Immature Squamous Metaplasia Research Articles

Dual Stain Immunohistochemical Localization of p16INK4A and ki-67

The primary goal of this study was to assess the clinical utility of a multiplexed immunohistochemical method using colocalization of p16 and Ki-67 in identifying high-grade cervical mucosal lesions. The study included formalin-fixed cervical biopsy specimens, representative of 297 diagnostic regions. They were subjected to 2 colors immunohistochemical staining for p16 and Ki-67 using an EnVision polymer-based method. The chromogens used were of DAB brown for the detection of p16 and alkaline phosphatase blue for Ki-67. Histologic regions were scored positive for either marker based on the detection of p16 or Ki-67 in >10% of the cells of interest. Positive test results with colocalization of p16/Ki-67 were found in 20 of 40 cases of cervical intraepithelial neoplasia 1 (n=40) and in all cases of cervical intraepithelial neoplasia 2/3 (n=32), squamous cell carcinoma (n=11), adenocarcinoma in situ (n=10), and invasive adenocarcinoma (n=8). Colocalization of p16/Ki-67 was also detected in few cells in 1 of 19 sections with tuboendometrial metaplasia but was not detected in normal squamous mucosa (n=78), normal endocervical mucosa (n=76), immature squamous metaplasia (n=13), or in microglandular hyperplasia (n=9). The p16 and Ki-67 are coexpressed in virtually 100% of cases of high-grade squamous and glandular lesions, but they are rarely coexpressed in normal tissues or in benign lesions of the squamous and glandular mucosa. Thus, multiplexed colocalization of p16 and Ki-67 is a practical and potentially powerful diagnostic approach to enhance the accuracy of cervical histopathologic diagnosis.

Cytomorphologic Features According to HPV DNA Type in Histologically Proven Cases of the Uterine Cervix

Background: This study investigated whether human papillomavirus (HPV) genotype is related to koilocytic changes in cervical cytology and histology, and what factors cause discrepancies among cytology, HPV DNA chip tests, and biopsies. Methods: We examined 174 of 949 cases histologically confirmed by both cytology and HPV DNA chip testing. We analyzed koilocytic changes in cytology and biopsies according to HPV genotype. Results: HPV-16 significantly coincided with nuclear size variation and hyperchromasia, although the cytomorphologic features correlated with other HPV genotypes were not statistically significant. By analyzing 68 cases in which there were discrepancies between the HPV DNA chip test and histological results, we confirmed that arti facts or glycogen acanthosis resulted in the over-diagnoses of four HPV-negative cases with normal cytology. Four diagnostic errors and four sampling errors were present in eight HPV-positive cases. The degree of nuclear size variation significantly influenced the cytologically under-diag nosed cases (p= 0.006). Conclusions: Other than HPV-16, HPV genotype exhibited no cytological or histological differences. The discrepancy between the results of HPV DNA chip test and histology was created by glycogen acanthosis, immature squamous metaplasia, artifacts, and sampling errors.

Upregulation of MUC4 in Cervical Squamous Cell Carcinoma: Pathologic Significance

MUC4 is a transmembrane glycoprotein more highly expressed in cervical dysplasia than benign cervical epithelium. We sought to determine whether MUC4 expression differs between benign and malignant cervical tissue. Fifty-eight patients with benign, dysplastic, or malignant cervical pathology were identified retrospectively, and representative sections were stained with a mouse monoclonal anti-MUC4 antibody. Semiquantitative analysis was performed on benign, dysplastic, and malignant regions by scoring staining intensity (0: negative, 1: weak, 2: moderate, and 3: strong) and distribution (focal <10%, multifocal=10%-60%, diffuse > or =60%). In samples with benign glycogenated squamous epithelium, only the parabasal cells had MUC4 staining, and 48.5% had an intensity of 2 or 3. All samples with immature squamous metaplasia were positive through the entire epithelial thickness. Cervical intraepithelial neoplasia (CIN) 1 samples had variable staining with an intensity similar to glycogenated squamous epithelium but distribution similar to squamous metaplasia. All CIN 3 (n=21) and invasive squamous cell carcinomas (n=17) had increased MUC4 staining intensity (P<0.001 and P<0.001) and increased diffuse staining (P<0.001 and P<0.001) compared with the limited staining in glycogenated squamous epithelium. In contrast, no differences in staining were observed between benign endocervical glands, adenocarcinoma in situ, and invasive adenocarcinoma. These expression patterns suggest that MUC4 is a lineage marker in benign cervical tissue that may have aberrant expression in squamous dysplasia and carcinoma. Further studies may elucidate the role of MUC4 in the development of squamous cell cervical cancer.

