Enhanced expression of hedgehog signaling molecules in squamous cell carcinoma of uterine cervix and its precursor lesions.

The hedgehog (Hh)-signaling pathway plays an essential role in normal development. Deregulation of this pathway is responsible for several types of cancers. The aim of this study was to determine the expression pattern and the extent of Hh-signaling molecules in squamous cell carcinoma of uterine cervix and its precursor lesions. A total of 106 uterine cervical cancers and related lesions (37 squamous cell carcinomas, 23 cervical intraepithelial neoplasia (CIN) III, 10 CIN II, four CIN I, 32 normal cervical epithelia) were immunohistochemically analyzed with anti-Shh, Indian Hh (Ihh), Patched (PTCH), Smoothened (Smo), Gli-1, Gli-2, Gli-3 antibodies on paraffin blocks. The results showed that the expression of all the Hh-signaling molecules was greatly enhanced in uterine cervical tumors, including carcinoma and its precursor lesions. The staining pattern was mainly cytoplasmic except for Gli-1/2, whose expression was observed in both cytoplasm and nucleus. In case of Ihh, PTCH, Smo and Gli-1, their expression in normal epithelium was completely absent or rare. The expression of all the seven Hh-signaling molecules mentioned above was significantly increased in CIN II/III and carcinoma, compared with that in normal epithelium (P < 0.05). The expression of Shh was increased by double; the first increase occurred in normal epithelium-CIN transition, and the second, during the progression of CIN to carcinoma. These results strongly suggest that the Hh-signaling pathways were extensively activated in carcinoma and CIN of uterine cervix. In conclusion, the Hh-signaling pathways may be involved in carcinogenesis of squamous cell carcinoma of uterine cervix and can be considered as a potential therapeutic target.     

Koilocytosis preceding squamous cell carcinoma in situ of uterine cervix

Association of koilocytic changes with cervical squamous cell carcinoma is well documented. The studies of such concurrent association may miss those cases of papillomavirus infection where cytomorphologic expression of virus has disappeared by the time carcinoma appears. The authors studied cytologic material before the diagnosis was made of cervical squamous cell carcinoma in situ in 25 patients. Twenty-two (88%) of the 25 patients showed koilocytosis compared with only 6 out of 57 (10.5%) in the control group. The findings of this study support a possible predisposing role of papillomavirus in squamous cell carcinoma of the cervix.     

Stereological estimates of nuclear volume in squamous cell carcinoma of the uterine cervix and its precursors

Summary Using modern stereology, this study was carried out to obtain base-line data concerning three-dimensional, mean nuclear size in precancerous and invasive lesions of the uterine cervix. Unbiased estimates of the volume-weighted mean nuclear volume (nuclear ¯v _v were obtained by point-sampling of nuclear intercepts in 51 pre-treatment biopsies from patients with invasive squamous cell carcinomas (SCC). Vertical sections from 27 specimens with cervical intraepithelial neoplasia (CIN) grades I through III were also investigated, along with 10 CIN III associated with microinvasion (CIN III+M). On average, nuclear ¯v _v was larger in SCC than in CIN III and CIN III + M together (2P=8.9·10^–5). A conspicuous overlap of nuclear ¯v _v existed between all investigated lesional groups. The reproducibility of estimates of nuclear ¯v _v in biopsies with SCC was acceptable (r=0.85 andr=0.84 in intra- and inter-observer studies, respectively). The efficiency of the sampling scheme was high, with more than 60% and more than 80% of the total observed variance contributed by differences between individual lesions with CIN and SCC, respectively. Estimates of nuclear ¯v _v based on sampling within the whole epithelial thickness and on sampling in the lower one-third in CIN I and the lower two-thirds in CIN II lesions were of the same magnitude. Approximate estimates of the absolute variation of nuclear ¯v _v were directly proportional to individual estimates of nuclear ¯v _v, whereas the relative variation of nuclear ¯v _v tended to decrease with increasing mean nuclear volume. Based on the rather small number of cases investigated, estimates of nuclear ¯v _v are unable to distinguish between different grades of CIN. However, the estimation of nuclear ¯v _v is well-suited for the purposes of objective grading of malignancy in SCC.     

