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The FIGO scheme is currently applied for tumor grading of endometrioid adenocarcinoma. The current report presents a series of ten cases of endometrioid carcinomas that when applying the FIGO grading does not fully convey the true biological nature of the disease. The squamous component of these tumors is malignant; it constitutes the predominant invasive component, and it often metastasizes to unconventional sites. Half of the cohort developed distant disease recurrence within 2 years, even those with early-stage disease. Somatic mutations were analyzed, targeting 101 genes in all ten cases, and mutations in PTEN, MMR, PIK3CA, ATM, RB1, and TP53 genes were detected, often multiple mutations in the same case. None of the cases revealed unique molecular signatures or previously unreported gene mutations. Immunohistochemical staining for beta-catenin showed aberrant nuclear staining in eight of ten cases and remaining two showed cytoplasmic and membranous staining. Aggressive behavior and unusual sites of metastases are observed in this series even in low-grade tumor. The FIGO grading on smaller samples may be deceptive for these cases. Even if FIGO is applied, the pathology report should emphasize the malignant squamous component and its potential significance so that the gynecologic oncology team can formulate appropriate adjuvant treatment upfront. This case series argues that this histology should be regarded as a high-grade endometrioid carcinoma and can show unusual metastatic patterns. Further research is needed with more cases within this histologic subtype to guide recommendations on adjuvant therapies for this aggressive tumor type. [ABSTRACT FROM AUTHOR]

Background: Renal pelvic urothelial carcinoma with multiple histological variants co-occurs with hydronephrosis and pyelonephritis extremely rarely. The diagnosis of renal pelvic urothelial carcinoma can be complicated by these conditions, leading to delayed or missed diagnosis or misdiagnosis. Case presentation: We report the evolutionary course of a rare case of renal pelvic urothelial carcinoma containing squamous and sarcomatoid differentiation associated with hydronephrosis and pyelonephritis in a low-functioning kidney. Preoperative clinical and imaging manifestations were highly suggestive of hydronephrosis and pyelonephritis; however, all corresponding therapeutic measures failed. Eventually, nephrectomy was performed, and postoperative pathological examination revealed renal pelvic urothelial carcinoma with squamous and sarcomatoid differentiation. Further residual ureter and bladder cuff resection was refused by the patient. Regular cisplatin-based postoperative chemotherapy and bladder perfusion were arranged, and cystoscopy and imaging examinations were performed regularly for follow-up. Conclusion: Hydronephrosis and pyelonephritis can mask the typical clinical and imaging manifestations of renal pelvic urothelial carcinoma. Renal pelvic malignancy should be considered in patients with intractable pyelonephritis and hydronephrosis. There is no standard treatment for renal pelvic carcinoma with multiple pathological types. Radical surgery is considered an appropriate option and should be performed as early as possible. Chemotherapy and immunotherapy may improve patient survival. [ABSTRACT FROM AUTHOR]

Urothelial carcinoma (UC) is prevalent, especially in elderly males. The high rate of recurrence, treatment regime, and follow-up monitoring make UC a global health and economic burden. Arsenic is a ubiquitous toxicant that can be found in drinking water, and it is known that exposure to arsenic is associated with UC development. Around 25% of diagnosed UC cases are muscle-invasive (MIUC) which have poor prognosis and develop chemoresistance, especially if tumors are associated with squamous differentiation (SD). The immortalized UROtsa cell line is derived from normal human urothelium and our lab has malignantly transformed these cells using arsenite (As3+). These cells represent a basal subtype model of MIUC and the tumors derived from the As3+-transformed cells histologically and molecularly resemble clinical cases of the basal subtype of MIUC that have focal areas SD and expression of the basal keratins (KRT1, 5, 6, 14, and 16). Our previous data demonstrate that KRT6 protein expression correlates to areas of SD within the tumors. For this study, we performed a lentiviral knockdown of KRT6 in As3+-transformed UROtsa cells to evaluate the effects on morphology, gene/protein expression, growth, colony formation, and cisplatin sensitivity. The knockdown of KRT6 resulted in decreased expression of the basal keratins, decreased growth, decreased colony formation, and increased sensitivity to cisplatin, the standard treatment for MIUC. The results of this study suggest that KRT6 plays a role in UC cell growth and is an exploitable target to increase cisplatin sensitivity for MIUC tumors that may have developed resistance to cisplatin treatment. [ABSTRACT FROM AUTHOR]

Introduction Local recurrence for upper tract urothelial carcinoma typically occurs within 2 years post‐surgery. We report a rare case of retroperitoneal recurrence as squamous cell carcinoma 10 years after nephroureterectomy. Case presentation A 67‐year‐old female was referred to our urology department for a left ureteral tumor. The surgical specimen of the laparoscopic left nephroureterectomy revealed urothelial carcinoma at the pT3 stage. Ten years post‐nephroureterectomy, magnetic resonance cholangiopancreatography revealed a mass lesion in the left retroperitoneum, a computed tomography‐guided biopsy revealed squamous cell carcinoma. Despite suspected distant metastases of other organ tumors, examinations such as digestive endoscopy and bronchoscopy did not reveal any tumor lesions. The patient was diagnosed with recurrent invasive urothelial carcinoma as a pathological feature of squamous cell carcinoma. Conclusion The decision‐making process for treating malignant tumors, such as in cases with recurrence as squamous cell carcinoma, can be challenging.

Abstract Background Renal pelvic urothelial carcinoma with multiple histological variants co-occurs with hydronephrosis and pyelonephritis extremely rarely. The diagnosis of renal pelvic urothelial carcinoma can be complicated by these conditions, leading to delayed or missed diagnosis or misdiagnosis. Case presentation We report the evolutionary course of a rare case of renal pelvic urothelial carcinoma containing squamous and sarcomatoid differentiation associated with hydronephrosis and pyelonephritis in a low-functioning kidney. Preoperative clinical and imaging manifestations were highly suggestive of hydronephrosis and pyelonephritis; however, all corresponding therapeutic measures failed. Eventually, nephrectomy was performed, and postoperative pathological examination revealed renal pelvic urothelial carcinoma with squamous and sarcomatoid differentiation. Further residual ureter and bladder cuff resection was refused by the patient. Regular cisplatin-based postoperative chemotherapy and bladder perfusion were arranged, and cystoscopy and imaging examinations were performed regularly for follow-up. Conclusion Hydronephrosis and pyelonephritis can mask the typical clinical and imaging manifestations of renal pelvic urothelial carcinoma. Renal pelvic malignancy should be considered in patients with intractable pyelonephritis and hydronephrosis. There is no standard treatment for renal pelvic carcinoma with multiple pathological types. Radical surgery is considered an appropriate option and should be performed as early as possible. Chemotherapy and immunotherapy may improve patient survival.

