Absence of Nuclear p16 Is a Diagnostic and Independent Prognostic Biomarker in Squamous Cell Carcinoma of the Cervix.

The tumor-suppressor protein p16 is paradoxically overexpressed in cervical cancer (CC). Despite its potential as a biomarker, its clinical value and the reasons for its failure in tumor suppression remain unclear. Our purpose was to determine p16 clinical and biological significance in CC. p16 expression pattern was examined by immunohistochemistry in 78 CC cases (high-grade squamous intraepithelial lesions (HSILs) and squamous cell carcinomas of the cervix -SCCCs). CC cell proliferation and invasion were monitored by real-time cell analysis and Transwell® invasion assay, respectively. Cytoplasmic p16 interactors were identified from immunoprecipitated extracts by liquid chromatography-tandem mass spectrometry, and colocalization was confirmed by double-immunofluorescence. We observed that SCCCs showed significantly more cytoplasmic than nuclear p16 expression than HSILs. Importantly, nuclear p16 absence significantly predicted poor outcome in SCCC patients irrespective of other clinical parameters. Moreover, we demonstrated that cytoplasmic p16 interacted with CDK4 and other unreported proteins, such as BANF1, AKAP8 and AGTRAP, which could sequester p16 to avoid nuclear translocation, and then, impair its anti-tumor function. Our results suggest that the absence of nuclear p16 could be a diagnostic biomarker between HSIL and SCCC, and an independent prognostic biomarker in SCCC; and explain why p16 overexpression fails to stop CC growth.

[Tissue collagenase MMP-14 and endogenous regulators of its activity in the corpus uteri in squamous cell carcinoma of the cervix]. / Tkanevaia kollagenaza MMP-14 i éndogennye reguliatory ee aktivnosti v tele matki pri ploskokletochnoi kartsinome sheiki matki.

AIM: to investigate the expression of the membrane-bound matrix metalloproteinase MT1-MMP (MMP-14), its tissue inhibitor TIMP-2, and the proMMP-14 activator furin in the corpus uteri from the vaginal wall to the bottom of the uterine cavity in squamous cell carcinoma of the cervix (SCCC). MATERIAL AND METHODS: Hysterectomy material was examined in patients with SCCC. Reverse transcriptase polymerase chain reaction (RT-PCR), immunohistochemistry (IHC), and enzyme assays were used. RESULTS: In SCCC, higher levels of MMP-14 expression were established in tumor cells, as evidenced by IHC (+3) and RT-PCR. IHC showed that the expression of MMP-14 was absent or insignificant in the normal uterine endometrial and myometrial tissues. However, that of MMP-14 mRNA was also found in the normal tissues to the bottom of the uterine cavity. Furin activity in the tumor was much higher than that in normal tissues. IHC indicated that TIMP-2 expression was low or absent in both the tumor and normal tissues. The expression of TIMP-2 mRNA was sufficiently obvious in both the tumor and normal tissues to the bottom of the uterine cavity. CONCLUSION: In SCCC, MMP-14 expression was substantially increased in tumors. The expression of MMP-14 and regulators of its activity is aimed at enhancing the tumor destructive (invasive) potential in the pericellular space and can occur (be induced) in the morphologically normal uterine tissue apparently with involvement of signaling through the epithelial-mesenchymal interaction. Data are important for understanding the role of MMP-14 in the development of a multistage process of carcinogenesis and may have prognostic value and an impact on therapeutic strategy for the patient.

Psoas abscess secondary to retroperitoneal distant metastases from squamous cell carcinoma of the cervix with thrombosis of the inferior vena cava and duodenal infiltration treated by Whipple procedure: A case report and review of the literature.