Dermal adnexal differentiation in a squamous cell carcinoma of the uterine cervix

The first case of a keratinizing squamous cell carcinoma of the uterine cervix with differentiation toward dermal adnexal structures is reported. A review of skin-associated structures in the non-neoplastic uterine cervix is given and the histogenesis discussed. Recent literature dealing with extracutaneous neoplasms with sebaceous differentiation is cited.     

Genetic alterations during the progression of squamous cell carcinomas of the uterine cervix.

Most cervical carcinomas appear to arise from cervical intraepithelial neoplasia (CIN) lesions. In addition to infection with high-risk human papilloma viruses, which is indicative of an increased risk of progression, alterations of oncogenes and tumor suppressor genes play a role. Genetic studies of CIN lesions, primary cervical carcinoma, and metastases may shed light on the relative importance of various genetic alterations involved in the progression of CIN to invasive carcinoma. We examined tumor material from 10 patients with squamous cell carcinoma of the uterine cervix and synchronous CIN lesions and lymph node metastases. The CIN component, invasive carcinoma, and lymph node metastases were analyzed separately for loss of heterozygosity (LOH) on the following loci: VHL (3p21), HLA region (6p22-23), PGL (11q 22-24), E6 associated protein (15q11-13), TP53 (17p13), DCC (18q21.1), and chromosomes 1, 2, 4, 9, 20, and X. Using immunohistochemistry, the expression of the EGF receptor, ERBB2, and TP53 was determined. In CIN lesions, frequent LOH was found at chromosome arms 3p, 6p, and 11q. Primary invasive carcinoma showed additional LOH at chromosome arms 6q, 17p, and 18q. In lymph node metastases, an additional locus on the X chromosome displayed LOH. All carcinomas and synchronous lesions but one showed high expression levels of the EGF receptor. TP53 staining, when present, was found in all synchronous lesions. Focal staining of ERBB2 was found in one CIN lesion, two invasive carcinomas, and four metastases. The molecular alterations accumulated in a fashion that paralleled the progression of the tumors. These results indicate that cervical tumorigenesis occurs in a stepwise fashion, including infection and integration of oncogenic HPV and several specific genetic alterations. Genes Chromosomes Cancer 26:346-354, 1999.     

Maspin expression in CIN 3, microinvasive squamous cell carcinoma, and invasive squamous cell carcinoma of the uterine cervix.

Maspin is a serine protease inhibitor with tumor suppression activity. It is expressed in normal breast and prostate tissue but is downregulated or absent in breast and prostate tumors. Recent reports have shown that decreased expression is associated with a greater propensity for metastasis in oral squamous cell carcinomas. We know that some high-grade cervical intraepithelial neoplasia progress to invasive carcinomas while others either persist at the same degree of atypia or regress. The pattern of maspin expression in cervical intraepithelial neoplasia-grade 3, microinvasive squamous carcinomas and overtly invasive squamous cell carcinomas of the uterine cervix was studied to determine the relationship between the extent of maspin expression and the progression of cervical intraepithelial neoplasia to squamous cell carcinoma. In total, 36 cases were evaluated: 18 cases of cervical intraepithelial neoplasia-grade 3, seven cases of microinvasive squamous cell carcinoma and 11 cases of invasive squamous cell carcinoma. A monoclonal antibody was used on paraffin-embedded tissues. Immunoreactivity was scored semiquantitatively using a scale of 0-3. The sums of the scores of the different groups were compared using the Mann-Whitney U-test. A significant decrease in maspin scores was noted between cervical intraepithelial neoplasia-grade 3 vs invasive squamous cell carcinoma (P<0.005), microinvasive squamous cell carcinoma vs invasive squamous cell carcinoma (P<0.05), and cervical intraepithelial neoplasia-grade 3 vs tumor emboli (P<0.005). Although not statistically significant, scores of cervical intraepithelial neoplasia-grade 3 associated with invasive squamous cell carcinoma were lower compared to that cervical intraepithelial neoplasia-grade 3 without invasive squamous cell carcinoma. These findings suggest that maspin likely plays a role in disease progression from in situ to invasive carcinoma. Virtual absence of maspin immunopositivity in tumor emboli indicates that maspin may also play a role in metastasis.     