Abstract Background Clear cell odontogenic carcinoma (CCOC) is an odontogenic carcinoma characterized by sheets and islands of vacuolated and clear cells. The diagnosis of atypical CCOC can pose a challenge when tumor cells deviate from their characteristic clear morphology, even with the aid of genetic profiling for CCOC identification. Case presentation In this manuscript, we detailed the inaugural instance of a recurrently recurring clear cell odontogenic carcinoma (CCOC) with pronounced squamous differentiation in a 64-year-old male. The primary tumor in this individual initially displayed a biphasic clear cell phenotype. However, subsequent to the third recurrence, the clear tumor cells were entirely supplanted by epidermoid cells characterized by eosinophilic cytoplasm, vesicular chromatin, and prominent nucleoli. Notable aggressive attributes such as necrosis, conspicuous cytological malignancy, perineural dissemination, and vascular invasion were noted. Additionally, the tumor progressed to manifest lung metastases. The tumor cells exhibited positive immunoreactivity for AE1/AE3, KRT19, Pan-CK, EMA, P40, P63, CK34βE12, and P53, while they tested negative for CK35βH11, KRT7, S-100, and neuroendocrine markers. The Ki-67 proliferation index was calculated at an average of 15%. Furthermore, FISH analysis unveiled the presence of the EWSR1::ATF1 gene fusion. Conclusions This case illustrated a rare and aggressive case of CCOC characterized by significant squamous differentiation upon recurrence of the tumor.

Background: Clear cell odontogenic carcinoma (CCOC) is an odontogenic carcinoma characterized by sheets and islands of vacuolated and clear cells. The diagnosis of atypical CCOC can pose a challenge when tumor cells deviate from their characteristic clear morphology, even with the aid of genetic profiling for CCOC identification. Case presentation: In this manuscript, we detailed the inaugural instance of a recurrently recurring clear cell odontogenic carcinoma (CCOC) with pronounced squamous differentiation in a 64-year-old male. The primary tumor in this individual initially displayed a biphasic clear cell phenotype. However, subsequent to the third recurrence, the clear tumor cells were entirely supplanted by epidermoid cells characterized by eosinophilic cytoplasm, vesicular chromatin, and prominent nucleoli. Notable aggressive attributes such as necrosis, conspicuous cytological malignancy, perineural dissemination, and vascular invasion were noted. Additionally, the tumor progressed to manifest lung metastases. The tumor cells exhibited positive immunoreactivity for AE1/AE3, KRT19, Pan-CK, EMA, P40, P63, CK34βE12, and P53, while they tested negative for CK35βH11, KRT7, S-100, and neuroendocrine markers. The Ki-67 proliferation index was calculated at an average of 15%. Furthermore, FISH analysis unveiled the presence of the EWSR1::ATF1 gene fusion. Conclusions: This case illustrated a rare and aggressive case of CCOC characterized by significant squamous differentiation upon recurrence of the tumor. [ABSTRACT FROM AUTHOR]

Objectives The characterization of DNA polymerase epsilon (POLE) mutations has transformed the classification of endometrial endometrioid carcinomas (EECs), highlighting the need for efficient identification methods. This study aims to examine the relationship between distinct morphologic features—namely, squamous morules and squamous differentiation (SD), as well as β-catenin expression—and the POLE mutation status in endometrial cancer (EC). Methods Our study included 35 POLE-mutated (POLE mut) EC cases and 395 non-POLE mut EEC cases. Results Notably, we observed no presence of morules in POLE mut cases, while SD was identified in 20% of instances. Conversely, morules and SD were identified in 12.7% and 26.1% of non-POLE mut EC cases, respectively, with morules consistently linked to a POLE wild-type status. The nuclear β-catenin expression is typically absent in tumors with wild-type POLE (wt-POLE) status. Conclusions Our findings suggest that the presence of either morules or nuclear β-catenin expression in EEC could practically rule out the presence of POLE mutations. These morphologic and immunohistochemical features can be used as preliminary screening tools for POLE mutations, offering significant savings in time and resources and potentially enhancing clinical decision-making and patient management strategies. However, further validation in larger, multi-institutional studies is required to fully understand the implications of these findings on clinical practice. [ABSTRACT FROM AUTHOR]

Objectives: It is essential yet highly challenging to preoperatively diagnose variant histologies such as urothelial carcinoma with squamous differentiation (UC w/SD) from pure UC in patients with muscle-invasive bladder carcinoma (MIBC), as their treatment strategy varies significantly. We developed a non-invasive automated machine learning (AutoML) model to preoperatively differentiate UC w/SD from pure UC in patients with MIBC. Methods: A total of 119 MIBC patients who underwent baseline bladder MRI were enrolled in this study, including 38 patients with UC w/SD and 81 patients with pure UC. These patients were randomly assigned to a training set or a test set (3:1). An AutoML model was built from the training set, using 13 selected radiomic features from T2-weighted imaging, semantic features (ADC values), and clinical features (tumor length, tumor stage, lymph node metastasis status), and subsequent ten-fold cross-validation was performed. A test set was used to validate the proposed model. The AUC of the ROC curve was then calculated for the model. Results: This AutoML model enabled robust differentiation of UC w/SD and pure UC in patients with MIBC in both training set (ten-fold cross-validation AUC = 0.955, 95% confidence interval [CI]: 0.944–0.965) and test set (AUC = 0.932, 95% CI: 0.812–1.000). Conclusion: The presented AutoML model, that incorporates the radiomic, semantic, and clinical features from baseline MRI, could be useful for preoperative differentiation of UC w/SD and pure UC. Clinical relevance statement: This MRI-based automated machine learning (AutoML) study provides a non-invasive and low-cost preoperative prediction tool to identify the muscle-invasive bladder cancer patients with variant histology, which may serve as a useful tool for clinical decision-making. Key Points: • It is important to preoperatively diagnose variant histology from urothelial carcinoma in patients with muscle-invasive bladder carcinoma (MIBC), as their treatment strategy varies significantly. • An automated machine learning (AutoML) model based on baseline bladder MRI can identify the variant histology (squamous differentiation) from urothelial carcinoma preoperatively in patients with MIBC. • The developed AutoML model is a non-invasive and low-cost preoperative prediction tool, which may be useful for clinical decision-making. [ABSTRACT FROM AUTHOR]