Squamous Metaplasia of the Ovarian Surface Epithelium and Subsurface Fibrosis: Distinctive Pathologic Findings in the Ovaries and Fallopian Tubes of Patients on Peritoneal Dialysis

Peritoneal dialysis is commonly used to treat patients with end-stage renal disease. Patients on long-term peritoneal dialysis develop edema and fibrosis of the peritoneal membrane, but the morphologic effects on the organs of the female genital tract are obscure. We noted squamous metaplasia of the ovarian surface epithelium in a patient on peritoneal dialysis, leading us to review all cases of peritoneal squamous metaplasia in our surgical pathology database. Squamous metaplasia of the peritoneum is rare, and we found only 3 examples. Two cases occurred in women on long-term peritoneal dialysis who were operated on for benign ovarian cystadenomas. The gynecologic pathology findings were similar in both cases, with immature and mature squamous metaplasia present extensively on the surfaces of the ovaries, and in 1 case, on the surface of the ipsilateral fallopian tube. The metaplastic epithelium was keratin and p63 positive. Staining for p63 highlighted areas where the metaplastic epithelium was only 1- or 2-cell layers thick and areas of more developed metaplasia. In addition, there was a broad band of fibrous tissue 1- to 2-mm thick beneath the surfaces. A third case of peritoneal squamous metaplasia involved the serosal surface of the small intestine in a woman who experienced complications after bariatric surgery. There were small nodules of squamous metaplastic epithelium on and beneath the serosal surface of the intestine, surrounded by acute and chronic inflammation and fibrosis. Based on our experience and limited information in the literature, there are 2 distinct patterns of squamous metaplasia of the peritoneum: a diffuse pattern of metaplasia associated with bandlike subsurface fibrosis in peritoneal dialysis patients and a micronodular pattern of metaplasia associated with inflammatory conditions. Dialysis-associated changes involving the ovary and fallopian tube form a mechanical barrier that could contribute to the low rate of fertility in peritoneal dialysis patients.

BD ProEx C: A Sensitive and Specific Marker of HPV-associated Squamous Lesions of the Cervix

BD ProEx C (ProEx C) is a recently developed immunocytochemical assay that targets the expression of topoisomerase II-alpha and minichromosome maintenance protein-2, 2 genes shown to be overexpressed in cervical cancers. Recent studies validated this reagent in liquid-based cytology specimens and suggested its usefulness as an adjunct in the diagnosis of challenging cases. Limited information is available on its expression in tissue sections. This study aims to assess ProEx C expression patterns in benign, atypical, and dysplastic lesions of the cervix and to compare these patterns with p16 and Ki67 expression and with the presence of human papilloma virus DNA as determined by in situ hybridization. ProEx C positivity was limited to the basal layers of the epithelium in 75% of benign cervices. In the remaining 25%, staining extended into the lower half of the epithelium particularly in areas of squamous metaplasia and immature squamous metaplasia. In 92% of high-grade dysplasias [cervical intraepithelial neoplasia (CIN) II and III] strong positive staining for ProEx C involved the lower and upper halves of the epithelium. Condylomas and CIN I showed greater variability in staining pattern with ProEx C positivity extending into the upper half of the epithelium in 48% of cases. Statistically significant correlations were noted with presence of human papilloma virus DNA and with p16/Ki67 expression. Atypical squamous metaplasia showed varied staining with 24% being positive. To summarize, ProEx C is a reliable marker for high-grade CIN that can be applied to tissue sections to confirm the diagnosis of high-grade CIN and to triage cases of atypical squamous metaplasia. ProEx C may also have a potential role in triaging patients with low-grade CIN. ProEx C expression patterns are similar to those for p16 and Ki67 with most discrepancies occurring in the CIN I category.

