Cervical Clear Cell Carcinoma Research Articles

Coelenterate and Germinal-Müllerian Papilloma Cervix: A Mini-Review

Coelenterate and Germinal-Müllerian Papilloma Cervix: A Mini-Review

Anticancer effect of a pyrrole-imidazole polyamide-triphenylphosphonium conjugate selectively targeting a common mitochondrial DNA cancer risk variant in cervical cancer cells.

Cervical cancer remains a major threat to women's health, especially in countries with limited medical resources, and new drugs are needed to improve patient survival and minimize adverse effects. Here, we examine the effects of a triphenylphosphonium (TPP)-conjugated pyrrole-imidazole polyamide (CCC-h1005) targeting the common homoplasmic mitochondrial DNA (mtDNA) cancer risk variant (ATP6 8860A>G) on the survival of cervical cancer cell lines, cisplatin-resistant HeLa cells and patient-derived cervical clear cell carcinoma cells as models of cervical cancer treatment. We found that CCC-h1005 induced death in these cells and suppressed the growth of xenografted HeLa tumors with no severe adverse effects. These results suggest that PIP-TPP designed to target mtDNA cancer risk variants can be used to treat many cervical cancers harboring high copies of the target variant, providing a foundation for clinical trials of this class of molecules for treating cervical cancer and other types of cancers.

Immunohistochemical and molecular analysis of an α-fetoprotein-producing cervical adenocarcinoma with clear cell morphology.

Adenocarcinomas with clear cell morphology may be associated with elevated serum alpha-fetoprotein levels in various organs. We report the case of an alpha-fetoprotein-producing cervical adenocarcinoma with clear cell morphology and compare it immunohistochemically, molecularly, and virologically with cervical clear cell carcinoma, gastric-type mucinous carcinoma, and ovarian clear cell carcinoma. A 51-year-old Japanese woman was initially diagnosed with cervical clear cell carcinoma. The tumor was resistant to standard surgery, radiotherapy, and chemotherapy. Serum carcinoembryonic antigen and alpha-fetoprotein were elevated. The tumor was immunohistochemically positive for alpha-fetoprotein, human chorionic gonadotropin, cytokeratin 20, spalt-like transcription factor 4, glypican 3, MUC6, and HIK1083. Gene panel testing revealed CCNE1 amplification, CDKN2A loss, and TP53 R282W. We compared the present case with 120 ovarian clear cell carcinoma cases using a tissue microarray. Only one case (0.8%) showed very limited immunohistochemical positivity for alpha-fetoprotein. Of the 54 cases in which serum carcinoembryonic antigen was measured, only one (1.9%) was elevated (19.9ng/mL). We diagnosed the case as alpha-fetoprotein-producing cervical gastric-type mucinous carcinoma with enteroblastic differentiation. In conclusion, alpha-fetoprotein-producing cervical adenocarcinoma is a rare but aggressive tumor. Clinicians and pathologists should be aware of this unfamiliar tumor, its diagnostic clues, prognostic markers, and treatment strategies.

Clear Cell Carcinoma (CCC) of the Cervix Is a Human Papillomavirus (HPV)-independent Tumor Associated With Poor Outcome: A Comprehensive Analysis of 58 Cases.

Cervical clear cell carcinoma (CCC) is a rare human papillomavirus-independent adenocarcinoma. While recent studies have focused on gastric-type endocervical adenocarcinoma (GTA), little is known about CCC. A total of 58 (CCCs) were collected from 14 international institutions and retrospectively analyzed using univariable and multivariable methods and compared with 36 gastric-type adenocarcinomas and 173 human papillomavirus-associated (HPVA) endocervical adenocarcinoma (ECA) regarding overall survival (OS) and recurrence-free survival (RFS). Most cases were FIGO stage I (72.4%), with Silva C pattern of invasion (77.6%), and the majority were treated with radical surgery (84.5%) and adjuvant therapy (55.2%). Lymphovascular invasion was present in 31%, while lymph node metastasis was seen in 24.1%; 10.3% were associated with abdominopelvic metastases at the time of diagnosis; 32.8% had recurrences, and 19% died of disease. We did not find statistically significant differences in OS and RFS between CCC and GTA at 5 and 10 years (P=0.313 and 0.508, respectively), but there were significant differences in both OS and RFS between CCC and HPVA ECA (P=0.003 and 0.032, respectively). Also, OS and RFS in stage I clear cell and GTA were similar (P=0.632 and 0.692, respectively). Multivariate analysis showed that OS is influenced by the presence of recurrence (P=0.009), while RFS is influenced by the FIGO stage (P=0.025). Cervical CCC has poorer outcomes than HPVA ECA and similar outcomes to human papillomavirus-independent GTA. Oncologic treatment significantly influences RFS in univariate analysis but is not an independent prognostic factor in multivariate analysis suggesting that alternative therapies should be investigated.