Abstract Background Since the human papillomavirus vaccines do not eliminate preexisting infections, nonsurgical alternative approaches to cervical intraepithelial neoplasia (CIN) have been required. We previously reported that FOXP4 (forkhead box transcription factor P4) promoted proliferation and inhibited squamous differentiation of CIN1‐derived W12 cells. Since it was reported that FOXP expressions were regulated by the androgen/androgen receptor (AR) complex and AR was expressed on the CIN lesions, in this study we examined the effects of androgen on CIN progression. Methods Since AR expression was negative in W12 cells and HaCaT cells, a human male skin‐derived keratinocyte cell line, we transfected AR to these cell lines and investigated the effects of dihydrotestosterone (DHT) on their proliferation and squamous differentiation. We also examined the immunohistochemical expression of AR in CIN lesions. Results DHT reduced the intranuclear expression of FOXP4, attenuating cell proliferation and promoting squamous differentiation in AR‐transfected W12 cells. Si‐RNA treatments showed that DHT induced the expression of squamous differentiation‐related genes in AR‐transfected W12 cells via an ELF3‐dependent pathway. DHT also reduced FOXP4 expression in AR‐transfected HaCaT cells. An immunohistochemical study showed that AR was expressed in the basal to parabasal layers of the normal cervical epithelium. In CIN1 and 2 lesions, AR was detected in atypical squamous cells, whereas AR expression had almost disappeared in the CIN3 lesion and was not detected in SCC, suggesting that androgens do not act to promote squamous differentiation in the late stages of CIN. Conclusion Androgen is a novel factor that regulates squamous differentiation in the early stage of CIN, providing a new strategy for nonsurgical and hormone‐induced differentiation therapy against CIN1 and CIN2.

Purpose: Endometrial carcinoma with strong enhancement on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is suggestive of high-grade type II endometrial carcinoma. However, low-grade type I endometrial carcinoma may also sometimes show strong enhancement. We hypothesized that squamous differentiation would contribute to the strong enhancement at the early phase on DCE-MRI-like uterine cervical squamous cell carcinoma and compared the DCE-MRI findings of endometrial carcinoma with and without squamous differentiation. Methods: DCE-MRI of endometrial carcinoma including 41 low-grade type I endometrial carcinomas without squamous differentiation (LG), 39 low-grade type I endometrial carcinomas with squamous differentiation (LGSD), and 20 high-grade type II endometrial carcinomas (HG) was retrospectively evaluated. Results: Significant difference in the time–intensity curves was found between LG and HG and LG and LGSD, whereas no significant difference was seen between HG and LGSD. Curve type 3 (initial signal rise which is steeper than that of the myometrium) was more frequent in HG (60%) and LGSD (77%) than in LG (34%). Conclusion: It should be recognized as a pitfall that high-grade type II endometrial carcinoma and low-grade type I endometrial carcinoma with squamous differentiation may show similar early strong enhancement on DCE-MRI. [ABSTRACT FROM AUTHOR]

Bladder carcinoma is one of the most common urological malignancies with many rare histological variants associated with various prognosis. The recognition of these rare histological variants of bladder carcinoma may be helpful in selecting appropriate therapeutic approach and to predict the prognosis of the patients. We present three such rare entities of urothelial carcinoma with squamous differentiation, squamous cell carcinoma of bladder and metastatic bladder carcinoma which are associated with bad prognosis.

Pleomorphic adenoma is the most common benign salivary gland neoplasm principally affecting the parotid gland of the salivary gland and the palate of the minor salivary gland. The term pleomorphic is assigned due to its varied histopathological presentation. We hereby describe a rare case of pleomorphic adenoma in a male patient in his 7th decade of life complaining of swelling in the hard palate for the past 3 years. This case report emphasizes the unique representation of squamous and lipomatous differentiation which was erroneously diagnosed as OSCC or mucoepidermoid carcinoma. We have also included a literature search of such cases that exhibited lipomatous and squamous differentiation in PA listed from the last 10 years.

Histological and lineage immunofluorescence examination revealed that healthy conducting airways of humans and animals harbor sporadic poorly differentiated epithelial patches mostly in the dorsal noncartilage regions that remarkably manifest squamous differentiation. In vitro analysis demonstrated that this squamous phenotype is not due to intrinsic functional change in underlying airway basal cells. Rather, it is a reversible physiological response to persistent Wnt signaling stimulation during de novo differentiation. Squamous epithelial cells have elevated gene signatures of glucose uptake and cellular glycolysis. Inhibition of glycolysis or a decrease in glucose availability suppresses Wnt-induced squamous epithelial differentiation. Compared with pseudostratified airway epithelial cells, a cascade of mucosal protective functions is impaired in squamous epithelial cells, featuring increased epithelial permeability, spontaneous epithelial unjamming, and enhanced inflammatory responses. Our study raises the possibility that the squamous differentiation naturally occurring in healthy airways identified herein may represent “vulnerable spots” within the airway mucosa that are sensitive to damage and inflammation when confronted by infection or injury. Squamous metaplasia and hyperplasia are hallmarks of many airway diseases, thereby expanding these areas of vulnerability with potential pathological consequences. Thus, investigation of physiological and reversible squamous differentiation from healthy airway basal cells may provide critical knowledge to understand pathogenic squamous remodeling, which is often nonreversible, progressive, and hyperinflammatory. [ABSTRACT FROM AUTHOR]

Background: Since the human papillomavirus vaccines do not eliminate preexisting infections, nonsurgical alternative approaches to cervical intraepithelial neoplasia (CIN) have been required. We previously reported that FOXP4 (forkhead box transcription factor P4) promoted proliferation and inhibited squamous differentiation of CIN1‐derived W12 cells. Since it was reported that FOXP expressions were regulated by the androgen/androgen receptor (AR) complex and AR was expressed on the CIN lesions, in this study we examined the effects of androgen on CIN progression. Methods: Since AR expression was negative in W12 cells and HaCaT cells, a human male skin‐derived keratinocyte cell line, we transfected AR to these cell lines and investigated the effects of dihydrotestosterone (DHT) on their proliferation and squamous differentiation. We also examined the immunohistochemical expression of AR in CIN lesions. Results: DHT reduced the intranuclear expression of FOXP4, attenuating cell proliferation and promoting squamous differentiation in AR‐transfected W12 cells. Si‐RNA treatments showed that DHT induced the expression of squamous differentiation‐related genes in AR‐transfected W12 cells via an ELF3‐dependent pathway. DHT also reduced FOXP4 expression in AR‐transfected HaCaT cells. An immunohistochemical study showed that AR was expressed in the basal to parabasal layers of the normal cervical epithelium. In CIN1 and 2 lesions, AR was detected in atypical squamous cells, whereas AR expression had almost disappeared in the CIN3 lesion and was not detected in SCC, suggesting that androgens do not act to promote squamous differentiation in the late stages of CIN. Conclusion: Androgen is a novel factor that regulates squamous differentiation in the early stage of CIN, providing a new strategy for nonsurgical and hormone‐induced differentiation therapy against CIN1 and CIN2. [ABSTRACT FROM AUTHOR]