CK17 and p16 expression patterns distinguish (atypical) immature squamous metaplasia from high‐grade cervical intraepithelial neoplasia

CK17 and p16 expression patterns distinguish (atypical) immature squamous metaplasia from high‐grade cervical intraepithelial neoplasia

Bland dyskaryosis: a new pitfall in liquid‐based cytology

To describe our experience in recognizing an unusual presentation of severe dyskaryosis at two large cytology centres using ThinPrep liquid-based cytology (LBC). LBC has been introduced in England following successful pilot studies. It is clear that LBC improves visualization and preservation of cells, and that sensitivity for high-grade dyskaryosis is at least as good as for conventional cytology, and may be better. Several variants of high-grade dyskaryosis have been described on conventional cytology, including small and pale cell dyskaryosis. These are also seen on LBC. We are reporting a new variant of dyskaryosis which in our experience is seen only in LBC specimens prepared by the Thinprep method, which we have named bland dyskaryosis. This has not to our knowledge been previously described. Bland dyskaryosis is characterized by cells with a high nuclear/cytoplasmic ratio, nuclear hyperchromasia and is present in groups with a chaotic architecture. The chromatin pattern appears bland at low power screening examination. On high power examination, however, the chromatin pattern can be seen to be subtly abnormal. Nuclear membranes are smooth. These changes mimic endocervical cells or immature squamous metaplasia at low power. Identification and description of cytological appearances observed in routine practice and correlation with histological diagnosis. The features of bland dyskaryosis should be disseminated through teaching activities. Recognition of this previously undescribed variant will prevent false negative reporting of LBC samples.

Variations of mitotic index in normal and dysplastic squamous epithelium of the uterine cervix as a function of endometrial maturation

Cervical intraepithelial neoplasia is a premalignant (dysplastic) lesion that is characterized by abnormal cellular proliferation, maturation and nuclear atypia. The intraepithelial distribution, density, and nature (typical or atypical) of mitotic figures are routinely utilized diagnostic criteria to grade dysplasia and to distinguish high-grade dysplasia from potential histologic mimics such as transitional metaplasia, atrophy or immature squamous metaplasia. In this study, we evaluated the total mitotic indices of the cervical epithelia in hysterectomy specimens from patients with and without dysplastic lesions and investigated a possible relationship between mitotic index and hormonal status, using the endometrial maturation phase as a surrogate indicator of the latter. Two hundred seventy-four cervices from hysterectomy specimens (135 cases without dysplasia, 33, 35 and 71 cases with grades 1, 2 and 3 cervical intraepithelial neoplasia, respectively) were analyzed. A cervical mitotic index (total mitotic figures/10 high-power fields in the most proliferative area) was determined for each case. The endometrium in each case was classified into atrophic, early proliferative, late proliferative and secretory. For all three dysplasia grades, cases in the proliferative endometrium group always had a higher average mitotic index than those in the secretory and atrophic endometrium groups; this observation also held true for the benign cases. Furthermore, in all three dysplasia grades, the average mitotic index was always lowest in the atrophic endometrium group. Although the mitotic index showed expected patterns of increases with increasing dysplasia grades for most of the endometrial phases, this was not a universal finding. Notably, the average mitotic index for our cervical intraepithelial neoplasia 1 cases with late proliferative endometrium was higher than our cervical intraepithelial neoplasia 2 cases with secretory and atrophic endometrium. It is concluded that hormonal status, as reflected in endometrial maturation, can significantly affect the mitotic index of dysplastic squamous epithelium of the uterine cervix. Our findings confirm that the pathologic grading of dysplasia, especially in equivocal cases such as in metaplastic squamous epithelium, should not be solely dependent on the finding mitoses in the cervical squamous epithelium. The full composite of histopathologic features should form the basis for this determination.

