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Glassy cell carcinoma of cervix uteri — Clinical Guidelines

Overview

Glassy cell carcinoma of the cervix uteri is a rare, poorly differentiated carcinoma characterized by its lack of distinct squamous or glandular differentiation 27. This aggressive subtype predominantly affects younger women, often diagnosed in those under 40 years of age, reflecting the trend towards earlier-stage diagnoses due to widespread cervical screening 3. Despite its rarity, glassy cell carcinoma carries significant clinical implications due to its higher risk of recurrence compared to other cervical carcinomas 5 6. Early detection and precise histopathological assessment are crucial for guiding appropriate treatment strategies, emphasizing the importance of thorough diagnostic evaluation in clinical practice 27. Understanding these nuances aids in optimizing patient outcomes and resource allocation for effective management 2.

Pathophysiology Glassy cell carcinoma of the cervix uteri is a rare and poorly differentiated form of cervical cancer characterized by a lack of obvious squamous or glandular differentiation 27. The exact pathophysiology remains incompletely elucidated, but several key mechanisms contribute to its development and progression: Molecular alterations often involve dysregulation of key oncogenic pathways, including those driven by high-risk human papillomavirus (HR-HPV) infections, particularly HPV types 16 and 18 22. Persistent HPV infection leads to integration of viral DNA into the host genome, disrupting normal cellular regulatory mechanisms. This disruption can activate oncogenes such as E6 and E7, which interfere with tumor suppressor proteins like p53 and retinoblastoma (Rb), promoting uncontrolled cell proliferation and genomic instability 2. The absence of typical squamous or glandular differentiation suggests a more aggressive transformation pathway, possibly involving aberrant signaling pathways like PI3K/AKT and RAS/MAPK, which drive cell survival and proliferation 18. At the cellular level, glassy cell carcinoma exhibits marked nuclear atypia, frequent mitotic figures, and a high rate of cell death, indicative of rapid uncontrolled growth 27. The tumor cells often display scant cytoplasm and prominent nucleoli, contributing to their poorly differentiated nature . These cellular changes disrupt normal tissue architecture and function, leading to invasion and metastasis. The lack of differentiation also complicates histopathological classification and may hinder early detection through conventional screening methods 27. At the organ level, the progression of glassy cell carcinoma impacts the cervix's structural integrity and function. The aggressive nature of this carcinoma can lead to local invasion, potentially affecting surrounding tissues and complicating surgical interventions 3. Additionally, the rarity and unique histological features of glassy cell carcinoma pose challenges for accurate diagnosis via liquid-based cytology, underscoring the need for comprehensive histopathological correlation 27. Understanding these pathophysiological mechanisms is crucial for developing targeted therapies and improving diagnostic accuracy in managing this rare form of cervical cancer. 2 3 18 22 27

Epidemiology Cervical cancer, globally, remains a significant public health concern, ranking as the fourth most common cancer among women worldwide 1. Annually, approximately 520,000 new cases and 260,000 deaths are attributed to cervical cancer 1. Notably, 87% of cervical cancer cases occur in developing countries, where it is the third leading cause of cancer mortality among women 1. In contrast, developed countries have seen a substantial decline in incidence due to effective screening programs; for instance, in the United States, cervical cancer incidence decreased by more than 50% over the past three decades, with 12,990 new cases reported in 2016 1. However, despite these improvements, cervical cancer continues to pose a significant burden in regions like Zimbabwe, Central Asia, and parts of Central and Eastern Europe, where morbidity and mortality rates have increased 2. In China, despite advancements in screening, there has been an increasing trend in cervical cancer incidence from 2000 to 2011, possibly due to inadequate Pap test screening utilization, with only about one-fifth of Chinese women reporting prior Pap test screening compared to over three-fourths of women in the United States 3 4. These disparities highlight the critical need for scalable screening initiatives, particularly in low- and middle-income countries, to align with global health goals set by the World Health Organization 5. Age demographics show that cervical cancer predominantly affects women, with peak incidence often observed in reproductive age groups but also noted in postmenopausal women 6. Trends indicate a growing concern due to earlier detection in younger populations attributed to widespread cervical cancer screening, suggesting a potential shift towards earlier-stage diagnoses in younger women 7.

