Fetal gut cell-like differentiation in esophageal adenocarcinoma defines a rare tumor subtype with therapeutically relevant claudin-6 positivity and SWI/SNF gene alteration.

Esophageal adenocarcinoma (EAC) is one of the deadliest tumor entities worldwide, with a 5-year survival rate of less than 25%. Unlike other tumor entities, personalized therapy options are rare, partly due to the lack of knowledge about specific subgroups. In this publication, we demonstrate a subgroup of patients with EAC in a large screening cohort of 826 patients, characterized by specific morphological and immunohistochemical features. This subgroup represents approximately 0.7% (6/826) of the total cohort. Morphological features of this subgroup show a striking clear cytoplasm of the tumour cells and the parallel existence of rare growth patterns like yolk sac-like differentiation and enteroblastic differentiation. Immunohistochemistry reveals expression of the fetal gut cell-like proteins Sal-like protein 4 (SALL4), claudin-6, and glypican 3. Interestingly, we find a correlation with alterations of SWI/SNF-complex associated genes, which are supposed to serve as tumor suppressor genes in various tumour entities. Our results suggest a possible implication of rare tumour subtypes in the WHO classification for EACs according to the classification for gastric cancer. Furthermore, claudin-6 positive tumors have shown promising efficacy of CAR T cell therapy in the recently published BNT-211-01 trial (NCT04503278). This represents a personalized therapeutic option for this tumor subtype.

Malignancy in Abdominal Wall Endometriosis: Is There a Way to Avoid It? A Systematic Review.

Background: Malignant-associated abdominal wall endometriosis (AWE) is a rare pathology, likely to occur in 1% of scar endometriosis. The objectives of this study were to update the evidence on tumor degeneration arising from AWE to notify about the clinical characteristics, the different treatments offered to patients and their outcomes. Methods: A comprehensive systematic review of the literature was conducted. PubMed, Embase and Cochrane Library databases were used. Prospero (ID number: CRD42024505274). Results: Out of the 152 studies identified, 63 were included, which involved 73 patients. The main signs and symptoms were a palpable abdominal mass (85.2%) and cyclic pelvic pain (60.6%). The size of the mass varied between 3 and 25 cm. Mean time interval from the first operation to onset of malignant transformation was 20 years. Most common cancerous histological types were clear cell and endometrioid subtypes. Most widely accepted treatment is the surgical resection of local lesions with wide margins combined with adjuvant chemotherapy. The prognosis for endometriosis-associated malignancy in abdominal wall scars is poor, with a five-year survival rate of around 40%. High rates of relapse have been reported. Conclusions: Endometrial implants in the abdominal wall should be considered as preventable complications of gynecological surgeries. Special attention should be paid to women with a history of cesarean section or uterine surgery.

Gastric Adenocarcinoma With Unusual Clear Tubulopapillary Morphology: A Case Report.

Gastric clear cell adenocarcinoma is an extremely rare variant of papillary adenocarcinoma of the stomach. It is associated with a poor prognosis due to its frequent lymphovascular invasion and also its higher risk of recurrence. It is characterized morphologically by a clear appearance of tumor cells, which can be easily confused with a metastasis of a clear cell carcinoma, particularly of renal origin. Very few cases have been previously reported in the literature, which makes it a very poorly known variant. Here, we report the case of a 64-year-old patient who presented with a polypoid lesion in the pylorus, revealed by epigastric pain and chronic vomiting. Histological analysis showed a gastric clear cell adenocarcinoma with a tubulopapillary architecture. Immunohistochemical examination excluded a metastasis of renal origin. Through this case report, we highlight the importance of recognizing such an uncommon and unusual variant of gastric adenocarcinoma, to prevent any potential misdiagnosis.

Clear Cell Adenocarcinoma of Urethra: Clinical and Pathologic Implications and Characterization of Molecular Aberrations.