P16 and Ki-67 immunostaining in atypical immature squamous metaplasia of the uterine cervix: correlation with human papillomavirus detection.

● Context.—Atypical immature squamous metaplasia (AIM) of the cervix is a loosely defined entity characterized by immature metaplastic cells with mild cytologic atypia. Objective.—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). Design.—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. Results.—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. Conclusion.—The combination of immunostaining for p16 and Ki-67 is helpful in limiting of the number of cases with nondiagnostic atypia of the cervix. (Arch Pathol Lab Med. 2007;131:1343–1349)

P16 and Ki-67 Immunostaining in Atypical Immature Squamous Metaplasia of the Uterine Cervix: Correlation With Human Papillomavirus Detection

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.

Clonality Analysis and Human Papillomavirus Infection in Squamous Metaplasia and Atypical Immature Metaplasia of Uterine Cervix

Atypical immature squamous metaplasia (ISM) of the uterine cervix often has histological features that overlap with the histological characteristics of high-grade cervical intraepithelial neoplasia. To identify the cellular basis and clinical significance of atypical immature metaplasia (AIM), 10 cases of AIM were analyzed for the clonal status, and the presence of human papillomavirus (HPV) infection. The physical status of HPV was also evaluated in HPV type 16 (HPV-16)-positive cases. Squamous metaplasias with no nuclear atypia (29 mature squamous metaplasias [SMs]) and a single case of ISM were analyzed as a control. Nine AIMs, 20 SMs, and a single case of ISM were informative for clonal analysis. Monoclonal composition of the lesion was demonstrated in 8 (89%) of 9 AIMs, but only in 2 (10%) of 21 cases of SM without atypia (AIM vs SM + ISM, 8/9 vs 2/21; P < 0.0001). High-risk HPV was detected in 6 (60%) of 10 AIMs, all were HPV-16, but only in 3 (13%) of 24 SMs with no atypia (2/23 SM and 1/1 ISM). The frequency of high-risk HPV infection was also significant between AIMs and SM with no atypia (6/10 vs 3/24; P < 0.001). Among the cases, which were informative for clonal analysis, all 5 AIMs positive for high-risk HPV were monoclonal in composition. Physical status of HPV was examined in HPV-16-positive cases. Human papillomavirus type 16 was present as a mixture of episomal form and integrated form in 4 of 6 AIMs. These observations imply that unlike SMs with no atypia, which arises as a result of reactive or inflammatory process, lesions with the histological characteristics of AIM may be indeed true precursors of cervical carcinoma.

CK17 and p16 expression patterns distinguish (atypical) immature squamous metaplasia from high‐grade cervical intraepithelial neoplasia (CIN III)

Regauer S & Reich O (2007) Histopathology50, 629–635 CK17 and p16 expression patterns distinguish (atypical) immature squamous metaplasia from high-grade cervical intraepithelial neoplasia (CIN III)AimsAtypical immature metaplasia (AIM) refers to a full-thickness intraepithelial basaloid lesion in the uterine cervix that features both metaplasia and atypia and is therefore difficult to distinguish from high-grade cervical intraepithelial neoplasia (CIN III). p16 is a marker for human papillomavirus (HPV)-induced dysplasia. Cytokeratin (CK) 17 is a marker for cervical reserve (stem) cells, which give rise to metaplasia. The aim was to determine whether AIM can be reclassified into metaplasia and CIN III based on p16 and CK17 immunohistochemistry.Material and resultsSeventy-five cervical biopsy specimens, curettings and cone excisions containing varying proportions of dysplasia and metaplasia and 20 cases regarded as AIM were analysed immunohistochemically with antibodies to CK17, p16 and p63. In immature metaplasia all proliferating cells were immunoreactive with antibodies to CK17 and p63, while p16 was negative. All dysplastic cells of CIN III demonstrated uniform immunoreactivity for p16 and p63, but were CK17–. Based on the reciprocal immunoreactivity of p16 and CK17, 17/20 cases of AIM were reclassified as metaplasia (n = 10) and CIN III (n = 7). Three cases of AIM stained for both CK17 and p16 and were classified as CIN III.Conclusion‘AIM’ is a helpful histological descriptor but it should not be used as a final diagnosis. Immunohistochemistry for p16 and CK17 allows distinction between metaplasia and high-grade CIN.