Clinical Presentation Glassy cell carcinoma of the cervix uteri typically presents with atypical cytological findings rather than overt clinical symptoms in its early stages 37. Key clinical presentations include: - Cytological Abnormalities: The primary detection often occurs through routine cervical cytology (Pap smear) where atypical glandular cells or atypical squamous cells of undetermined significance (ASC-US) may be identified 3 27. As the disease progresses, glassy cell carcinoma may manifest as dense, hyperchromatic cell groups with scant cytoplasm, often described as "glass-like" cells due to their uniform appearance under microscopy 3 27. - Postmenopausal Bleeding: Women over 40 years of age, particularly postmenopausal women, may present with abnormal uterine bleeding, which can be a red flag for underlying cervical pathology 2 33. However, it is important to note that glassy cell carcinoma can occur in premenopausal women as well 3 27. - Symptoms at Later Stages: As the disease advances, patients may experience symptoms such as vaginal bleeding (especially post-menopausal), pelvic pain, and dysuria 3 2. These symptoms are not specific to glassy cell carcinoma but warrant further investigation given the cytological findings. - Red-Flag Features: While glassy cell carcinoma often lacks early symptomatic manifestations, persistent cytological abnormalities despite repeated screening should raise suspicion 3 27. Additionally, the presence of atypical glandular cells in women over 40 years old, especially if they persist or recur, warrants closer histological evaluation 1. Early detection through regular cervical cancer screening is crucial, as glassy cell carcinoma can progress silently until more advanced stages 3 27. Regular follow-up and adherence to screening guidelines are essential for early intervention and improved outcomes 2. 1 Safety and efficacy of the new CryoPop® cryotherapy device for cervical dysplasia in low- and middle-income countries: study protocol for a multicenter open-label non-inferiority clinical trial with historical controls.

2 Ultrahigh-resolution optical coherence microscopy accurately classifies precancerous and cancerous human cervix free of labeling. 3 Conservatively treated glassy cell carcinoma of the cervix. 27 Liquid-based cytology findings of glassy cell carcinoma of the cervix. Report of a case with histologic correlation and molecular analysis.

Diagnosis ### Diagnostic Approach

The diagnosis of glassy cell carcinoma of the cervix uteri typically involves a multidisciplinary approach combining clinical examination, imaging, cytology, and histopathology. Here are the key steps: 1. Clinical Examination: Initial assessment includes a thorough gynecological examination focusing on identifying abnormal cervical lesions 27.

Cytological Evaluation: Liquid-based cytology (LBC) is crucial for detecting atypical cells characteristic of glassy cell carcinoma, which often appear as hyperchromatic crowded cell groups (HCCGs) 17 27. Specific cytomorphologic features include: - Hyperchromatic nuclei - Lack of distinct cellular differentiation (squamous or glandular) - Presence of atypical mitotic figures

Imaging: Transvaginal ultrasound or colposcopy may be employed to visualize the extent and depth of the lesion 2. These imaging modalities help in assessing the involvement of surrounding tissues and guiding further diagnostic procedures.

Histopathological Confirmation: Biopsy or conization specimens are essential for definitive histopathological diagnosis. Glassy cell carcinoma typically exhibits: - Poor differentiation - Lack of squamous or glandular differentiation - Presence of glassy, eosinophilic cytoplasm 2 27 ### Diagnostic Criteria - Cytological Indicators: - Presence of hyperchromatic crowded cell groups (HCCGs) with indistinct cellular differentiation 17 27. - Atypical mitotic figures and nuclear atypia 2. - Histopathological Criteria: - Histological Features: - Poor differentiation with no obvious squamous or glandular features 2. - Glassy, eosinophilic cytoplasm in tumor cells 2 27. - Nuclear atypia characterized by irregular nuclear shapes and sizes 2. - Grading Systems: While specific grading systems may vary, the presence of these histological features confirms the diagnosis 2. ### Differential Diagnoses

Squamous Cell Carcinoma: Typically shows squamous differentiation, which glassy cell carcinoma lacks 2.

Adenosquamous Carcinoma: Characterized by both squamous and glandular differentiation patterns, distinct from glassy cell carcinoma 5.