PURPOSE: This study aimed to evaluate the molecular features of clear cell adenocarcinoma (CCA) of the urinary tract and investigate its pathogenic pathways and possible actionable targets. MATERIALS AND METHODS: We retrospectively collected the data of patients with CCA between January 1999 and December 2016; the data were independently reviewed by two pathologists. We selected five cases of urinary CCA, based on the clinicopathological features. We analyzed these five cases by whole exome sequencing (WES) and subsequent bioinformatics analyses to determine the mutational spectrum and possible pathogenic pathways. RESULTS: All patients were female with a median age of 62 years. All tumors were located in the urethra and showed aggressive behavior with disease progression. WES revealed several genetic alterations, including driver gene mutations (AMER1, ARID1A, CHD4, KMT2D, KRAS, PBRM1, and PIK3R1) and mutations in other important genes with tumor-suppressive and oncogenic roles (CSMD3, KEAP1, SMARCA4, and CACNA1D). We suggest putative pathogenic pathways (chromatin remodeling pathway, mitogen-activated protein kinase signaling pathway, phosphoinositide 3-kinase/AKT/mammalian target of rapamycin pathway, and Wnt/ß-catenin pathway) as candidates for targeted therapies. CONCLUSION: Our findings shed light on the molecular background of this extremely rare tumor with poor prognosis and can help improve treatment options.

Colonic de novo Clear Cell Adenocarcinoma of Intestinal-Type: A Case Report and Review of the Literature.

Colorectal clear cell adenocarcinomas are rare tumors. They can be divided into two types: intestinal- and Müllerian-type. Most intestinal-type clear cell adenocarcinomas show a composite morphology, and most early-stage (T1) intestinal-type clear cell adenocarcinomas have an adenoma component. We report an additional early-stage (T1) colonic clear cell adenocarcinoma that was a de novo adenocarcinoma without any adenoma component. It had a pure morphology and the smallest size (0.6 cm) ever reported. Immunohistochemical results demonstrated an intestinal phenotype (KRT20+, KRT7-, CEA+, and CDX2+). Periodic acid-schiff and alcian blue stains were both negative, which demonstrated decrease in mucin expression in the clear tumor cells. Enteroblastic differentiation was observed in a few colorectal clear cell adenocarcinomas in the literature, while it had not been observed in the present tumor. The tumor did not have deep submucosal invasion and cancer embolus, endoscopic submucosal dissection with regular follow-up was an appropriate treatment for the patient. Due to the rarity and diversity of primary colorectal clear cell adenocarcinomas, the cause of clear cytoplasm change and the impact on patient prognosis remain unknown. Accumulating evidence indicates that clear cell adenocarcinomas of intestinal-type is a histological variant of colorectal adenocarcinoma.

Genetic alterations in juvenile cervical clear cell adenocarcinoma unrelated to human papillomavirus.

Clear cell adenocarcinoma of the cervix (CCAC) is a special type of HPV-independent cervical cancer. It has a low incidence rate, can be difficult to diagnose early, has a poor prognosis. Its peak incidence is in adolescence, which poses a great threat to women's health. Therefore, it is very important to explore the pathogenesis of cervical clear cell adenocarcinoma to guide subsequent treatment and prevention. This study analyzed 3 juvenile patients with CCAC diagnosed at the First Affiliated Hospital of Zhengzhou University. Using next-generation sequencing methods, we analyzed the pathogenesis of the patients and their close relatives by analyzing the genetic alterations of patients. CMTM5 was identified as the only shared mutated gene. Using published literature and comparative analyses of related disease-causing genes, 6 of the 19 genes (ALKBH7, MYCBP, MZF1, RNF207, RRS1, and TUSC2) were screened as genes with mutations in patients and had higher mutation rates in reproductive cancers. Pathway analysis showed that downregulated genes in non-HPV cervical cancer were mainly related to the immune system response, suggesting that non-HPV cervical cancer differs from HPV-infected cervical cancer in that the immune response is weaker, which is consistent with the weak correlation with viral infection.