Survivin和BDKRB1与宫颈鳞癌的发生与发展

目的探讨Survivin、缓激肽受体B1（bradykinin receptor B1,BDKRB1）在宫颈鳞癌（cervical squamous celi carcinomas,CSCC）发生、发展中的作用。方法采用半定量RT—PCR方法检测8例宫颈炎组织、13例宫颈上皮内瘤变（Cervical intraepithelial neopiasia,CIN）Ⅰ级、17例CINⅡ-Ⅲ级,31例CSCC组织中survivin和BDKRBImRNA表达,并将二者表达情况进行统计分析。结果sBrvivin及BDKRB1的表达量随宫颈病变由宫颈炎到CIN再到CSCC的进展逐渐升高;二者在CSCC组织中的表达随CSCC临床分期的升高逐渐升高,并与年龄、临床分期、浸润深度、脉管浸润、淋巴结转移、病理分级等临床病理参数相关;Spearman等级相关分析结果显示BDKRB1表达与survivin表达呈高度正相关（r=0．722,P〈0．005）;COX多元回归分析结果显示年龄、淋巴结转移伴脉管浸润、survivin和BDKRB1的表达为影响SCC患者预后的独立因素,随宫颈癌病理分级和临床分期的升高,CSCC病人的生存时间明显缩短。结论survivin和BDKRB1在CSCC的发生、发展、浸润和转移过程中起着重要作用并与CSCC病人的不良预后相关,检测survivin和BDKRBI1在宫颈病变组织中的表达有望用于CSCC的早期诊断和预后判断,靶向survivin的基因治疗与特异性BDKRB1拮抗剂联合应用有望改善CSCC患者的预后。     

Small-cell neuroendocrine carcinoma of the uterine cervix associated with micro-invasive squamous cell carcinoma and adenocarcinoma in situ

A case of small-cell neuroendocrine carcinoma of the uterine cervix associated with squamous cell carcinoma and adenocarcinoma In situ is reported. The tumor consisted mainly of uniform small cells with a population of intermediate cells that resembled carclnold tumor cells. Foci of micro-invasive squamous cell carcinoma and adenocarcinoma In situ were recognized separately, adjacent to the main tumor. Both Gri-mellus stain and Immunostalning of serotonin were positive for small-cell and Intermediate-cell carcinoma. Neurosecre-tory granules were demonstrated by electron microscopy. Mlcroaclnl with positive mucln staining and microvilli-like structures suggested glandular or exocrine differentiation of trie tumor. Three distinctive types of differentiation, neuroendocrine, exocrine and squamous characteristics, were expressed In the tumor.     

Glassy cell carcinoma of the uterine cervix

Two cases of glassy cell carcinoma which is considered to be a poorly differentiated mixed adenosquamous cell carcinoma in the uterine cervix are described. Its cytologic and histologic findings are distinctive. The tumor cells had moderately amount and ground-glass cytoplasms, and had large nuclei containing a prominent nucleoli.     

Proliferative activity in dysplasia, carcinoma in situ and microinvasive carcinoma of the uterine cervix

Proliferative activity of various human uterine cervical lesions obtained by conization was examined by measuring the proportion of mitotic cells including abnormal mitosis and the nuclear DNA content by a microspectrophotometer. Twelve ratios of mitotic cells calculated in the present study showed a step-wise increase from normal squamous cell epithelium through various grades of dysplasia to carcinoma in situ (CIS). The great difference between moderate and severe dysplasia was observed. All ratios in CIS with bulky outgrowth (CIS(b)) were the highest. The nuclear DNA content in various lesions also indicated the great difference between moderate and severe dysplasias in the DNA histograms. Severe dysplasia had a wider distributed DNA histogram without distinct modes similar to those in CIS and the non-invasive areas of the microinvasive carcinoma. These results may suggest that severe dysplasia but not slight or moderate dysplasia is a direct precursor lesion for uterine cervical epidermoid carcinoma.     