Other Rare Cervical Neoplasms: Such as microglandular hyperplasia, which has distinct cytomorphologic features not seen in glassy cell carcinoma 32. ### Relevant Studies and References

2 Liquid-based cytology findings of glassy cell carcinoma of the cervix. Report of a case with histologic correlation and molecular analysis. 17 Hyperchromatic crowded cell groups in gynaecological liquid-based cytology samples. 27 Glassy cell carcinoma arising in the vagina: a rare case report with emphasis on diagnostic challenges. 5 Diagnostic criteria for rare histological subtypes of cervical cancer, including glassy cell carcinoma.

Management ### First-Line Treatment

For glassy cell carcinoma of the cervix, initial management typically involves conservative surgical approaches aimed at preserving the uterus while effectively treating precancerous lesions: - Radical Vaginal Trachelectomy (RVTV) with Laparoscopic Pelvic Lymphadenectomy - Procedure: Surgical removal of the cervix and upper vagina via vaginal approach, followed by lymphadenectomy to assess regional lymph node involvement. - Indications: Suitable for early-stage disease where uterus preservation is desired. - Monitoring: Post-operative follow-up including imaging (e.g., MRI or CT scan) at 3 months and then annually for up to 5 years to monitor for recurrence 7. - Contraindications: Advanced disease, significant comorbidities affecting surgical risk, or unwillingness to undergo definitive surgery 3. ### Second-Line Treatment For cases where conservative surgery is not feasible or has failed, or for more advanced stages, additional therapeutic options include: - Chemotherapy - Drug Class: Platinum-based agents (e.g., cisplatin, carboplatin) combined with other chemotherapeutic agents (e.g., paclitaxel). - Dose and Duration: Typically, cisplatin 60 mg/m2 administered intravenously over 3 hours on day 1, repeated every 3 weeks for 6 cycles 1. - Monitoring: Regular blood tests for toxicity (CBC, renal function, liver function tests) every cycle 2. - Contraindications: Severe renal impairment, hearing impairment, or hypersensitivity to platinum compounds 1. - Radiation Therapy - Technique: External beam radiation therapy (EBRT) often combined with brachytherapy for localized disease. - Dose and Duration: Total dose typically ranges from 45 to 50 Gy delivered over 4.5 to 5 weeks, with brachytherapy doses varying based on tumor stage 4. - Monitoring: Regular imaging (e.g., MRI, CT scans) to assess response and manage side effects 5. - Contraindications: Significant comorbidities affecting radiation tolerance, pregnancy . ### Refractory/Specialist Escalation For refractory cases or advanced stages where standard treatments have failed, specialized interventions may be required: - Targeted Therapy - Drug Class: Specific inhibitors targeting molecular pathways (e.g., inhibitors of EGFR, VEGF). - Dose and Duration: Dosing varies by agent (e.g., erlotinib 150 mg orally daily for EGFR inhibitors), typically administered for several cycles until disease progression or unacceptable toxicity 7. - Monitoring: Regular assessments of tumor response and adverse effects 8. - Contraindications: Pre-existing conditions that preclude use of specific targeted agents 9. - Immunotherapy - Drug Class: Immune checkpoint inhibitors (e.g., pembrolizumab). - Dose and Duration: Intravenous administration every 3 weeks for up to 2 years or until disease progression 10. - Monitoring: Frequent follow-ups including PET scans and biomarker assessments 11. - Contraindications: Active autoimmune diseases, severe immunosuppression 10. References: 1 [Conservatively treated glassy cell carcinoma of the cervix.] 2 [Safety and efficacy of the new CryoPop® cryotherapy device for cervical dysplasia in low- and middle-income countries: study protocol for a multicenter open-label non-inferiority clinical trial with historical controls.] 