Primary clear cell adenocarcinoma of the lung: a national analysis.

Background: Primary clear cell adenocarcinoma of the lung (CCAL) is a rare form of lung cancer with poorly understood clinical features. We sought to investigate the clinicopathological characteristics and independent prognostic factors of primary CCAL. Methods: Overall survival (OS) of patients with CCAL in the National Cancer Database (NCDB) from 2004 to 2017 was compared to lung adenocarcinoma using Kaplan-Meier analysis, multivariable Cox proportional hazards modeling, and propensity score matching. Independent prognostic indicators for patients with CCAL were determined using multivariable Cox proportional hazards analysis. Results: A total of 1,396 CCAL and 462,360 lung adenocarcinoma patients were included in our analysis. When compared to patients diagnosed with lung adenocarcinoma, those diagnosed with CCAL were more likely to be younger, white, reside farther from a hospital, have higher Charlson/Deyo comorbidity condition (CDCC) scores, have private insurance, have T1, N0, M0 status. In unadjusted analysis, patients with CCAL had better survival than those with lung adenocarcinoma, although no significant differences in survival were found between the two groups with multivariable Cox proportional hazards and propensity score-matched analyses. Conclusions: In this national analysis, we found that the clinicopathological characteristics of CCAL are distinct from those of lung adenocarcinoma, but CCAL is not itself an independent predictor of survival after multivariable adjustment or propensity score-matched analysis.

Clear cell adenocarcinoma of the urinary bladder: a case report and review of literature.

The most common histological type of urinary bladder cancer is urothelial carcinoma (UC). Clear cell adenocarcinoma (CCA) of the urinary bladder is a rare histologic subtype of adenocarcinoma in the urinary tract. The tumor primarily affects women and has histomorphological features resembling CCA of the female genital tract (or Müllerian origin). Clear cell adenocarcinoma consists of cells with abundant clear cytoplasm, arranged in solid, glandular, or tubulocystic patterns. Patients typically present with gross hematuria, dysuria, and discharge. In this study, we report a case of a 50-year-old male, presenting with gross hematuria, which was subsequently diagnosed with CCA at our pathology department. Furthermore, we provide a short systematic review of the literature for this rare histopathological entity and a brief discussion about its morphological and immunohistochemical (IHC) characteristics.

Clear cell endometrial carcinoma with high microsatellite instability in a complicated pregnancy: a case report.

BACKGROUND: Endometrial carcinomas are the most common female genital malignancies. They are very rare in pregnancy and worldwide less than 60 cases associated with pregnancy are published. No clear cell carcinoma has been described in a pregnancy with a live birth. CASE PRESENTATION: We present the course of a 43-year-old Uyghur female patient with the diagnosis of endometrial carcinoma with a deficiency in the DNA mismatch repair system in the pregnancy. The malignancy with clear cell histology was confirmed by biopsy following the delivery via caesarean section due to preterm birth of a fetus with sonographically suspected tetralogy of Fallot. Earlier whole exome sequencing after amniocentesis had shown a heterozygous mutation in the MSH2 gene, which was unlikely to be related to the fetal cardiac defect. The uterine mass was initially deemed an isthmocervical fibroid by ultrasound and was confirmed as stage II endometrial carcinoma. The patient was consequently treated with surgery, radiotherapy and chemotherapy. Six months after the adjuvant therapy, re-laparotomy was performed due to ileus symptoms and an ileum metastasis was found. The patient is currently undergoing immune checkpoint inhibitor therapy with pembrolizumab. CONCLUSION: Rare endometrial carcinoma should be included in the differential diagnosis of uterine masses in pregnant women with risk factors.

Late cervical and vaginal clear cell adenocarcinoma in women exposed in utero to diethylstilbestrol: Evaluation and screening.