Precursor Lesions of Cervical Clear Cell Carcinoma: Evidence For Origin From Tubo-Endometrial Metaplasia.

Cervical clear cell carcinoma (CCC) is an HPV-independent tumor historically associated with in-utero exposure to diethylstilboestrol. With the cessation of diethylstilboestro use, most contemporary cases are sporadic and of uncertain pathogenesis, with no established precursor lesion. Following the detection of 3 incidental "early" (FIGO stage IA1) cervical CCCs, all of which displayed adjacent tubo-endometrial metaplasia, we examined further cases, including resection specimens, of this tumor in an attempt to delineate potential precursors. We identified tubo-endometrial metaplasia in proximity to the tumor in 5 of 5 additional primary cervical CCCs, with some tubo-endometrial glands exhibiting subtle mild cytologic atypia. This observation adds to the sparse existing literature proposing tubo-endometrial metaplasia as a precursor to sporadic cervical CCC, with possible progression via an "atypical" transitional phase to malignancy. We also review the published literature regarding possible precursor lesions of primary cervical CCC.

Establishment and characterization of patient‐derived organoids from a young patient with cervical clear cell carcinoma

Cervical clear cell carcinoma (cCCC) constitutes an extremely rare subtype of cervical cancer. Consequently, its pathogenesis remains largely unknown, with no cell lines established from primary tumors. Here, we report the first establishment of cCCC organoids, from biopsy samples of a 23‐year‐old patient diagnosed with cCCC. By applying a protocol that we recently optimized for gynecological tumors, we were able to propagate a patient‐derived cell line (PDC) for more than 6 months as organoids. This PDC tolerated cryopreservation and proliferated either as spheroids or adherent cells, and developed xenografts in immunodeficient mice, ensuring robust utility as a cell line. Intriguingly, the resected tumor focally contained serous carcinoma (SC) in a tiny protruding lesion. Both organoids and derivative xenografts resembled the CCC component of the original tumor in histology, immunostaining profile, and genome‐wide copy number changes, including focal gain of MET. Genomic analysis revealed that both organoids and the CCC component harbored only a few mutations, of which 2 mutations were shared in common. In contrast, the SC component showed a mutator‐phenotype and prominent genome instability along with biallelic inactivation of TP53, but none of them were found in organoids or the CCC component. The PDC proved sensitive to major chemotherapeutic agents and MET inhibitors. These observations clearly indicated that the PDC, designated as YMC7, can be used as a novel cCCC cell line and provide novel insights into the pathogenesis of mixed cervical adenocarcinoma. As a valuable resource for rare cancer, it will likely contribute to investigations in many fields.

The Evaluation of Clinicopathological and Immunohistochemical Findings of Cervical Clear Cell Carcinoma in a Bitch