Distinct Molecular Alterations in Complex Endometrial Hyperplasia (CEH) With and Without Immature Squamous Metaplasia (Squamous Morules)

Distinct Molecular Alterations in Complex Endometrial Hyperplasia (CEH) With and Without Immature Squamous Metaplasia (Squamous Morules)

Atypical immature cervical metaplasia: immunoprofiling and longitudinal outcome

Atypical proliferations of immature cervical squamous metaplasia were reviewed and correlated with p16 and Ki-67 expression to determine whether immunoprofiling could enable more conventional classification. The longitudinal outcome of atypical immature metaplasia (AIM) and predictive role of biomarker expression were also investigated. All atypias of immature squamous metaplasia in the year 2000 were reviewed and stained with p16 and Ki-67. Biomarker features were evaluated and the Ki-67 index calculated. Diagnoses were correlated with the immunoprofile of each antibody, both separately and combined. The progression to squamous intraepithelial lesion (SIL) of lesions reclassified as AIM was determined, and biomarker immunoprofiles were correlated with outcome. The 172 atypias were reviewed as 3 (1.7%) negative, 54 (31.4%) benign, 60 (34.9%) AIM, 43 (25%) low-grade SIL (LSIL), and 12 (6.9%) high-grade SIL (HSIL). HSIL correlated significantly with a combined high index (>15%) and p16 diffusely positive profile (P = .01). Benign diagnoses correlated significantly with a low index (1%-15%) and p16 negative or focal profile (P = .01). AIM and LSIL correlations were not significant, but their profiles were very variable and nearly identical. AIM was the only pathology in 43 cases, and follow-up was available for 32 (74.4%). SIL developed in 66% (50% LSIL and 16% HSIL) and p16 positivity correlated (P = .02). p16 and Ki-67 immunoprofiling are reliable in reclassifying some atypical proliferations of immature squamous metaplasia as HSIL and some as benign. The similarity between AIM and LSIL in regard to their immunoprofile as well as outcome suggests AIM is a morphological type of LSIL.

Tubular Adenoma of the Skin with Follicular and Sebaceous Differentiation

The main controversies regarding tubular apocrine adenoma and papillary eccrine adenoma are whether they are two distinct entities or are the very same tumor, and if so, which lineage of differentiation (apocrine versus eccrine) it pursues. We report two cases of tubular adenoma with follicular and, in one case, additionally, sebaceous differentiation. The features in both cases indicated apocrine differentiation of the tubular component. One patient was a 60-year-old woman with a 1-year history of a solitary nodule on the scalp. The other patient was a 48-year-old woman with a solitary nodule of unknown duration located on the back. In both patients, the tumors were surgically removed. The patients were alive and well 2.5 and 2 years after surgery, respectively. The histologic features that both cases had in common included the combination of a tubular adenoma, foci of follicular differentiation, and areas of immature squamous metaplasia. In case 1, follicular differentiation was seen in the form of strands of basaloid cells surrounded by a stroma resembling the embryonic perifollicular sheath. Some aggregates of basaloid cells were juxtaposed with small collections of plump fibroblasts, imparting a resemblance to rudimentary follicular germs associated with follicular papillae. Many minute lumens surrounded by more eosinophilic cells were seen within the strands. In case 2, follicular differentiation was seen as several infundibulocystic structures surrounded by isthmic epithelium housing scattered mature sebocytes. In addition, there were areas reminiscent of desmoplastic trichoepithelioma (columnar trichoblastoma). In both cases, the areas with immature squamous metaplasia were represented by solid nodules that were mostly devoid of lumens and a peripheral basal/myoepithelial cell layer. In conclusion, these two cases of cutaneous tubular adenoma with accompanying follicular and sebaceous differentiation give further support to the proposition that the majority of these neoplasms have apocrine differentiation. Rare cases occurring in the sites normally devoid of apocrine glands may represent the eccrine counterpart.

