomavirus (HPV) infection has been reported in cervical cancer and precancerous lesions. Many studies also have shown that p16INK4a overexpression is of diagnostic value for high-risk HPV-related cervical cancer and precursors. Lobular endocervical glandular hyperplasia (LEGH) is a rare lesion of the uterine cervix. There is one report about HPV infection and few studies on p16INK4a expression in LEGH. Therefore, we 1) detected HPV infection and examined p16INK4a expression and 2) observed the relationship between HPV and p16INK4a overexpression in LEGH. The immunohistochemical expression of p16INK4a was studied in 24 cases of LEGH. HPV DNA was also evaluated in these cases using a polymerase chain reaction technique. Strong (++) p16INK4a immunoreactivity was observed in 10 (41.7%) of the 24 LEGH cases; a moderate (+) pattern was observed in 9 (37.5%) cases; a weak (+) pattern was observed in 2 (8.3%) cases; and the remaining 3 (12.5%) cases showed negative expression. Overall, p16INK4a overexpression was seen in 87.5% of the cases (21/24). HPV DNA was not detected in any of the 24 LEGH cases. These results suggest that p16INK4a overexpression is independent of HPV infection in LEGH.

Absence of Human Papillomavirus Infection in Minimal Deviation Adenocarcinoma and Lobular Endocervical Glandular Hyperplasia

The human papillomavirus (HPV) is basically always detected in squamous cell carcinoma of the cervix and its precursors; a high incidence of HPV also has been reported in adenocarcinoma and adenocarcinoma in situ of the uterine cervix. Lobular endocervical glandular hyperplasia (LEGH) was first described by Nucci in 1999. It is difficult to differentiate minimal deviation adenocarcinoma (MDA) from LEGH preoperatively or postoperatively by clinical and pathologic features. The relationships between HPV and MDA or LEGH have not been studied well because of the rare incidence of the two diseases. To our knowledge, the HPV status in LEGH has not been reported. This study was designed to investigate HPV infection in MDA and LEGH, using the polymerase chain reaction (PCR) technique. Tumor tissue lesions were microdissected and the detection of HPV and its typing were analyzed by PCR-based assay. As the control, HPV DNA was detected in all cases of squamous cell carcinoma and three of five cases of adenocarcinoma. However, no HPV DNA was detected in any of the 10 cases of LEGH or in the 3 cases of MDA. These results suggest that MDA and LEGH are probably not related to HPV infection.

Difference in cytoplasmic localization pattern of neutral mucin among lobular endocervical glandular hyperplasia, adenoma malignum, and common adenocarcinoma of the uterine cervix.

To investigate whether the cytoplasmic localization pattern of neutral mucin differs between lobular endocervical glandular hyperplasia (LEGH) and cervical adenocarcinoma (CxAd), including minimal-deviation adenocarcinoma (MDA), or adenoma malignum, alcian blue (pH 2.5)/periodic acid-Schiff (AB-PAS) staining was performed to formalin-fixed paraffin-embedded tissue sections of 13 lesions of LEGH and 53 tumors of CxAd, including 6 tumors of MDA. The cytoplasmic localization of neutral mucin was classified as a "whole cytoplasmic pattern," in which neutral mucin filled the cytoplasm entirely, or as an "apical pattern," in which neutral mucin was localized in the subsurface area only. Cytoplasmic neutral mucin patterns were detected in all 13 cases of LEGH and in 19 cases (36%) of CxAd, including five cases of MDA. The localization of neutral mucin was always the whole cytoplasmic pattern in 13 cases of LEGH, but was the apical pattern in these 19 cases of CxAd. The other 34 cases of CxAd, including 1 case of MDA, corresponded to the acid mucin pattern stained purple or blue or no staining pattern by AB-PAS. Among the 53 cases of CxAd, the apical neutral mucin pattern was an indicator of poorer patient prognosis by univariate and multivariate analyses. The examination of cytoplasmic localization of neutral mucin might be applicable, not only to differential diagnosis between LEGH and CxAd, including MDA, but also to estimate clinical aggressiveness of CxAd.