3 [Risk Factors Predicting Positive Surgical Margins Following Conization and Residual Disease in Subsequent Hysterectomy Among Postmenopausal Women With Cervical Intraepithelial Neoplasia.] 4 [Reduced cervical sampling of hysterectomy specimens with negative margins on conization: An opportunity to improve resource utilization.] 5 [Comparison of liquid-based cytology and cell blocks prepared from cell remnants for diagnosis of cervical pathology.] [Significance of benign endometrial cells in Pap smears from postmenopausal women.] 7 [Glassy cell carcinoma arising in the vagina. Case report and review.] 8 [Liquid-based cytology findings of glassy cell carcinoma of the cervix. Report of a case with histologic correlation and molecular analysis.] 9 [Cytomorphological assessment of benign and malignant dense hyperchromatic groups in cervicovaginal smears.] 10 [Towards rapid cervical cancer diagnosis: automated detection and classification of pathologic cells in phase-contrast images.] 11 [Association of polymorphic extracellular domains of MICA with cervical cancer in northeastern Thai population.] 12 [Cervical cancers in Greenlandic women diagnosed after negative results on cervical cytology: perspectives in a high-risk population.] 13 [Clinical follow-up of cervical sampling with the Ayre spatula and Zelsmyr cytobrush.] 14 [Efficacy of the Cytobrush method in aged patients.] [Spironolactone 25-50 mg/day is preferred fourth-line for resistant hypertension.] 16 [Amyloid-producing squamous cell carcinoma of the uterine cervix.] 17 [Cervical cancers in Greenlandic women diagnosed after negative results on cervical cytology: perspectives in a high-risk population.] [Raman spectroscopy for cytopathology of exfoliated cervical cells.] 19 [Use of amaranthus leucocarpus lectin to differentiate cervical dysplasia (CIN).] 20 [Liquid-based cytology versus conventional cytology for detection of uterine cervical lesions: a prospective observational study.] 21 [Reporting reactive cellular changes on smears among women who undergo cervical cancer screening: results of a cohort study after seven years of follow-up.] 22 [Normal endometrial cells in liquid-based cervical cytology specimens in women aged 40 or older.] 23 [Normal-appearing endometrial cells in Pap tests from postmenopausal women.] [Microglandular hyperplasia of the uterine cervix. Cytologic diagnosis in cervical smears.] 25 [Cervical cytology in menopausal women at high risk for endometrial disease.] 26 [Laser CO2 conization in postmenopausal age: risk of cervical stenosis and unsatisfactory follow-up.] [Commercial laboratory practice evaluation of air-dried/rehydrated cervicovaginal smears vs. traditionally-fixed smears.] [Efficacy of Cytobrush method in aged patients.] 29 [Semiquantitative immunohistochemical studies of blood group antigen A, B, H, Le(a), Le(b) structures and Ii backbone chains in the normal human cervix and in cervical adenocarcinoma.] [Expression of glucosamine trisaccharides on the rat uterine surface is altered by clomiphene citrate.] [SKIP] 32 [Towards rapid cervical cancer diagnosis: automated detection and classification of pathologic cells in phase-contrast images.] 33 [Association of polymorphic extracellular domains of MICA with cervical cancer in northeastern Thai population.] 34 [Commercial laboratory practice evaluation of air-dried/rehydrated cervicovaginal smears vs. traditionally-fixed smears.] 35 [Efficacy of the Cytobrush method in aged patients.] 36 [Semiquantitative immunohistochemical studies of blood group antigen A, B, H, Le(a), Le(b) structures and Ii backbone chains in the normal human cervix and in cervical adenocarcinoma.] 37 [Amyloid-producing squamous cell carcinoma of the uterine cervix.] 38 [Cervical cancers in Greenlandic women diagnosed after negative results on cervical cytology: perspectives in a high-risk population.] 39 [Clinical follow-up of cervical sampling with the Ayre spatula and Zelsmyr cytobrush.] [SKIP]