Abstract Background We report a surgical case of urothelial carcinoma of the renal pelvis, resulting in diagnostic difficulties on cytological examination. Case presentation A man in his late 70s underwent nephrectomy for giant hydronephrosis and renal cysts after nephrostomy and renal cyst puncture and drainage. On all cytological examinations performed before surgery, including nephrostomy urine, renal cyst fluid, catheterized bladder urine, and bladder washings, we were unable to make any conclusive diagnosis of malignancy. The pathological diagnosis of the surgical specimen concluded that this was a case of high-grade urothelial carcinoma of the renal pelvis with focal squamous differentiation (pT4). Liver and lung metastases were identified 3 months after surgery, and the patient died 2 months later. Conclusion It was very difficult to make a conclusive diagnosis using cytological specimens because of the presence of a small number of atypical cells with severe degenerative changes. Since clinicians cannot predict the potential for malignancy on preoperative imaging findings, it is critical to consider the difficulties in clinically making a correct diagnosis of urothelial carcinoma of the upper urinary tract, especially in cases complicated with giant hydronephrosis.

BACKGROUND:Papillary thyroid carcinoma with squamous differentiation (PTC-SD) is a poorly understood pathologic finding of unknown clinical significance. Selected case reports have suggested that PTC-SD is an aggressive tumor with a poor prognosis. Here we present the largest case series of PTC-SD reported in the United States. MATERIALS AND METHODS:The cancer registry at our tertiary care referral center was reviewed to identify all patients from 1995-2015 who had been diagnosed with PTC-SD on initial total thyroidectomy or lymph node dissection for recurrent disease. All cases were reviewed by an endocrine pathologist to confirm the diagnosis. Patient demographic, pathology, and outcomes data were collected and reviewed. RESULTS:During the study period, ten patients were diagnosed with PTC-SD, six in the primary tumor at the time of initial surgery, and four in lymph node metastases during surgery for recurrent disease. The median age at diagnosis was 56 y and half of the patients were male. Aggressive features such as multifocality (67%), extrathyroidal extension (67%), positive margin (89%), lymph node metastases (80%), and extranodal extension (60%) were far more prominent than is typically seen in classic PTC. Long-term follow-up (median 56.5 mo) demonstrated high rates of locoregional recurrence (60%), pulmonary metastases (30%), and mortality (10%). CONCLUSIONS:Squamous differentiation is a rare finding in PTC that is associated with aggressive pathologic features and poor long-term outcomes. This phenomenon may represent a step in progression toward dedifferentiation; thus, patients with PTC-SD should have close, life-long surveillance and should be treated according to evidence-based guidelines for high-risk thyroid cancers.

Introduction: The incidence of anaplastic transformation of thyroid cancer from Papillary Thyroid Carcinoma (PTC) is a rare tumor event, which ranges from 1 to 2 % of all cases of thyroid malignancy. Anaplastic transformation is often reported in primary lesions, but is rarely found in metastatic lesions from Differentiated Thyroid Carcinoma (DTC)., Presentation of Case: This case report reports a unique tumor process where a 70-year-old woman had a metastatic lesion in the Mandible from PTC which transformed into ATC with histological features resembling squamous cell carcinoma-type. Immunohistochemical examination was able to prove that the lesion in the Mandible is a type of undifferentiated Thyroid carcinoma (anaplastic) with a squamous pattern originating from PTC., Discussion: This type of tumor with histological variant images that resemble other types of tumors is a challenge for diagnosis and appropriate management, so understanding the variants of this type of ATC is important for better management., Conclusion: Although rare, anaplastic transformation can occur in metastatic sites of PTC. This necessitates the need for early accurate diagnosis through IHC assessment and somatic mutation testing so that appropriate treatment can be delivered., Competing Interests: Conflict of interest statement The authors declare no conflict of interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Although the human papillomavirus (HPV) vaccine is effective for preventing cervical cancers, this vaccine does not eliminate pre‐existing infections, and alternative strategies have been warranted. Here, we report that FOXP4 is a new target molecule for differentiation therapy of cervical intraepithelial neoplasia (CIN). An immunohistochemical study showed that FOXP4 was expressed in columnar epithelial, reserve, and immature squamous cells, but not in mature squamous cells of the normal uterine cervix. In contrast with normal mature squamous cells, FOXP4 was expressed in atypical squamous cells in CIN and squamous cell carcinoma lesions. The FOXP4‐positive areas significantly increased according to the CIN stages from CIN1 to CIN3. In monolayer cultures, downregulation of FOXP4 attenuated proliferation and induced squamous differentiation in CIN1‐derived HPV 16‐positive W12 cells via an ELF3‐dependent pathway. In organotypic raft cultures, FOXP4‐downregulated W12 cells showed mature squamous phenotypes of CIN lesions. In human keratinocyte‐derived HaCaT cells, FOXP4 downregulation also induced squamous differentiation via an ELF3‐dependent pathway. These findings suggest that downregulation of FOXP4 inhibits cell proliferation and promotes the differentiation of atypical cells in CIN lesions. Based on these results, we propose that FOXP4 is a novel target molecule for nonsurgical CIN treatment that inhibits CIN progression by inducing squamous differentiation. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to evaluate the prognosis of patients with T1N0M0 urothelial carcinoma with squamous differentiation (UCSD) or glandular differentiation (UCGD) because it has not been determined whether these variant histologies behave more aggressively than pure urothelial carcinoma (PUC). Patients and Methods: Ninety-nine patients diagnosed with pT1N0M0 bladder cancer and treated conservatively with transurethral resection of bladder tumor at Kanazawa University Hospital between 2007 and 2019 were included in this study. The overall survival, cancer-specific survival (CSS), and recurrence-free survival of the variant histology and PUC groups were evaluated and compared. Results: The variant histology group had significantly lower overall survival (p=0.006) and CSS (p=0.0095) than the PUC group did. Variant histology was found to be an independent prognostic factor in univariate and multivariate analyses for overall survival and CSS. On the other hand, no significant difference in progression-free survival was observed between the two groups (p=0.439). However, the variant histology group had significantly lower overall survival (p=0.004) and CSS (p=0.004) after progression. Conclusion: The prognosis for patients with pT1 bladder cancer with UCSD or UCGD treated conservatively with transurethral resection of bladder tumor was poor. Considering the worse prognosis of these patients after stage progression, early radical cystectomy could be recommended. [ABSTRACT FROM AUTHOR]