Background: Clear cell carcinoma (CCC) of the cervix is a rarely seen malignant tumor which is classified in adenocarcinomas of the endometrium. It is responsible for 2.15-3.0% of endometrial tumors. The diagnosis is difficult and is still controversial in uterine carcinomas. Macroscopically, masses were protruding to endometrial surface. However, the definitive diagnosis was carried by microscopical evaluation. The cells contain clear cytoplasm. The cells are seen in this pattern because there is either glycogenation or secretoric activity in the cells.Case: In the present case, clinicopathologic and immunohistochemical findings of clear cell carcinoma of the cervix were defined in a 3 year-old spayed Golden retriever bitch. Previously spayed bitch, which had vaginal discharge for the last month-long, was submitted to the Department of Obstetrics and Gynecology, Ankara University, Faculty of VeterinaryMedicine. In the general clinical examination, vaginoscopy was performed and vaginal cytology was obtained from smear. The source of discharge was detected as cervix uteri. In vaginal cytologic examination, erythrocyte, neutrophile and superficial cells were observed. In abdominal ultrasonography, a hypoechoic mass was detected at cranial part of the urinary bladder. To evaluate the general health condition of the dog, total blood counting and serum biochemistry were analyzed in addition to assessing its hormone prophlye. Estrogen and progesterone levels were evaluated. Estradiol (E2) level was measured as 23 pg/mL and progesterone level was measured as 1.96 ng/mL from collected serum. The cervical mass in diameters of 3x4x2.5 cm was removed in operation. In macroscopical examination, it had spherical and regularly shape.After the macroscopical examination, tissue samples were fixed in 10% buffered formalin. Then, the samples stained with Haematoxylin-Eosin (H&E), Masson’s trichrome and PAS stainings, respectively. At the macroscopic and histological examinations, the mass was diagnosed as clear cell carcinoma. Immunohistochemically, the tumor was stained with CK19 α-SMA, vimentin, desmin, TGF-β, VEGF, CEA, ER and PR markers. Other markers gave moderate to severe reactions in exception for no or weak ER and PR positivities. In direction of these results, clear cell carcinoma of cervix had been found remarkably due to first description in a spayed bitch on the basis of knowledge.Discussion: Clear cell carcinoma (CCC) is one type of the endometrial carcinomas. It is frequently known to have aggressive behavior and unfavorable prognosis. In human counterparts, clear cell carcinoma is frequently reoccurred in caudoabdominal and pelvic region even after being removed. The occurrence of clear cell carcinoma has highly increasedwith diethylstilbestrol usage during pregnancy. The situation on uterine carcinoma is nearly same in domestic animals. It is related to prolonged estrogenism. In this case, the bitch has been under prolong exposure to estrogenic effect. Indeed the estradiol level was high when compared to spayed female. Also, it is thought that the reason of high estradiol leveldoes not depend on the ovarian remnant. It is believed this situation may be relevant to exogen hormone usage. Vaginal smear confirmed erythrocyte (due to bleeding), predominantly superficial cells to it’s under estrogenic effect even despite being spayed.Keywords: clear cell carcinoma, cervix, clinicopathology, marker, bitch.

Clear Cell Carcinoma of the Cervix With Choriocarcinomatous Differentiation: Report of an Extremely Rare Phenomenon Associated With Mismatch Repair Protein Abnormality

The presence of trophoblastic differentiation or nongestational choriocarcinoma in a carcinoma is rare but has been described in various organs, including in the female genital tract. We report a cervical clear cell carcinoma admixed with a component of choriocarcinoma in a 52-year-old woman, only the second report of this combination in the literature. Immunohistochemically, the tumor exhibited isolated loss of staining with the mismatch repair protein MSH6. We review the literature on trophoblastic differentiation in cervical carcinoma.

Cervical Clear Cell Adenocarcinoma Infected with Human Papillomavirus Type 18 in an Adolescent

BackgroundCervical clear cell carcinoma is one of the rare subtypes of cervical adenocarcinomas. Few cases of cervical clear cell carcinoma have been reported in adolescents. CaseWe present here a case of a 14-year-old adolescent female diagnosed with a stage II cervical clear cell carcinoma. The patient had no sexual history or diethylstilbestrol-exposure in utero. Polymerase chain reaction identified in the tumor the presence of human papillomavirus type 18, a high-risk genotype for cervical cancer development. The ovaries were retained during surgery and the patient was still alive without recurrence after 9 years. Summary and ConclusionPositivity of HPV18 nucleic acids suggests an association between high risk HPV infection and cervical clear cell carcinoma in the case. Furthermore, in the treatment of young patients with cervical carcinoma, the risks associated with loss of ovarian function should be weighed against that of potential ovarian metastasis.

Absence of Human Papillomavirus Infection and Activation of PI3K-AKT Pathway in Cervical Clear Cell Carcinoma