Prognostic significance of Langerhans' cell infiltration in radiation therapy for squamous cell carcinoma of the uterine cervix

Prognostic significance of Langerhans' cell (LC) infiltration in cancer nests was studied in 391 patients with squamous cell carcinomas of the uterine cervix. They were treated with radiation therapy alone. Langerhans' cells were identified by immunohistochemical staining for S100 protein. Langerhans' cells were present mainly in the intercellular spaces of tumor cells. The LC infiltration rates were higher in stage II (31.0%) or stage III (26.9%) than in stage I (17.5%) or stage IV (7.8%). The patients with LC infiltration showed a significantly better five-year survival rate than those without LC infiltration (68% and 56.1%, respectively). This significant difference was observed especially in stage III and it was suggestive in stage IV diseases. These results suggest that LCs in cancer nests may play a significant role in the immunologic defense against cancer in advanced stage of cervical cancer.     

Perivascular epithelioid cell tumor of the uterine cervix identified on a conventional cervical smear

Perivascular epithelioid cell tumors (PEComas) most frequently involve the uterus, particularly the uterine corpus and very occasionally the cervix. One case of PEComa identified using a conventional cervical smear has previously been documented. Herein, we present the second such case. The patient was a 51‐year‐old woman with abnormal genital tract bleeding. Samples collected for conventional cervical smears were submitted for cytopathological examination, which revealed discohesive monotonous tumor cells showing epithelioid morphology, ample cytoplasm that was pale to weakly eosinophilic, and mildly enlarged nuclei. The cytopathological features were well correlated with histopathological findings. Upon immunohistochemistry, the tumor cells were positive for both melanocytic and smooth muscle markers. Based on these findings, PEComa was diagnosed. Subsequently, a total hysterectomy with bilateral salpingo‐oophorectomy was performed, revealing that the tumor (28 × 22 × 12 mm) was located at the superficial part of the endocervix. We propose that the cytopathological findings described herein can guide the diagnosis of PEComa, even though this tumor is rare. Diagn. Cytopathol. 2015;43:1011–1016. © 2015 Wiley Periodicals, Inc.     

Senescence and apoptosis in carcinogenesis of cervical squamous carcinoma.

Senescence and apoptosis are two key mechanisms that protect against cancer development. Many cell cycle regulators, such as p14(ARF), p15(INK4b) and p16(INK4a), are important in G1 cell cycle arrest and oncogene-induced senescence. The bcl-2 protein is one of the key components that control apoptosis, while the p53 protein plays key roles in both mechanisms. The genes of these key regulator proteins are often mutated or deleted in various malignancies. It is unknown how senescence and apoptosis are regulated in one of the most common tumors of the female genital tract, cervical squamous cell carcinoma (SCC). In this study the, expression of senescence, apoptosis and proliferation markers in normal cervical epithelium, cervical intraepithelial neoplasia (CIN) and SCC are characterized via immunohistochemical staining for p14(ARF), p15(INK4b), p16(INK4a), bcl-2, p53 and Ki-67 in tissue microarray blocks containing 20 samples each of normal cervix, moderate-to-severe cervical dysplasia (CIN II-III) and invasive SCC. Samples are derived from 60 total cases of cervical biopsies and cervical conizations. Results showed that the proliferation marker, Ki-67, is markedly increased, and the senescence markers, p15(INK4b), p16(INK4a) and p14(ARF) are overexpressed in both dysplasia and carcinoma. P53 immunostain is negative in all normal cervical tissue, and positive in dysplasia and carcinoma. Although the expression of bcl-2 is increased in dysplasia, this marker is negative in approximately half of SCC cases. These results suggest that some senescence pathways are activated and are still maintained in cervical dysplasia and carcinoma. However proliferation is increased and carcinogenesis is not thwarted, leading to eventual development of cervical cancer. Other mechanisms, such as those that account for the apparent overexpression of p53 and paradoxical loss of bcl-2 expression in some SCC cases, as well as additional senescence and apoptotic pathways, may play key roles carcinogenesis of cervical SCC.