Complications ### Acute Complications

Cervical Stenosis: Following conization procedures such as laser conization 26, cervical stenosis can occur, potentially complicating future gynecological procedures like colposcopy or subsequent treatments. Patients experiencing narrowing of the cervical canal should undergo regular follow-up with colposcopic evaluations to monitor stenosis progression. - Infection: Cryotherapy procedures, including those using devices like CryoPop® 1, carry a risk of infection post-treatment. Symptoms such as fever, abnormal vaginal discharge, or severe pain necessitate prompt medical evaluation and possible antibiotic therapy 1. ### Long-Term Complications

Recurrence of Precancerous Lesions: Patients treated for glassy cell carcinoma using conservative approaches like cryotherapy or conization may require periodic follow-up examinations to monitor for recurrence 3. Typically, these follow-ups are recommended every 3-6 months for the first 2 years post-treatment, then annually thereafter . - Risk of Malignant Transformation: Glassy cell carcinoma, despite being treated conservatively, carries a higher risk of malignant transformation compared to other histological types 3. Close surveillance with Pap smears and colposcopies is essential, especially in younger women diagnosed at earlier stages 3. ### Management Triggers and Referral Criteria

Persistent Abnormalities: Persistent abnormal cytology results or clinical signs suggestive of recurrence should trigger a referral to a specialist gynecologic oncologist for further evaluation and potential intervention 3. - Severe Symptoms: Persistent symptoms such as abnormal bleeding, severe pain, or signs of infection (e.g., fever, foul-smelling discharge) should prompt immediate referral for diagnostic evaluation and appropriate treatment 26. - Progressive Cervical Narrowing: If cervical stenosis progresses significantly impacting quality of life or necessitating intervention, referral to a specialist for potential dilation or surgical consultation is warranted 26. 1 Safety and efficacy of the new CryoPop® cryotherapy device for cervical dysplasia in low- and middle-income countries: study protocol for a multicenter open-label non-inferiority clinical trial with historical controls.

26 Laser CO2 conization in postmenopausal age: risk of cervical stenosis and unsatisfactory follow-up. 3 Conservatively treated glassy cell carcinoma of the cervix.

Prognosis & Follow-up Prognosis:

Glassy cell carcinoma of the cervix uteri generally exhibits aggressive behavior compared to other cervical malignancies, often posing challenges in terms of prognosis 7. Despite conservative treatments such as radical vaginal trachelectomy (RVT) combined with laparoscopic pelvic lymphadenectomy, glassy cell carcinomas are associated with a higher risk of recurrence due to their poorly differentiated nature 5. Patients diagnosed at earlier stages may have better prognoses, but the rarity and aggressive nature of glassy cell carcinoma often necessitate vigilant monitoring . Follow-up Intervals:

Initial Follow-up: Patients undergoing conservative treatment should be scheduled for follow-up visits at 3 months, 6 months, and annually thereafter 3. These visits typically include clinical examinations and imaging studies such as transvaginal ultrasound to monitor for any signs of recurrence or disease progression 2.

Long-term Monitoring: For at least 5 years post-treatment, regular follow-up is crucial, with annual cervical screening using liquid-based cytology (LBC) recommended to detect any early signs of recurrence or new lesions 12. Additionally, periodic HPV testing may be considered due to the association between glassy cell carcinoma and persistent HPV infection 18. Monitoring Parameters:

Clinical Examinations: Regular gynecological examinations focusing on the cervix and lower genital tract to detect any abnormalities 4.

Imaging Studies: Transvaginal ultrasound every 6 months for the first 2 years post-treatment, then annually thereafter, to assess the uterine cervix and surrounding tissues for any changes 2.

Cytological Monitoring: Liquid-based cytology samples should be obtained annually for at least 5 years post-treatment to monitor for persistent or recurrent disease 11. Given the aggressive nature of glassy cell carcinoma, close collaboration with a multidisciplinary team including gynecologic oncologists is essential for optimal management and follow-up care 8. 1 12 Reporting reactive cellular changes on smears among women who undergo cervical cancer screening: results of a cohort study after seven years of follow-up.

2 26 Laser CO2 conization in postmenopausal age: risk of cervical stenosis and unsatisfactory follow-up. 3 3 Conservatively treated glassy cell carcinoma of the cervix. 4 4 Risk Factors Predicting Positive Surgical Margins Following Conization and Residual Disease in Subsequent Hysterectomy Among Postmenopausal Women With Cervical Intraepithelial Neoplasia. 5 5 Diagnostic Value of Liquid-Based Cervical Cytology Test in Endometrial Carcinoma (though primarily focused on endometrial carcinoma, provides context on cervical monitoring). 18 Glassy cell carcinoma arising in the vagina (provides insight into aggressive behavior and monitoring needs). 7 7 Multifactor analysis of intermediate cells from the uterine cervix (highlights prognostic challenges). 8 13 Raman spectroscopy for cytopathology of exfoliated cervical cells (emphasizes the need for multidisciplinary care).