Cervical cancer is the second most common cancer in females worldwide, and the majority of squamous cell carcinomas and adenocarcinomas are associated with high-risk human papillomavirus (HPV) infection. However, the relationship between clear cell carcinoma of the cervix (CCCC) and HPV is unclear. In this study, we sought to determine if HPV infection is associated with CCCC and to elucidate the signaling pathways involved. We collected samples from 13 CCCC patients and collated the relevant clinicopathologic data. We then evaluated the presence of HPV types 16, 18, 31, 33, 35, 52, and 58 by broad-spectrum amplification by polymerase chain reaction and HPV types 39, 45, 51, 56, 59, and 68 by nested polymerase chain reaction assay that combines degenerate E6/E7 consensus primers and type-specific primers from extracted genomic DNA. Immunohistochemistry was used to analyze the expression of EGFR (epidermal growth factor receptor), HER2, PTEN (phosphatase and tensin homolog), phospho-AKT, phospho-mTOR (mammalian target of rapamycin), p16, and p53. EGFR and HER2 gene amplification was determined by fluorescence in situ hybridization. Patients with stage IB CCCC had a better 3-year overall survival rate compared with those with advanced-stage cancer (100% vs 44%; P = 0.014). High-risk HPVs were not detected in any of the cases examined. EGFR immunostaining was observed in 9 (75%) of 12 patients, HER2 in 3 (25%) of 12, PTEN in 6 (50%) of 12, and phospho-AKT in 7 (58%) of 12, and phospho-mTOR in 6 (50%) of 12. EGFR amplification could not be detected, but HER2 amplification was identified in 1 of (12.5%) 8 cases. Patients with stage I CCCC demonstrated good overall survival and rare recurrence. Clear cell carcinoma of the cervix is unrelated to high-risk HPV infection; hence, current vaccines will not prevent the incidence of CCCC. However, increased EGFR or HER2 expression or activation of AKT or mTOR was observed in all cases, indicating that inhibitors of tyrosine kinases or the AKT-mTOR pathway may be suitable treatment regimens for CCCC.

Tumor seeding incidentally found two years after robotic—Assisted radical nephrectomy for papillary renal cell carcinoma. A case report and review of the literature

INTRODUCTIONPort-site metastasis or peritoneal spread after laparoscopic surgery for urological malignancies is a rare phenomenon accounting for 0.09% and 0.03% of the cases respectively. PRESENTATION OF CASEWe present a case of tumor seeding in the omentum found in a female patient after previous transperitoneal robotic-assisted radical nephrectomy (RARN) for papillary renal cell carcinoma (RCC). Two years after the robotic operation, the patient was diagnosed with cervical clear cell carcinoma and underwent radical hysterectomy with lymphadenectomy and omentectomy. A neoplastic omental nodule was incidentally identified intraoperatively. Pathological characteristics and immunohistochemistry revealed features of papillary RCC. Two years after the hysterectomy, the patient is clinically cancer free, without any adjuvant therapy for her cervical cancer. DISCUSSIONTo the best of our knowledge, we report the first case of tumor seeding in the omentum following RARN for organ confined low grade papillary (T2aN0M0) RCC. No risk factors that could explain the tumor seeding were identified. The neoplastic cells had a low proliferative index (Ki-67<5%) and a decreased capability to metastasize. CONCLUSIONTumor seeding as a result of robotic assisted laparoscopic nephrectomy, although rare, might represent a novel way of tumor inoculation deprived of or with low malignant potential.

Neoadjuvant Chemotherapy Followed by Cesarean Radical Hysterectomy in a Triplet Pregnancy Complicated by Clear Cell Carcinoma of the Cervix: A Case Presentation and Literature Review

To report a triplet pregnancy complicated by clear cell cervical carcinoma that was managed using neoadjuvant chemotherapy followed by caesarean radical hysterectomy. A 26-year-old woman had a diagnosis of cervical clear cell carcinoma, which was International Federation of Gynecology and Obstetrics stage IB1, at 18 weeks of gestation during a triplet pregnancy. Owing to the patient's strong desire for full-term pregnancy, 3 cycles of neoadjuvant chemotherapy was administered after magnetic resonance imaging evaluation of the tumor. The patient underwent cesarean delivery and radical hysterectomy at gestational week 32. The hysterectomy specimen revealed stage IB1 clear cell adenocarcinoma of the cervix. The neonates and the mother did not have any complications related to the treatment during 36 months of follow-up. To the best of our knowledge, this is the first report of a triplet pregnancy complicated by cervical clear cell carcinoma that was successfully treated with neoadjuvant chemotherapy and cesarean radical hysterectomy. Our experience and literature review suggest that neoadjuvant chemotherapy for cervical carcinoma diagnosed during pregnancy is associated with excellent oncologic and fetal outcome; therefore, it may be considered as a temporary fertility-sparing approach in selected patients with a strong desire for full-term pregnancy. Nonetheless, additional research and long-term follow-up are needed to reach a more definitive conclusion.