BACKGROUND: Psoas abscess is a rare clinical disease of various origins. Most common causes include hematogenous spread of bacteria from a different primary source, spondylodiscitis or perforated intestinal organs. But rarely some abscesses are related to malignant metastatic disease. CASE PRESENTATION: In this case report we present the case of a patient with known squamous cell carcinoma of the cervix treated with radio-chemotherapy three years prior. She now presented with a psoas abscess and subsequent complete inferior vena cava thrombosis, as well as duodenal and vertebral infiltration. The abscess was drained over a prolonged period of time and later was found to be a complication caused by metastases of the cervical carcinoma. Due to the massive extent of the metastases a Whipple procedure was performed to successfully control the local progress of the metastasis. CONCLUSION: As psoas abscess is an unspecific disease which presents with non-specific symptoms adequate therapy may be delayed due to lack of early diagnostic results. This case report highlights the difficulties of managing a malignant abscess and demonstrates some diagnostic pitfalls that might be encountered. It stresses the necessity of adequate diagnostics to initiate successful therapy. Reports on psoas abscesses that are related to cervix carcinoma are scarce, probably due to the rarity of this event, and are limited to very few case reports. We are the first to report a case in which an extensive and complex abdominal procedure was needed for local control to improve quality of life.

Sarcopenia Is an Independent Prognostic Factor for Squamous Cell Carcinoma of the Cervix Treated With Concurrent Chemoradiotherapy.

BACKGROUND/AIM: To investigate sarcopenia as a predictor of prognosis before concurrent chemoradiotherapy (CCRT) in patients with squamous cell carcinoma (SCC) of the cervix using the new psoas muscle index (PMI) cutoff value for sarcopenia in Japanese women. PATIENTS AND METHODS: We included 134 patients with SCC of the cervix treated with CCRT. CT images were taken within one month before treatment. Measurements of PM and skeletal muscle (SM) area were taken at the L3 level using a CT image analysis system (Synapse Vincent). Whole-pelvic external beam radiotherapy (EBRT) with 50 Gy was performed. High-dose-rate intracavitary brachytherapy and boost EBRT doses were administered. The patients received 40 mg/m2 of cisplatin weekly during CCRT. Kaplan-Meier analysis and the log-rank test were used to compare survival rates. RESULTS: The five-year overall survival (OS) and five-year progression-free survival of all 134 patients were 86.1% and 77.3%, respectively. Univariate analysis revealed that only PMI had a significant association with OS (PMI <3.92 cm2/m2 in the sarcopenia group vs. PMI ≥3.92 cm2/m2 in the non-sarcopenia group, p=0.0112), with no significant differences in age, advanced stage of disease, tumor size, lymph node enlargement, serum SCC, or SMI. Multivariate analysis revealed that PMI is the only independent prognostic factor for OS, but none of the factors were found to have a significant association with PFS. CONCLUSION: PMI as an indicator of sarcopenia was found to be an independent prognostic factor for patients with SCC of the cervix who underwent CCRT.

Understanding the Molecular Mechanism of miR-877-3p Could Provide Potential Biomarkers and Therapeutic Targets in Squamous Cell Carcinoma of the Cervix.

No therapeutic targets and molecular biomarkers are available in cervical cancer (CC) management. In other cancer types, micro-RNA-877-3p (miR-877-3p) has been associated with events relevant for CC development. Thus, we aimed to determine miR-877-3p role in CC. miR-877-3p levels were examined by quantitative-PCR in 117 cervical lesions and tumors. Effects on CC cell proliferation, migration, and invasion were evaluated upon anti-miR-877-3p transfection. miR-877-3p dependent molecular mechanism was comprehensively explored by proteomics, dual-luciferase reporter assay, western blot, and immunohistochemistry. Cervical tumors expressed higher miR-877-3p levels than benign lesions. miR-877-3p promoted CC cell migration and invasion, at least partly by modulating cytoskeletal protein folding through the chaperonin-containing T-complex protein 1 complex. Notably, miR-877-3p silencing synergized with paclitaxel. Interestingly, miR-877-3p downregulated the levels of an in silico-predicted target, ZNF177, whose expression and subcellular location significantly distinguished high-grade squamous intraepithelial lesions (HSILs) and squamous cell carcinomas of the cervix (SCCCs). Cytoplasmic ZNF177 was significantly associated with worse progression-free survival in SCCC. Our results suggest that: (i) miR-877-3p is a potential therapeutic target whose inhibition improves paclitaxel effects; (ii) the expression and location of its target ZNF177 could be diagnostic biomarkers between HSIL and SCCC; and (iii) cytoplasmic ZNF177 is a poor-prognosis biomarker in SCCC.