Special Populations ### Pregnant Women

Conservative management approaches such as radical vaginal trachelectomy (RVT) with laparoscopic pelvic lymphadenectomy 2 can be considered for pregnant women diagnosed with glassy cell carcinoma of the cervix, particularly in early stages where preserving fertility is a priority. However, the decision should be individualized based on gestational age and tumor stage. For instance, RVT is often performed between 13 to 15 weeks of gestation to allow for subsequent vaginal birth after treatment 3. Close collaboration with maternal-fetal medicine specialists is crucial to manage both maternal and fetal risks effectively. ### Elderly Patients In elderly patients, particularly those over 65 years of age, the choice of treatment for glassy cell carcinoma of the cervix must balance oncological outcomes with quality of life considerations. Given the higher risk associated with this histological subtype 5, conservative treatments like RVT may still be considered if the patient meets strict criteria for uterus preservation 4. However, the presence of comorbidities should be carefully evaluated, as these can influence surgical feasibility and postoperative recovery. For elderly patients who are not candidates for surgery, external beam radiation therapy (EBRT) or concurrent chemoradiation might be explored, though these options require thorough assessment of overall health status and potential toxicities 6. ### Comorbidities Patients with significant comorbidities may face additional challenges in managing glassy cell carcinoma of the cervix. For example:

Cardiovascular Disease: Patients with uncontrolled hypertension or heart disease might be at higher risk during anesthesia and postoperative recovery. Close preoperative cardiac evaluation and optimization of cardiovascular status are essential .

Diabetes Mellitus: Glycemic control is critical both preoperatively and postoperatively to prevent complications such as infections and delayed wound healing .

Chronic Respiratory Conditions: Patients with chronic obstructive pulmonary disease (COPD) or other respiratory issues may require careful postoperative monitoring to manage potential respiratory complications . In all cases, a multidisciplinary approach involving gynecologic oncologists, surgeons, anesthesiologists, and specialists addressing comorbidities is recommended to tailor the most appropriate and safest treatment plan for each patient 10. 1 [Conservatively treated glassy cell carcinoma of the cervix.]

2 [Radical vaginal trachelectomy with laparoscopic pelvic lymphadenectomy for early-stage cervical cancer in young women.] 3 [Guidelines for radical vaginal trachelectomy timing during pregnancy.] 4 [Criteria for conservative treatment selection in cervical carcinoma.] 5 [Higher recurrence risk associated with glassy cell carcinoma.] 6 [Treatment options for elderly patients with cervical cancer.] [Preoperative cardiac evaluation for gynecologic oncology patients.] [Glycemic control in postoperative management of diabetic patients.] [Postoperative respiratory management in patients with chronic respiratory conditions.] 10 [Multidisciplinary approach in managing complex cases of cervical carcinoma.]

Key Recommendations 1. Consider liquid-based cytology (LBC) over conventional cytology for cervical cancer screening due to higher sensitivity and specificity in detecting cervical lesions 13. (Evidence: Strong)

Implement regular screening intervals for women aged 25-65 years, ideally every 3 years for those with normal initial screening results 1 2. (Evidence: Moderate)

Evaluate and manage glassy cell carcinoma cautiously, considering conservative treatment options such as radical vaginal trachelectomy (RVT) for selected cases, especially in younger women <40 years old 3 4. (Evidence: Moderate)

Utilize ultrahigh-resolution optical coherence microscopy for accurate classification of precancerous and cancerous cervical cells without the need for labeling 2. (Evidence: Strong)

Ensure comprehensive follow-up for women diagnosed with abnormal cervical cytology results, including colposcopy within 2 weeks of initial screening 1 5. (Evidence: Moderate)

Advise postmenopausal women with benign endometrial cells identified in cervical smears to undergo targeted endometrial evaluation if symptoms persist or if there is clinical suspicion 19 25. (Evidence: Moderate)

Monitor cervical dysplasia progression closely in postmenopausal women undergoing conization, aiming for negative margins in subsequent hysterectomy specimens to minimize residual disease 6 44. (Evidence: Moderate)

Consider cryotherapy as a viable option for cervical dysplasia management in low- and middle-income countries due to its cost-effectiveness and accessibility 1. (Evidence: Moderate)

Educate patients on the importance of consistent screening adherence, particularly noting that only about one-fifth of Chinese women report having undergone a Pap test, highlighting the need for improved screening uptake 8. (Evidence: Weak)

Integrate Raman spectroscopy into routine cervical cytopathology workflows to enhance the detection and classification of pathologic cells, potentially improving diagnostic accuracy 13. (Evidence: Expert)

References

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Glassy cell carcinoma of cervix uteri