Clear cell adenocarcinoma of the uterine cervix in a young pregnant woman: a case report with immunohistochemical study

The patient was a 30-year-old-pregnant woman (para 1, gradiva 1) without in utero exposure to diethylstilbestrol. A papillary and flat lesion was found by colposcopy in the uterine cervix in the routine examination at 10 pregnancy weeks. Biopsies showed papillary and tubular proliferation of malignant cells with clear glycogen-rich cytoplasm and malignant hobnail cells and were diagnosed as clear cell adenocarcinoma. The patient was treated by radical hysterectomy. The lesion of the cervix (10 × 15 × 5 mm) was clear cell adenocarcinoma with mild invasion into shallow myometrium (pTIb). An immunohistochemical study showed that the tumor cells were positive for pancytokeratins (AE1/3, CAM5.2, KL-1, and polyclonal wide), cytokeratin (CK) 7, CK8, CK18, CK19, epithelial membrane antigen, CA 125, p53 protein, and Ki-67 antigen (labeling = 95%). The tumor cells were negative for high-molecular weight CK (34βE12), CK5/6, CK14, CK20, vimentin, AFP, CEA, desmin, S100 protein, α-smooth muscle antigen, CD34, estrogen receptor, progesterone receptor, chromogranin, synaptophysin, neuron-specific enolase, and CD56. The patient is now of free of tumor. In the English literature, the present case is the second case of cervical clear cell adenocarcinoma during pregnancy, and the first case of cervical clear cell carcinoma investigating a wide range of immunoreactive antigens.

Clear cell carcinoma of the cervix: A multi-institutional review in the post-DES era

Objective To conduct an outcome analysis of patients with cervical clear cell carcinoma (CCCC) in the post-DES era. Methods A retrospective review was conducted at 3 major gynecologic cancer centers of all primary CCCC between 1982 and 2004. Results CCCC was confirmed in 34 patients. Median age was 53 years. DES exposure was confirmed in 2 (6%) patients. A history of smoking was elicited in 22%, and of abnormal Pap smear 18% patients. Primary surgical resection was performed in all stage I or IIA patients ( n = 26); they displayed superior 3-year overall survival (OS) compared to advanced stage ( n = 8) patients (91% vs. 22%, p < 0.001). Pelvic lymph node involvement was noted in 25%; all patients with positive para-aortic nodes (20% of patients sampled) had positive pelvic nodes. All node positive patients were treated with adjuvant radiation, but nevertheless displayed reduced progression free (31% vs 92%, p < 0.001) and overall survival (80% vs. 100%, p = 0.02). Adjuvant radiotherapy did not appear to impact OS in patients with negative lymph nodes. Discussion This series provides insight into the management of early stage CCCC in the post-DES era. Although these patients may be at slightly higher risk of nodal spread, clear cell histology by itself does not appear to portend a worse prognosis than squamous cell carcinoma of the cervix in the absence of traditional risk factors. Our data suggest that patients with low risk early stage CCCC may be managed with radical surgery alone, without the need for adjuvant chemotherapy or radiation.

Pediatric radical abdominal trachelectomy for cervical clear cell carcinoma: A novel surgical approach

Introduction Clear cell carcinoma of the cervix and vagina is rare in the pediatric population. Many of these tumors are associated with prior intrauterine diethylstilbestrol (DES) exposure. All DES-associated tumors are believed to contain microsatellite instability (MI). Historically, the recommended treatment is radical hysterectomy and pelvic lymphadenectomy, which result in infertility in all cases. Radical abdominal or vaginal trachelectomy and pelvic lymph node dissection is a new technique utilized in adult women with early cervical cancer who wish to retain fertility. This novel approach is also pertinent to the pediatric patient and is described in this report. A molecular analysis is also performed to determine if these are DES-associated tumors. Methods Due to the narrow vaginal anatomy in pediatric patients, a vaginal approach is not possible, and an abdominal approach is performed. The resection includes the cervix, upper vagina, parametrium, and paracolpos. Pelvic lymphadenectomy is performed in a similar manner to the adult patient. Matched pairs of normal and tumor DNA from both cases were examined for evidence of MI using a consensus panel of microsatellite markers. Results Two girls aged 6 and 8 years and without history of DES exposure presented with vaginal bleeding. Vaginoscopy revealed cervical polyp in both cases. Biopsies demonstrated clear cell cancer stage IB1 in both patients. They underwent radical abdominal trachelectomy and bilateral pelvic lymph node dissection along with anastomosis of uterine isthmus to upper vagina. Intraoperative frozen-section analysis confirmed negative uterine and vaginal margins. No adjuvant treatment was given and both girls remain disease free. Neither tumor showed evidence for MI, confirming that these are not DES-associated tumors. Conclusion To our knowledge, this is the first report of radical abdominal trachelectomy in the pediatric age group and it is likely to include the youngest patient with clear cell carcinoma of the uterine cervix not associated with DES exposure. This novel approach is feasible and appears safe in the pediatric age group.