Abstract Background Human papillomavirus (HPV) is a well‐established mucosotropic carcinogen, but its impact on urothelial neoplasm is unclear. We aimed to clarify the clinical and pathological features of HPV‐related urothelial carcinoma (UC). Methods Tissue samples of 228 cases of UC were obtained from the bladder, upper and lower urinary tract, and metastatic sites to construct a tissue microarray. The samples were analyzed for the presence of HPV by a highly sensitive and specific mRNA in situ hybridization (RISH) technique (RNAscope) with a probe that can detect 18 varieties of high‐risk HPV. We also conducted immunohistochemistry (IHC) for a major HPV capsid antibody and DNA‐PCR. Results The HPV detection rates varied among the methods; probably due to low HPV copy numbers in UC tissues and the insufficient specificity and sensitivity of the IHC and PCR assays. The RISH method had the highest accuracy and identified HPV infection in 12 (5.2%) of the cases. The histopathological analysis of the HPV‐positive UC showed six cases of usual type UC, five cases of UC with squamous differentiation (UC_SqD), and one case of micropapillary UC. The HPV detection rate was six‐fold higher in the cases of UC_SqD than in the other variants of UC (odds ratio [OR] =8.9, p = 0.002). In addition, HPV infection showed a significant association with tumor grade (OR =9.8, p = 0.03) and stage (OR =4.7, p = 0.03) of UC. Moreover, the metastatic rate was higher in HPV‐positive than in negative UC (OR =3.4). Conclusion These data indicate that although the incidence of HPV infection in UC is low, it is significantly associated with squamous differentiation and poor prognosis. Furthermore, our observations show that RNAscope is an ideal method for HPV detection in UC compared with the other standard approaches such as IHC and PCR assays.

Abstract Background Primary ovarian serous carcinomas (OSC) with extensive squamous differentiation is a rare, and histological diagnostic criteria and biological behavior have not been fully established. We present an extremely rare case of primary OSC of the ovary with squamous differentiation. Case presentation A 58-year-old (gravidity 3, parity 2) female was admitted complaining of abdominal distention for 6 months. No apparent tumor in the cervix was found by a physical examination. Serum levels of cancer antigen 125 (CA125) was elevated (2723.0 IU/L). Macroscopically, a 7 cm tumor of the left uterine adnexa, a 5 cm tumor of the right adnexa, and a 3 cm tumor of the omentum were found. Histological and immunochemical tests confirmed a diagnosis of OSC with squamous differentiation. Debulking surgery with tumor resection was performed. The patient was subsequently received postoperative chemotherapy. Conclusions In summary, OSC with extensive squamous differentiation is a rare, and the inter- and intratumor heterogeneity may be the reason for this phenomenon. Histological diagnostic criteria and biological behavior have not been fully established because of the limited data.

Simple Summary: Homeobox (HOX) genes encode homeodomain proteins that regulate a wide range of molecular pathways. The homeodomain is highly conserved and binds to DNA. One exception is homeodomain-only protein (HOPX) that lacks DNA-binding capacity. HOPX plays a crucial role in development and its functional impairment is associated with a variety of diseases, including cancer. Loss of HOPX function occurs in a wide range of cancer types, where it functions as a tumor suppressor gene. Understanding the molecular mechanisms by which HOPX regulates carcinogenesis will likely lead to the development of new therapeutic approaches. Homeobox genes are master regulators of morphogenesis and differentiation by acting at the top of genetic hierarchies and their deregulation is associated with a variety of human diseases. They usually contain a highly conserved sequence that codes for the homeodomain of the protein, a specialized motif with three α helices and an N-terminal arm that aids in DNA binding. However, one homeodomain protein, HOPX, is unique among its family members in that it lacks the capacity to bind DNA and instead functions by interacting with transcriptional regulators. HOPX plays crucial roles in organogenesis and is expressed in both embryonic and adult stem cells. Loss of HOPX expression is common in cancer, where it functions primarily as a tumor suppressor gene. In this review, we describe the function of HOPX in development and discuss its role in carcinogenesis. [ABSTRACT FROM AUTHOR]

Background: We report a surgical case of urothelial carcinoma of the renal pelvis, resulting in diagnostic difficulties on cytological examination. Case presentation: A man in his late 70s underwent nephrectomy for giant hydronephrosis and renal cysts after nephrostomy and renal cyst puncture and drainage. On all cytological examinations performed before surgery, including nephrostomy urine, renal cyst fluid, catheterized bladder urine, and bladder washings, we were unable to make any conclusive diagnosis of malignancy. The pathological diagnosis of the surgical specimen concluded that this was a case of high-grade urothelial carcinoma of the renal pelvis with focal squamous differentiation (pT4). Liver and lung metastases were identified 3 months after surgery, and the patient died 2 months later. Conclusion: It was very difficult to make a conclusive diagnosis using cytological specimens because of the presence of a small number of atypical cells with severe degenerative changes. Since clinicians cannot predict the potential for malignancy on preoperative imaging findings, it is critical to consider the difficulties in clinically making a correct diagnosis of urothelial carcinoma of the upper urinary tract, especially in cases complicated with giant hydronephrosis. [ABSTRACT FROM AUTHOR]

Introduction Lymphoceles are sometimes formed after pelvic lymph node dissection. However, recurrence at lymphoceles has not been reported previously. Here, we report a case of rapid prognosis of the recurrence at a lymphocele after nephroureterectomy. Case presentation A 78‐year‐old man underwent retroperitoneoscopic radical nephroureterectomy with pelvic lymphadenectomy for left ureteral urothelial carcinoma. The histopathological diagnosis was high‐grade invasive urothelial carcinoma with squamous differentiation. Follow‐up computed tomography at 3 months postoperatively showed a lymphocele with a small solid component, in the left pelvic region. At 7 months postoperatively, he presented with severe fatigue, and computed tomography showed a solid tumor had replaced the lymphocele. Computed tomography‐guided biopsy was performed and histopathological diagnosis was squamous cell carcinoma. Conclusion This report provides support for possible recurrence at the lymphocele after nephroureterectomy. If lymphocele occurs after surgery for malignant disease, it is recommended to follow up with the possibility of recurrence in the lymphatic cysts in mind.