A rare case of gastric squamous-cell carcinoma metastasized from the cervix.

Gastric squamous-cell carcinoma (SqCC) metastasized form the cervix is rarely detected in endoscopic examination, although cervical carcinoma is the second most common in gynecologic malignancy. A 59-year-old female visited a clinic for anorexia, and an esophago-gastro-duodenoscopy (EGD) revealed multiple submucosal tumors (SMTs) of the stomach. After she was referred, an image-enhanced endoscopy enhanced multiple SMTs with white spots, whose findings were irregular micro-vascular patterns in the mucosa with irregular/absent micro-surface pattern. We took endoscopic biopsies, whose histological diagnoses were SqCC in the layer of the lamina propria under normal epithelium. Positron emission tomography-CT, CT and magnetic resonance imaging revealed an irregularly enhanced mass of the cervix, the irregularly thickening wall of the stomach and peritoneal nodules. Palliative care alone was administered based on poor condition associated with the Stage IV cervical carcinoma. In this case, endoscopic detection of gastric SqCC might provide a tip to make final diagnosis of primary site of cervical SqCC. The numbers of endoscopic examination become increasing, so further deep awareness of such patterns of metastasis in cervical cancer are required.

Adenocarcinoma of the uterine cervix: Pathologic features, treatment options, clinical outcome and prognostic variables.

Adenocarcinoma accounts for 10-25% of all cervical cancers, and its relative and absolute rate has raised over the past decades. Most, but not all the authors, reported that adenocarcinoma has a greater propensity to lymph node, ovarian and distant metastases and a worse prognosis compared with squamous cell carcinoma. However, whether histologic type is an independent prognostic factor is still a debated issue. Moreover, adenocarcinoma is a very heterogenous disease, including different histological subtypes. Whereas radical hysterectomy and definitive radiotherapy achieve the same clinical outcome in early stage squamous cell carcinoma, surgery seems to obtain better survival compared with definitive radiotherapy in early stage adenocarcinoma. Chemoradiation is the standard treatment for locally advanced cervical cancer regardless of histologic type, although several retrospective studies showed that patients with adenocarcinoma were more likely to die than those with squamous cell carcinoma both before and after concurrent chemoradiation era. The prognostic relevance of biological variables, such as cyclin-dependent kinase inhibitors, p53, cyclooxygenase-2 [COX-2], cell surface tyrosine-kinases and programmed death-ligand [PD-L1], is still under investigation. Palliative chemotherapy is the only treatment option for persistent or recurrent cervical adenocarcinoma not amenable with surgery and radiotherapy. The use of immune checkpoint inhibitors as well as a therapeutic strategy targeting cell surface tyrosine kinases should be adequately explored in this clinical setting.

Adenoid basal carcinoma combined with invasive squamous cell carcinoma of uterine cervix: A case report of a 37-year-old woman and literature review.