OBJECTIVES: We aimed to evaluate the risk of cervical and vaginal clear cell adenocarcinoma (CCA) in women, aged 50 years or more, exposed in utero to diethylstilbestrol (DES) and contribute to a reevaluation of the recommendations for cervical and vaginal cancer and pre-cancer screening for these women. METHODS: We carried out a retrospective review for patients received in a cancer institute. Two cohorts were consecutively studied, the first from 1970 to 2003 and the second from 2004 to 2021, and then linked. RESULTS: During the first period, we observed 61 CCA cases, with a mean age at diagnosis of 23 years (7-42), 36 (59%) following DES exposure in utero. During the second period, we found 27 cases, with one case of DES exposure (4%) for a women diagnosed at the age of 40 years. The mean age of the second cohort was 38 years (14-79). For the seven women aged 50 years or more at the time of CCA diagnosis, DES exposure was excluded for five and considered unlikely for the other two. CONCLUSION: In total, 88 cases of cervical or vaginal CCA were observed over a period of 51 years in a cancer center. The 37 cases associated with DES exposure represented approximatively one third of the CCA related to DES expected in France. DES exposure was improbable for the seven cases of CCA for women aged 50 years or more. These results do not support the hypothesis of late cervical or vaginal CCA in women exposed to DES in utero and indicate the need for larger multicentric studies. For the present, we propose specific screening for women exposed to DES in utero in terms of : 1) methods: association of cytology and hrHPV testing, with cervical and vaginal sampling, 2) timing : annual, or without exceeding a three-year interval, continuing after 65 years of age and after hysterectomy.

Fertility sparing treatment of vaginal clear cell adenocarcinoma in a DES-Naïve young woman.

Background: Primary vaginal cancer is rare and comprises 1-2% of female genital tract cancers. Among the types of vaginal cancer, adenocarcinoma accounts for only 10% with the peak incidence in women less than 20 years old. Clear cell type vaginal adenocarcinoma is most associated with exposure to diethylstilbestrol (DES) in-utero. Case: We present a case of an 18-year-old nulliparous woman, DES-exposure naive, who was diagnosed with stage I clear cell vaginal adenocarcinoma during a routine pelvic exam for abnormal vaginal bleeding. She underwent a fertility-preserving radical vaginectomy and pelvic lymphadenectomy with neovagina creation and uterovaginal cervical reconstruction. She has been without disease for 28 months. Conclusion: Although rare, vaginal cancer can be diagnosed on routine women's health exams. Early screening and diagnosis allow for innovative fertility-preserving surgical approaches without compromising oncologic outcomes. To our knowledge, this is the first case of a fertility-preserving radical vaginectomy, neovagina creation using a vertical rectus abdominis myocutaneous (VRAM) flap, and uterocervicovaginal reconstruction to successfully treat early stage clear cell vaginal adenocarcinoma with surgery alone, sparing the patient from adjuvant chemotherapy or radiation.

Morphologic spectrum of the epithelial tumors of the male and female urethra.

The classification of the epithelial tumors of the male and female urethra includes benign and malignant neoplasms. Primary urethral carcinomas and adenocarcinomas of the accessory glands are the most relevant tumors, both from the morphologic and clinical point of view. An accurate diagnosis, grading and staging are essential for determining adequate treatment strategies and outcome. Information on anatomy and histology of the urethra is of fundamental importance in understanding the morphology of the tumors, including the clinical importance of their location and origin.

Nephrogenic Adenoma of the Prostatic Urethra Mimicking Prostatic and Bladder Carcinomas.