We compared oncologic outcomes of squamous cell carcinoma (SCC) and urothelial carcinoma with squamous differentiation (SqD). Patients with SqD were significantly more likely to have extravesical and nodal positive disease. The 5-year RFS for SCC and SqD were 77% and 59.8 %, respectively. Multivariate analysis identified advanced pT stage, nodal positive disease and SqD histology as independent predictors of 5-year RFS. Introduction: In this study we aim to compare clinicopathological characteristics and cancer specific survival between patients treated with radical cystectomy for pure squamous cell carcinoma (SCC) and urothelial carcinoma with squamous differentiation (SqD). Patients and Methods: We reviewed data of 1737 consecutive patients treated with radical cystectomy and urinary diversion between Januar y 2004 and Februar y 2014. Only patients with pure SCC or SqD were included in the analysis. Squamous differentiation was defined as intercellular bridges or keratinization in the tumor. Clinicopathological data and recurrence free survival (RFS) were compared between patients diagnosed with SCC and SqD. Results: SCC and SqD were found in 318 and 223 patients, respectively. Mean age was 57 ± 8.3 years in SCC and 58.8 ± 7.8 in SqD (P = .008). A higher proportion of female patients was observed in SCC group compared to SqD (31.8% vs. 22% P < .0001). Patients with SqD were more likely to have extravesical (58.3% vs. 46.2%: P = .006) and nodal positive disease (34.5% vs. 14.5%: P < .0001) than pure SCC patients. Bilharzial eggs were found in 61% of SCC vs. 46% of SqD (P = .001).; The median (IQR) follow up period for SCC and SqD was 63 (12-112) months and 23 months (9-74.7), respectively. The 5-year RFS for SCC and SqD were 77% and 59.8 %, respectively (P < .0001).; Multivariate cox regression analysis identified advanced pT stage (OR: 1.9, 95% CI: 1.3-2.86, P = .0001), nodal positive disease (OR: 1.6, 95% CI: 1.1-2.48, P = .01) and SqD histology (OR: 1.6, 95% CI: 1.14-2.31, P = .007 as independent predictors of 5-year RFS. Conclusion: Patient with SCC had significantly higher 5-year RFS in comparison to SqD. The higher rate of extravesical disease and lymph node metastasis in SqD patients is indicative of aggressive behavior of this histologic type. [ABSTRACT FROM AUTHOR]

The expression and prognostic role of programmed death ligand-1 (PD-L1) on tumor-infiltrating immune cells (TICs) has not been determined in urothelial carcinoma (UC) with variant histology. We retrospectively reviewed 90 patients (44 with micropapillary variant of UC (MPUC) and 46 with UC with squamous differentiation (UCSD)) who underwent radical cystectomy between January 2013 and December 2019. The expression of PD-L1 in TICs was measured using the VENTANA (SP-142) immunohistochemistry assay and dichotomized using a 5% cutoff value (positive ≥ 5%). Kaplan–Meier survival analysis was used to estimate recurrence-free survival (RFS), and multivariable Cox proportional hazard models were used to identify factors predicting tumor recurrence. Overall, positive PD-L1 expression in TICs was confirmed in 50 of 90 (55.6%) patients (40.1% (18/44) of MPUC and 69.9% (32/46) of UCSD). RFS was significantly shorter in patients with positive PD-L1 expression in TICs than in those with negative PD-L1 expression both in MPUC (p = 0.005) and UCSD (p = 0.046). Positive PD-L1 expression in TICs was significantly associated with an increased risk of tumor recurrence in both MPUC (HR = 1.85; 95% CI: 1.323–2.672; p = 0.017) and UCSD (HR = 1.58; 95% CI: 1.162–2.780; p = 0.032). In conclusion, positive PD-L1 expression in TICs was significantly associated with poorer RFS in both MPUC and UCSD patients. Our results support the use of adjuvant immunotherapy in these patients if they test positive for PD-L1 in their TICs. [ABSTRACT FROM AUTHOR]

Adamantinoma is a locally aggressive or malignant tumor, accounting for <0.5% of all primary bone tumors. The tumor usually progresses slowly, with a relatively promising prognosis. Primary or metastatic spinal adamantinoma of bone are rarer. Only four cases have been documented till date. We present two cases of aggressive spinal adamantinoma whose microphotography and radiographic appearance were unusual, with extensive involvement of multiple segments and rapid progression. Case 1 was a 36-year-old woman, presenting with back pain, progressive numbness and motor weakness, who was diagnosed with metastatic adamantinoma in the T2, T7, L2, and L4. She underwent spondylectomy three times to resect these lesions, respectively. Case 2 was a 68-year-old male with complaints of severe left back pain. MRI revealed destructive changes in T1-T4. He underwent posterior decompression (T1-T3), partial vertebrectomy (T2), fixation and fusion (C5-C7, T4-T6). The pathology of two patients was metastatic spinal adamantinoma, whose primary lesions were from tibia and femoral adamantinoma, respectively. Rapid squamous progression was observed in specimens of T2 and T7 lesions of Case 1 in two months. Twenty-five months after surgery, Case 1 developed paralysis, but she refused to receive further examination and treatment. Two months after surgery, Case 2 presented with an upper back pain again. The MRI revealed an increase in osseous destruction and paravertebral mass size. He was administered radiotherapy, with his upper back pain partially relieved. The biological behavior of classic adamantinoma is highly unpredictable, often exhibiting more aggressive behavior upon recurrence or metastasis. The pathological diagnosis of adamantinoma should be confirmed by preoperative biopsy. En bloc resection with a wide margin is the preferred treatment for primary spinal adamantinoma. Radiation therapy can partially relieve the pain. [ABSTRACT FROM AUTHOR]

Epithelial myoepithelial carcinoma (EMC) is an uncommon low-to-intermediate grade salivary gland malignancy that accounts for 1% of all tumors arising in salivary glands. About 80% of these tumors affect the parotid gland. These lesions either arise de novo or from existing pleomorphic adenoma (PA). Histologically, these tumors reveal a biphasic cell population with inner ductal epithelial cells and peripheral myoepithelial cells. There are many histologic variants of EMC, but sebaceous, verocay-like differentiation and high-grade transformation is very rarely reported. This article describes a 48-year-old female patient diagnosed with EMC ex PA with unique histologic differentiation. [ABSTRACT FROM AUTHOR]