Adenoid basal carcinoma (ABC) is uncommon malignancy of the uterine cervix and it can be pure or combined with cervical intraepithelial lesions. There were less than 20 cases of ABC combined with invasive squamous carcinoma (mixed type) in English literature. These cases had similar properties as seen at postmenopausal women and diagnosed with abnormal cervical smear findings. Here we present a case of 37-year-old woman who suffered from spotting and received endocervical curettage. The pathological report revealed squamous cell carcinoma (SCC) of the cervix. The patient underwent type 3 radical hysterectomy and bilateral pelvic and para-aortic lymph node dissection. The final pathological report revealed SCC coexisting with ABC. Human papillomavirus (HPV) 16,18 and others (11 types) were negative in both components of the mixed tumor by in situ hybridization detection. Our case was cytokeratin 7 negative, cytokeratin 8 positive and p63 positive which supports the hypothesis that mixed type cervical carcinoma originates from endocervical reserve cells.

Presentación inusual de compromiso metastásico cutáneo por carcinoma escamocelular de cuello uterino / Unusual presentation of metastatic skin involvement in a patient with squamous cell carcinoma of the cervix: Case report

Resumen El cáncer de cuello uterino ocupa el cuarto lugar dentro de las neoplasias de origen ginecológico a nivel global, representando un 85% de los casos en países en vías de desarrollo. Las metástasis cutáneas de origen ginecológico son altamente infrecuentes, observándose con mayor frecuencia en las neoplasias malignas de ovario, seguidas del adenocarcinoma endometrial y de cuello uterino y, menos frecuentemente, las de subtipo escamocelular. En la actualidad, existen alrededor de 80 reportes de casos citados en la literatura de metástasis cutáneas secundarias a un carcinoma de cuello uterino; sin embargo, ninguno con localización en la piel del cuello que se origine de un subtipo histológico escamocelular. En Colombia, no hay casos reportados hasta la fecha. Se presenta el caso de una paciente de 43 años que consulta por sangrado vaginal, dolor abdominal y una extensa placa tumoral exofítica de aspecto metastásico en la piel del cuello y del hombro izquierdo, encontrando al examen clínico inicial una masa tumoral en el cuello uterino con confirmación histológica de un carcinoma escamocelular como neoplasia primaria. Se hace diagnóstico de Carcinoma de cuello uterino estadio IVB y se inicia un tratamiento con intención paliativa con radioterapia y posterior quimioterapia sistémica. La enfermedad metastásica de origen ginecológico a nivel cutáneo confiere un mal pronóstico, con una supervivencia reportada de 1 a 37 meses después de su diagnóstico, por lo cual se deduce que la prevención y el diagnóstico temprano, particularmente en cáncer de cuello uterino, es de vital importancia en la población general.

Abstract Cervical cancer is the fourth most common cancer among gynecological neoplasms globally, representing 85% of cases in developing countries. Cutaneous metastases of gynecological origin are very rare, observed more frequently in ovarian malignancies, followed by endometrial and cervical adenocarcinoma and less frequently those of the squamous cell subtype. Currently there are about 80 case reports cited in the literature of cutaneous metastases secondary to cervical carcinoma, however, none with localization in the skin of the neck originated from a squamous cell histological subtype. In Colombia, there are no reported cases to date. We present the case of a 43-year-old patient who consulted for abdominal pain, vaginal bleeding and an extensive exophytic tumor plaque of metastatic appearance in the skin of the neck and left shoulder, finding a tumor mass in the cervix with histological confirmation of a squamous cell carcinoma as primary tumor. A diagnosis of stage IVB cervical carcinoma is made, and treatment is initiated with palliative intention with radiotherapy and subsequent systemic chemotherapy. Cutaneous metastatic disease of gynecological origin confers a poor prognosis, with a reported survival of 1 to 37 months after its diagnosis, for which prevention and early diagnosis, particularly in cervical cancer, is of vital importance in the general population.

Prognostic significance of metastatic lymph node ratio in squamous cell carcinoma of the cervix.