Distinct Molecular Alterations in Complex Endometrial Hyperplasia (CEH) With and Without Immature Squamous Metaplasia (Squamous Morules)

Several molecular alterations, most commonly PTEN mutations but also K-ras mutations, microsatellite instability, and beta-catenin mutations have been detected in endometrioid endometrial carcinoma (EEC). Specifically, mutations in the beta-catenin gene are seen in 15% to 20% of EECs, whereas immunohistochemical expression of beta-catenin ranges from 13% to 44%, nuclear staining being concentrated in areas of immature squamous metaplasia (squamous morules). Complex endometrial hyperplasia with atypia (CEH-A) is a well-known precursor of EEC, which can also show immature squamous metaplasia. In this study, we compared the immunohistochemical and molecular profiles of 13 CEH-A with and 11 CEH-A without squamous morules (SM) for mutations of beta-catenin, PTEN, K-ras, and microsatellite instability (MSI). In all cases of CEH-A with SM, beta-catenin immunostaining showed strong and diffuse nuclear expression in areas of SM and weak to moderate nuclear expression in the glandular component. Six different beta-catenin mutations were found in 7 of 13 cases (54%) (G34E, G34V, S33C, D32Y, S33F, D32A); however, no mutations of the PTEN or K-ras genes were identified. beta-Catenin immunostaining showed focal nuclear staining in only 2 cases of CEH-A without SM. Only 1 case had a beta-catenin mutation (S45A), which was associated with a K-ras mutation (G12D). Another 3 cases had both PTEN and K-ras mutations (C296Stop Ex 8 and G12V, 244del C Ex 7 and G12D, 251ins TGAT Ex 7 and G13D), and one had a PTEN mutation (G230E Ex 7) only. Of all 24 cases, only 1 case of CEH-A without SM showed MSI. In conclusion, marked differences in the molecular profiles regarding beta-catenin, PTEN, and K-ras mutations were observed between CEH-A with and without SM. beta-catenin mutations might represent a signaling pathway leading to a distinctive morphology in hyperplastic/neoplastic endometrium with SM. Other molecular events such as K-ras or PTEN mutations are likely to occur in CEH-A independently from beta-catenin. Furthermore, morphologic differences between CEH-A with SM and CEH-A without SM seem to correlate, at least to some extent, with the clinical course of the disease. In our series, cases of CEH-A with SM and beta-catenin alterations appeared to have a less aggressive behavior when compared with CEH-A without SM and with K-ras and PTEN mutations.

High intraepithelial expression of estrogen and progesterone receptors in the transformation zone of the uterine cervix

Objective Because sex hormones may be involved in tumor initiation and progression, we analyzed the presence of hormone receptors in the transformation zone of the uterine cervix where the majority of human papillomavirus infections and associated (pre)neoplastic lesions develop. Study design By using 23 total hysterectomy samples from young women who underwent surgery for noncervical benign uterine disease, we analyzed, by immunohistologic techniques, the in situ expression of estrogen (E 2-R) and progesterone (P 4-R) receptors in the transformation zone and ectocervix of the same women. Results The expression of estrogen receptors and progesterone receptors is significantly higher in the transformation zone compared with the ectocervix. Immunohistochemical localization indicated that hormone receptor-positive cells are mainly observed in (para)basal and intermediate cell layers in both the transformation zone and ectocervical epithelium. When transformation zone samples were segregated into epithelial tissues with a predominantly mature (7/23 samples) or immature (16/23 samples) squamous metaplasia, only biopsy specimens with immature squamous metaplasia showed a significantly higher density of hormone receptor-positive cells compared with ectocervical epithelium ( P<.01). Conclusion Our results suggest that the cervical transformation zone may be at increased risk of the development of cancer because of a high sensitivity to sex hormone regulation.