Adamantinoma is a locally aggressive or malignant tumor, accounting for

Adamantinoma-like Ewing sarcoma is a rare variant of Ewing sarcoma with histologic and immunohistochemical evidence of squamous differentiation. This variant most commonly occurs in the head and neck region with a few cases reported in the long bones of the limbs. It may be associated with poorer clinical outcome and could pose a diagnostic challenge, particularly if it occurs in older patients or as a metastatic lesion. We present a case of Ewing sarcoma in the metatarsal of an 11-year-old boy that manifested adamantinoma-like morphology after neoadjuvant chemotherapy. Chemotherapy has been reported to induce neuronal maturation and rhabdoid morphology in cases of Ewing sarcoma, but no reports of treatment-induced squamous differentiation with P40/P63 expression have been demonstrated. This is also the first documented case treated with a pedicled osteocutaneous fibular transfer in a metatarsal malignancy, which is usually treated by either ray or below-knee amputation. [ABSTRACT FROM AUTHOR]

Background: Human papillomavirus (HPV) is a well-established mucosotropic carcinogen, but its impact on urothelial neoplasm is unclear. We aimed to clarify the clinical and pathological features of HPV-related urothelial carcinoma (UC). Methods: Tissue samples of 228 cases of UC were obtained from the bladder, upper and lower urinary tract, and metastatic sites to construct a tissue microarray. The samples were analyzed for the presence of HPV by a highly sensitive and specific mRNA in situ hybridization (RISH) technique (RNAscope) with a probe that can detect 18 varieties of high-risk HPV. We also conducted immunohistochemistry (IHC) for a major HPV capsid antibody and DNA-PCR. Results: The HPV detection rates varied among the methods; probably due to low HPV copy numbers in UC tissues and the insufficient specificity and sensitivity of the IHC and PCR assays. The RISH method had the highest accuracy and identified HPV infection in 12 (5.2%) of the cases. The histopathological analysis of the HPVpositive UC showed six cases of usual type UC, five cases of UC with squamous differentiation (UC_SqD), and one case of micropapillary UC. The HPV detection rate was six-fold higher in the cases of UC_SqD than in the other variants of UC (odds ratio [OR] =8.9, p = 0.002). In addition, HPV infection showed a significant association with tumor grade (OR =9.8, p = 0.03) and stage (OR =4.7, p = 0.03) of UC. Moreover, the metastatic rate was higher in HPV-positive than in negative UC (OR =3.4). Conclusion: These data indicate that although the incidence of HPV infection in UC is low, it is significantly associated with squamous differentiation and poor prognosis. Furthermore, our observations show that RNAscope is an ideal method for HPV detection in UC compared with the other standard approaches such as IHC and PCR assays. [ABSTRACT FROM AUTHOR]

Gastric-type adenocarcinoma (GAS) of the cervix is a human papilloma virus (HPV)–independent, aggressive, and chemo-resistant adenocarcinoma. However, although the histopathological features of GAS have been extensively investigated, squamous differentiation has not been mentioned. This study aimed to elucidate the frequency of GAS with squamous differentiation and describe their clinicopathological characteristics. We retrospectively evaluated 78 patients with GAS (n = 13) and adenosquamous carcinoma (n = 65) diagnosed between 2000 and 2020. Two patients with GAS with squamous differentiation were identified. Both tumors showed advanced stage (pT2bN1) and had predominant GAS and merged squamous cell carcinoma components without p16-block positivity and HPV DNA. Gastric-type adenocarcinoma in situ was confirmed in both cases. Some cases of GAS could show squamous differentiation mimicking the usual, HPV-associated, adenosquamous carcinoma. GAS with squamous differentiation is recognized as an HPV-independent cancer. [ABSTRACT FROM AUTHOR]

Background: Primary ovarian serous carcinomas (OSC) with extensive squamous differentiation is a rare, and histological diagnostic criteria and biological behavior have not been fully established. We present an extremely rare case of primary OSC of the ovary with squamous differentiation.Case Presentation: A 58-year-old (gravidity 3, parity 2) female was admitted complaining of abdominal distention for 6 months. No apparent tumor in the cervix was found by a physical examination. Serum levels of cancer antigen 125 (CA125) was elevated (2723.0 IU/L). Macroscopically, a 7 cm tumor of the left uterine adnexa, a 5 cm tumor of the right adnexa, and a 3 cm tumor of the omentum were found. Histological and immunochemical tests confirmed a diagnosis of OSC with squamous differentiation. Debulking surgery with tumor resection was performed. The patient was subsequently received postoperative chemotherapy.Conclusions: In summary, OSC with extensive squamous differentiation is a rare, and the inter- and intratumor heterogeneity may be the reason for this phenomenon. Histological diagnostic criteria and biological behavior have not been fully established because of the limited data. [ABSTRACT FROM AUTHOR]

Endometrial endometrioid carcinoma (EEC) represents approximately 75-80% of endometrial carcinoma cases. Three hundred and thirty-six patients with EEC followed-up in the authors’ medical center between 2010 and 2018 were included in our study. Two hundred and seventy-two low and intermediate EEC patients were identified using the European Society for Medical Oncology criteria and confirmed by histopathological examination. Recurrence was reported in 17 of these patients. The study group consisted of patients with relapse. A control group of 51 patients was formed at a ratio of 3:1 according to age, stage, and grade, similar to that in the study group. Of the 17 patients with recurrent disease, 13 patients (76.5%) were Stage 1A, and 4 patients (23.5%) were Stage 1B. No significant difference was found in age, stage, and grade between the case and control groups (p > 0.05). Body mass index, parity, tumor size, lower uterine segment involvement, SqD, and Ki-67 index with p

Primary prostate squamous cell malignancies are rare and very aggressive. A 65-year-old man presented to our institution with clinical and radiographic findings concerning for advanced prostatic malignancy. Surgical pathology of the tumor revealed poorly differentiated carcinoma with squamous differentiation, and histopathological markers were positive for markers of squamous differentiation negative for all urothelial and prostatic markers.