PURPOSE: Metastatic lymph node ratio (MLNR) was reported to be an important prognostic factor in several tumors. However, depth of primary tumor invasion is also important in cervical cancer prognostic analysis. In this study, the objective was to determine if MLNR can be used to define a high-risk category of patients with squamous cell carcinoma of the cervix (SCC). And we combined MLNR and depth of invasion to investigate whether prognosis of SCC can be predicted better. PATIENTS AND METHODS: We performed a retrospective review of patients with SCC who underwent radical hysterectomy and pelvic lymphadenectomy at QiLu Hospital of Shandong University from January 2007 to December 2009. Prognostic factors for disease-free survival (DFS) and overall survival (OS) were identified by univariate and multivariate analyses. RESULTS: One hundred and ninety-eight patients met the inclusion criteria and were included in the analysis. By cut-point survival analysis, MLNR cutoff was designed as 0.2. On multivariate analysis, an MLNR >0.2 was associated with a worse OS (hazard ratio [HR] =2.560, 95% CI 1.275-5.143, P=0.008) and DFS (HR =2.404, 95% CI 1.202-4.809, P=0.013). Depth of invasion cutoff was designed as invasion >1/2 cervix wall and was associated with a worse OS (HR =1.806, 95% CI 1.063-3.070, P=0.029) and DFS (HR =1.900, 95% CI 1.101-3.279, P=0.021). In addition, subgroup analysis revealed significant difference in OS and DFS rates between different MLNR categories within the same depth of invasion category (P<0.05), however, not between different depth of invasion categories within the same MLNR category (P>0.05). CONCLUSION: MLNR may be used as the independent prognostic parameter in patients with SCC. Combined MLNR and depth of invasion can predict both OS and DFS better in SCC than one factor. Besides, MLNR appears to be a better prognostic value than depth of invasion for SCC.

Squamous cell carcinoma arising in mature cystic teratoma of ovary.

Squamous cell carcinoma of the ovary is a rare condition and usually arises in mature cystic teratoma (MCT) or dermoid cyst of the ovary. The reported incidence of malignant transformation in MCT is approximately 2%. A case of squamous cell carcinoma arising in a dermoid cyst of the ovary presenting at an early stage is presented here. A 53-year-old postmenopausal lady, presented with the complaint of pain in right lower abdomen since one month and a large complex abdomino-pelvic mass on examination and investigations. Final histopathology was reported as squamous cell carcinoma of left ovary arising from dermoid cyst and a benign dermoid cyst in the right ovary. The patient was assigned to squamous cell carcinoma of the ovary arising in a mature cystic teratoma, surgical stage Ic2. In view of the poor prognosis, adjuvant chemotherapy was started.

Analysis of 30 patients with persistent or recurrent squamous cell carcinoma of the cervix within one year after concurrent chemoradiotherapy / 中国肿瘤临床

Objective:To investigate the treatment failure sites, risk factors, and survival rates of patients with persistent or recur-rent squamous cell carcinoma (SCC) of the cervix within one year after concurrent chemoradiotherapy (CCRT). Methods:Clinical data of 30 patients with persistent or recurrent SCC of the cervix within one year after CCRT between June 2006 and June 2011 were ana-lyzed retrospectively. These data were compared with those of another 35 SCC cases without recurrence after complete remission. These 35 patients were treated homeochronously (from 2006 to 2011) and randomized in the control group. Results:Among the 30 pa-tients, 25 exhibited distant metastases;14 of these 25 patients were observed within six months after CCRT. Univariate analysis showed a higher incidence of pelvic or para-aortic lymphadenectasis and SCC-ag>10 ng/mL in the group with persistent or recurrent disease be-fore treatment (P10 ng/mL were found as the independent risk factors. Palliative chemotherapy ranked as the first method used to treat patients. The two-year survival rate was 21.7%, and the median survival time was 17 months. Conclusion:Patients with persistent or recurrent SCC of the cervix after CCRT possibly exhibited a high rate of distant metastasis with poor prognosis. The pre-therapeutic pelvic or para-aortic lymph node enlargement and SCC-ag>10 ng/mL were found as the independent risk factors of per-sistent or recurrent SCC within one year after CCRT.