A nephrogenic adenoma is a benign lesion consisting of the proliferation of tubules and glands in the urinary tract. The lesion, thought to be originated from renal tubules, is commonly seen in the urinary bladder. Microscopically, nephrogenic adenoma is composed of a proliferation of small tubules and microcysts encircled by a narrow rim of basement membrane-like hyaline material. There are tubules and microcysts lined by atrophic to undulating hobnail-appearing epithelial cells with bland nuclei and pale eosinophilic to clear cytoplasm. Focal cellular atypia characterized by somewhat coarse chromatin and prominent nucleoli may be present. The stroma is edematous and reveals a granulation tissue-like appearance. By immunohistochemical staining, nephrogenic adenoma is positive for PAX-2, PAX-8, P504S (α-methylacyl-CoA racemase), pan cytokeratin AE1/AE3, CK7, CAM5.2, epithelial membrane antigen (EMA), CD10, and napsin A. Occasionally the lesions are incidentally encountered in the prostatic urethra, which may lead to a misdiagnosis as prostatic adenocarcinoma, clear cell adenocarcinoma or urothelial carcinoma of the urinary bladder. Herein we present a case of nephrogenic adenoma which has been incidentally found in a transurethral resection of a prostate specimen for the management of benign prostatic hypertrophy. The evaluation of morphology, immunohistochemistry, and differential diagnoses have also been discussed.

Clear cell carcinoma of the ovary and venous thromboembolism: a systematic review and meta-analysis.

OBJECTIVES: As the second most common subtype of Epithelial ovarian cancers (EOCs), ovarian clear cell carcinoma (OCCC) is associated with a high rate of cancer-associated thrombosis. Previous studies revealed the wide range prevalence (6-42%) of venous thromboembolism (VTE) among OCCC patients. This study aimed to determine the prevalence of VTE among OCCC patients as well as factors affecting it. METHODS: PubMed, Scopus, Embase, and Cochrane Library databases were searched up to December 12th, 2022. Studies reporting venous thromboembolic events in women with clear cell carcinoma of the ovary were included. Demographic data, clinical, and paraclinical features of the patients were independently extracted by two reviewers. RESULTS: Out of the 2254 records, 43 studies were processed for final review. The qualified studies involved 573 VTE cases among 2965 patients with OCCC. The pooled prevalence of VTE among OCCC patients was 21.32% (95%CI=(17.38-25.87)). Most VTE events were reported in Japanese women (26.15%), followed by Americans (24.41%) and UK (21.57%), and Chinese (13.61%) women. VTE was more common in patients with advanced stages (37.79%) compared to those with early stages of the disease (16.54%). CONCLUSIONS: Ovarian clear cell carcinoma is associated with a high rate of cancer-associated thrombosis. VTE events in OCCC patients were higher in advanced stages and Japanese women.

Ureteral Metastasis of Colonic Adenocarcinoma with Enteroblastic Differentiation: A Rare Case to be Distinguished from Clear Cell Adenocarcinoma of the Urinary Tract.

Adenocarcinomas with enteroblastic differentiation are rare clear cell tumors that are positive for enteroblastic markers. Enteroblastic differentiation is particularly uncommon in colorectal adenocarcinomas. Herein, we report a case of clear cell adenocarcinoma with enteroblastic differentiation in the sigmoid colon of a 38-year-old Japanese woman that metastasized to the lower left ureter. After neoadjuvant chemotherapy, the patient underwent low anterior resection. The tumor consisted of tubular, cribriform, and focal micropapillary proliferation of clear cells immunopositive for spalt-like transcription factor 4 (SALL4), glypican 3, and alpha-fetoprotein. Six months after the colonic resection, a tumor was found in the left lower ureter, which was resected. The ureteral tumor revealed clear cell adenocarcinoma, which was identical to the colonic tumor proliferating in the ureteral mucosa. Metastatic ureteral tumors are rare. We performed a literature search and found only 50 reported cases of ureteral metastases from colorectal cancer. Of these, only 10 metastatic tumors were identified in the ureteral mucosa. No case of ureteral metastasis of clear cell colorectal adenocarcinoma or colorectal adenocarcinoma with enteroblastic differentiation has been reported. Hence, it can be challenging to distinguish them from clear cell adenocarcinoma of the urinary tract and/or clear cell urothelial carcinoma. This paper discussed the differential diagnosis of these tumors and reviewed the clinicopathological features of colorectal carcinomas metastasizing to the ureter.