Immunohistochemical localization of survivin in benign cervical mucosa, cervical dysplasia, and invasive squamous cell carcinoma.

Survivin is an inhibitor of apoptosis protein (IAP) that is expressed in fetal development and in cancer Survivin expression in premalignant lesions remains undefined. We obtained 73 samples of cervical squamous tissue, including 31 normal, 17 low- and 15 high-grade squamous intraepithelial lesions (LSILs, HSILs), and 10 squamous cell carcinomas (SCCs)from cone biopsy and hysterectomy specimens, and stained for survivin using an immunoperoxidase method. Nuclear staining was detected in normal mucosa, LSILs, and HSILs; staining intensity was greatest in cases with morphologic evidence of human papillomavirus (HPV) infection. In situ hybridization of serial sections demonstrated colocalization of HPV DNA and survivin. Cytoplasmic staining was observed in immature squamous metaplasia and in SCCs. Survivin expression in immature metaplastic squamous mucosa may reflect a rolefor survivin in normal squamous differentiation. However, the histologic correlation between nuclear staining and HPV infection suggests involvement of survivin in HPV-mediated disruption of normal cellular maturation.

Ber‐EP4 immunoreactivity depends on the germ layer origin and maturity of the squamous epithelium

To map the expression of Ber-EP4 in well-differentiated squamous epithelia, metaplastic squamous epithelia and dysplastic squamous epithelia of different origins. Squamous epithelium of different origin was stained using a standard immunohistochemistry method applied to paraffin sections. We found that normal squamous epithelium of the oral cavity, oesophagus, uterine cervix, vagina, anal canal, and branchial cysts are Ber-Ep4-negative, as are the mature squamous metaplasia of bronchial mucosa, urinary bladder mucosa and uterine cervical mucosa. In contrast, immature squamous metaplasia of bronchial mucosa, or uterine cervical mucosa, and squamous dysplasia of oral mucosa of endodermal origin, or uterine cervical mucosa in most cases expressed Ber-EP4. Squamous epithelia of ectodermal origin never express Ber-EP4, whether normal, hyperplastic, dysplastic or neoplastic. In contrast, squamous epithelium of endodermal origin sometimes contains the target glycoproteins of Ber-EP4 when immature, metaplastic, dysplastic or neoplastic. The results indicate that the differences in expression of Ber-EP4 in squamous epithelium depend primarily on germ layer origin, and on the maturity of the epithelium.

Benign Cellular Changes in Pap Smears

We reviewed consecutive cases classified as benign cellular changes (BCC) over a four-month period. Cases classified as BCC were retrieved from the cytology files. A search was carried out to identify the previous Pap smears and concomitant cervical biopsies. One thousand one hundred three cases (23% of our gynecologic smears) were classified as BCC. Ninety-two patients (8.3%) underwent concurrent cervical biopsies. Specific infections accounted for 8% of BCC cases; reactive changes accounted for 92%. Of the biopsy specimens, 8.3% had no significant pathologic change. The most common biopsy diagnoses were cervicitis (31.5%), immature squamous metaplasia (16.3%) and reserve cell hyperplasia (10.8%). Miscellaneous benign diagnoses accounted for 21.7%. Cervical intraepithelial neoplasia (CIN) 1/human papillomavirus (HPV) was present in 14% of cases. All patients with biopsy diagnoses of CIN 1 had at least two previous abnormal Pap smears. Previous biopsy reports were available for review in 127 (12%) of the 1,103 patients. Of these 127 cases, 53.5% had a previous diagnosis of CIN/HPV; 9.4% had invasive carcinoma. A benign diagnosis was reported in 36.5%. The majority of BCC cases are due to reactive and inflammatory processes. In patients with a previous history of CIN, BCC may be of some significance. In patients with no significant prior cervical abnormalities, a Pap smear classified as BCC represents a reactive process.