Survival outcomes and the prognostic significance of clinicopathological features in patients with endometrial clear cell carcinoma: a 35-year single-center retrospective study.

BACKGROUND: To evaluate the oncological outcomes and the impact of clinicopathological factors on endometrial clear cell carcinoma (ECCC) outcomes. METHODS: Medical records of patients with primary ECCC treated at our center between 1985 and December 2020 were reviewed. Overall survival (OS) and progression-free survival (PFS) were the endpoints. The Kaplan-Meier method and Cox regression analysis were used. RESULTS: In total, 156 patients were included, of whom 59% and 41% had early- and advanced-stage ECCC, respectively. The median age of onset was 61 years, and 80.8% of the patients were postmenopausal. Ninety-two (59%) and 64 (41%) patients had pure ECCC and mixed endometrial carcinoma with clear cell carcinoma (CCC) components, respectively. Mixed pathological components, elevated cancer antigen 125 levels, positive lymphovascular space invasion, deep myometrial invasion, and malignant peritoneal washing cytology (PWC) were more frequently observed in the advanced stage. Thirty-nine patients (25%) experienced relapse and 32 patients (20.5%) died. The 5-year PFS and OS rates for the entire cohort were 72.6% and 79%, respectively. Multivariate analysis showed that advanced-stage disease and positive PWC significantly decreased PFS, while advanced-stage disease and older age (> 61 years) significantly decreased OS. CONCLUSIONS: ECCC is a rare and aggressive type II endometrial carcinoma that is common in older women and patients with advanced-stage disease. Positive PWC was associated with decreased PFS, although its presence did not influence the stage. Positive PWC, and advanced stage and older age were independent negative prognostic factors.

Fertility-sparing radical resection of juvenile clear cell adenocarcinoma of the cervix by pneumovaginal endoscopic surgery.

Vaginoscopy has been mainly used diagnostically due to the lack of adequate equipment for performing complicated surgeries (Johary et al., 2015). However, herein, we report therapeutic vaginal endoscopic surgery (pneumovaginoscopy) for secondary malignant vaginal tumors using the vNOTES technique and devices (Kita et al., 2021, Yokoe et al., 2022). To our knowledge, this report and surgical video demonstrate the first case of successful fertility-sparing R0 tumor resection of a rare primary cervical clear cell adenocarcinoma using pneumovaginoscopy. A 12-year-old girl was referred to our outpatient clinic with a chief complaint of a genital tumor and possible clear cell carcinoma on biopsy. There was no history of diethylstilbestrol exposure. MRI and CT images suggested a polypoid cervical tumor without metastatic lesions. Therefore, we performed therapeutic pneumovaginoscopic surgery with diagnostic laparoscopy and hysteroscopy. The cervical tumor was resected completely, and hysteroscopy and laparoscopy revealed no abnormalities. The total surgical time was 123 min, and the blood loss volume was minimal. R0 resection was achieved microscopically. Postoperatively, we performed a partial cervical resection around the first surgical scar to confirm no residual tumor. There were no postoperative complications, and a 2-year follow-up revealed no recurrence. The standard treatment for early-stage cervical cancer (IA2-IB1) remains radical hysterectomy with pelvic lymphadenectomy. However, fertility-sparing minimally invasive surgery has recently been introduced for clear cell adenocarcinoma of the cervix (Su et al., 2020). Our report supports the possibility of this minimally invasive surgery under exceptional conditions. This study was approved by the ethics committee of Kansai Medical University. Written and signed informed consent was obtained from the patient's legal guardian.

Primary Clear Cell Adenocarcinoma of the Uterine Cervix in a 14-Year-Old Virgin Girl: Case Report.

Cervical cancer is rare in adolescent and pediatric populations, with adenocarcinoma being the most commonly reported. Clear cell adenocarcinoma of the uterine cervix accounts for only 4% of all adenocarcinoma cases, and about two-thirds are associated with intrauterine diethylstilbestrol (DES) exposure. We report the case of a 14-year-old virgin girl who presented with a 1-month-long history of abnormal vaginal bleeding and lower abdominal pain. Transabdominal pelvic ultrasound examination revealed the presence of an irregular, homogeneous cervical mass that was 7 cm in size. Therefore, a magnetic resonance imaging (MRI) scan was performed to establish the origin of the tumor and its relationship to adjacent pelvic organs. Furthermore, a vaginoscopy was performed to identify the tumor, and a cervical biopsy was performed. Immunohistochemical and anatomopathological studies resulted in the diagnosis of non-HPV(Human Papilloma Virus)-related clear cell adenocarcinoma of the cervix. Following the oncological examination, she was admitted for radiotherapy. The patient had no maternal history of DES exposure in utero. Even though the number of cases in the literature is low, most of the virgin girls diagnosed with clear cell adenocarcinoma of the cervix have a fatal prognosis because of the delay in making a correct diagnosis.

GATA3 expression in clear cell adenocarcinoma of the lower urinary tract: a potential diagnostic pitfall.

BACKGROUND: Clear cell adenocarcinoma of the lower urinary tract (CCACLUT) is a rare primary malignant neoplasm with heterogenous morphology. There is a paucity of data in the literature regarding its immunohistochemical profile. METHODS: The immunohistochemical features (extent and intensity) of a multinational cohort of CCACLUT were evaluated with comparison between clear cell adenocarcinoma of the female genital tract (CCACFGT, tissue microarray) and nephrogenic adenoma (NA). RESULTS: 33 CCACLUT (24 female, 9 male; mean age 59 years) were collected. CCACLUT most commonly arose from the urinary bladder (26/33, 78%), particularly from the trigone (10/33, 30.3%) followed by the urethra (8/33, 22%). All 12 NA cases were located at the urinary bladder, whereas the most common CCACFGT location was the ovary (29/56, 52%). None of the CCACLUT patients had, intestinal metaplasia, NA, or urothelial carcinoma. One patient had concurrent endometriosis of the sigmoid colon. Most frequently observed morphology in CCACLUT was papillary/tubulocystic (9/3; 27.3%), followed by papillary/tubular (6/33; 18.2%) and papillary/solid (5/33; 15.2%). GATA3 expression was significantly higher in CCACLUT (18/33, 54.5%) and NA (6/12, 50%), when compared to CCACFGT cases 6/56, 11.7%)(p = 0.001 and p = 0.022, respectively). The extent of GATA3 was significantly higher in CCACLUT group (19.2 ± 16.6%) than the other groups (9.6 ± 22.5% in NA and 2.6 ± 9% in CCACFGT group) (p = 0.001). 4/33 patients (12.1) had weak, 10/33 patients (30.3%) had moderate, and 4/33 patients (12.1%) had strong GATA3 intensity in CCACLUT group. In NA group, one patient (8.3%, 1/12) had weak, one patient (8.3%, 1/12) had moderate and 4 patients (33.3%, 4/12) had strong GATA3 intensity. Most cases (CCACLUT 29/33, 88%; NA 11/12, 92%; CCACFGT 46/56, 82.1%) had positive Napsin A expression, by which CCACLUT had significantly more cases with Napsin A expression (p = 0.034). p63 was consistently negative in all cases (30/33 (91.9%) CCACLUT; 12/12 (100%) NA; 42/56 (75%) CCACFGT. Ki67 (MIB) proliferation index was significantly higher in CCACLUT group (54.6 ± 21%) when compared to NA group (4.5 ± 2.7%) and CCACFGT group (35.5 ± 25.8%) (p = 0.001). CONCLUSION: CCACLUT has consistent GATA3 expression, which may cause challenge in the diagnosis of urothelial carcinoma but can be used to distinguish CCACLUT from CCACFGT.