The expression and prognostic role of programmed death ligand-1 (PD-L1) on tumor-infiltrating immune cells (TICs) has not been determined in urothelial carcinoma (UC) with variant histology. We retrospectively reviewed 90 patients (44 with micropapillary variant of UC (MPUC) and 46 with UC with squamous differentiation (UCSD)) who underwent radical cystectomy between January 2013 and December 2019. The expression of PD-L1 in TICs was measured using the VENTANA (SP-142) immunohistochemistry assay and dichotomized using a 5% cutoff value (positive ≥ 5%). Kaplan–Meier survival analysis was used to estimate recurrence-free survival (RFS), and multivariable Cox proportional hazard models were used to identify factors predicting tumor recurrence. Overall, positive PD-L1 expression in TICs was confirmed in 50 of 90 (55.6%) patients (40.1% (18/44) of MPUC and 69.9% (32/46) of UCSD). RFS was significantly shorter in patients with positive PD-L1 expression in TICs than in those with negative PD-L1 expression both in MPUC (p = 0.005) and UCSD (p = 0.046). Positive PD-L1 expression in TICs was significantly associated with an increased risk of tumor recurrence in both MPUC (HR = 1.85; 95% CI: 1.323–2.672; p = 0.017) and UCSD (HR = 1.58; 95% CI: 1.162–2.780; p = 0.032). In conclusion, positive PD-L1 expression in TICs was significantly associated with poorer RFS in both MPUC and UCSD patients. Our results support the use of adjuvant immunotherapy in these patients if they test positive for PD-L1 in their TICs.

Objective: To evaluate the effect of variant histology on pathological and survival findings in patients undergoing radical cystectomy due to muscle invasive bladder cancer. Materials and methods: Data from 146 patients with radical cystectomy performed due to muscle-invasive urothelial carcinoma between January 2006 to November 2016 at our clinic were investigated. The preoperative and postoperative data of patients with variant histology were compared with nonvariant urothelial carcinoma patients. Then of patients with variant histology only those with squamous differentiation (SqD) were compared with nonvariant urothelial carcinoma patients in terms of preoperative, postoperative and survival data. Results: Of the 146 patients, 23 had carcinoma with variant histology. Of these, 17 had SqD, 4 had glandular differentiation, 1 patient had plasmocytoid variant and 1 patient had sarcomatoid variant. In patients with variant histology, postoperative T stage and upstaging was higher, with no difference observed in terms of overall and cancer-specific survival compared with nonvariant urothelial cancer patients. SqD patients were observed to have higher postoperative T stage compared to nonvariant urothelial cancer patients, with no significant difference observed in terms of survival. Conclusions: In cystectomy pathologies, patients with variant histology (especially SqD patients) were observed to have proportionally higher T stage compared to nonvariant urothelial carcinoma; however there were no significant differences for overall survival and cancer-specific survival.

Purpose: Urothelial carcinoma with squamous differentiation (UCSD) is the most common histologic variant in bladder cancer (BCa). Previously, some studies have linked the presence of UCSD with the risk of worse survival outcomes in BCa patients. However, such association is still controversial. In this study, we performed a meta-analysis to clarify the clinicopathological characteristics and to further investigate the prognostic value of UCSD in BCa. Methods: A systematic literature search was performed in electronic databases including PubMed, Embase, Chinese National Knowledge Infrastructure and Wanfang Data until October 2018. Subgroup analyses were performed according to different treatments and study outcomes. Results: Total of 13,284 patients were enrolled in 19 studies which were included in this meta-analysis. The percentage of female patients with UCSD was significantly higher than those with pure urothelial carcinoma. UCSD was correlated with tumor stage T3/T4, tumor grade 3, positive surgical margin, and lymph node involvement. Moreover, the recurrence rate was higher in patients with UCSD after surgery. UCSD was associated with poorer disease-free survival (DFS). No significant difference of cancer-specific survival (CSS) or overall survival (OS) was found on multivariable analysis between the two groups. Conclusions: Our study demonstrated that UCSD in BCa was associated not only with unfavorable clinicopathological features, but also with high risk of recurrence and poorer prognosis for DFS. However, UCSD is not independently significant for CSS and OS. Well-designed randomized study with larger sample size is warranted to verify the findings and to further explore the role of UCSD in BCa. [ABSTRACT FROM AUTHOR]

Abstract Background The independent prognostic role of squamous differentiation in pT1 bladder urothelial carcinoma has not been reported in previous studies. This article describes the impact of squamous differentiation on tumor recurrence and survival, and whether this histologic variant could indeed alter definitive treatment, based on single center-based retrospective data. Methods Totally, we retrieved (1)1449 histologically confirmed pT1 bladder urothelial carcinoma patients without histologic variants; (2)227 pT1 bladder urothelial carcinoma patients with squamous differentiation in our institution, from May 2004 to Oct 2015. The total amount of high/low grade urothelial carcinoma patients was 991/685 respectively. Transurethral resection of bladder tumor (TURBT) and intravesical chemotherapy were performed as initial treatments for all the patients. The clinical and pathological characteristics, treatment and survival outcomes were compared between squamous differentiation-positive and squamous differentiation-negative patients. Results In our study, 14% urothelial carcinoma patients were detected with squamous differentiation. The mean age of all the patients examined was 66.4, of whom 82% were males. The 5-year cancer specific survival rates were 69% for squamous differentiation-positive patients and 91% for squamous differentiation-negative patients (p

Background: The programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway is a potent negative regulator of T-cell-mediated immune response that is upregulated in many neoplasms. Pancreaticobiliary adenosquamous carcinoma (PB-ASC) is an aggressive cancer that carries a poorer prognosis compared with pure pancreaticobiliary adenocarcinoma (PB-AC). To date, there is little published information regarding PD-L1 expression in PB-ASC. The aim of the study was to examine the relationship between PD-L1 expression and tumor-infiltrating lymphocytes in PB-ASC and PB-AC., Methods: We evaluated 15 PB-ASCs (10 pancreatic, 5 gallbladder) and 34 control PB-ACs (22 pancreatic ductal, and 12 gallbladder) for tumor expression of PD-L1 using anti-PD-L1 (E1L3N) antibody. All tumors were classified into three immune phenotypes: immune inflamed (II), immune excluded (IE), and immune desert (ID) according to the distribution of tumor-infiltrating lymphocytes in tumor tissues., Results: The frequency of PD-L1 expression was significantly higher in PB-ASC (10/15; 66.7%) than in PB-AC (3/34; 8.8%). In PB-ASC, PD-L1 expression occurred exclusively in the squamous component in six cases, exclusively in the glandular component in one case, and in both the squamous and the glandular components in three cases. PD-L1 expression in PB-ASC was irrespective of the tumor immune status, whereas its expression in PB-AC was observed only in tumors with the II or IE phenotype. The ID phenotype was relatively rare (4/15; 26.7%) in PB-ASC compared with PB-AC (22/34; 65%; P=0.02)., Conclusions: PB-ASCs are notably enriched in inflammatory response and showed significantly higher PD-L1 expression than PB-AC (P<0.001), suggesting a potential therapeutic role for immune checkpoint inhibitors in managing patients with PB-ASC., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-9/coif). The authors have no conflicts of interest to declare., (2024 Journal of Gastrointestinal Oncology. All rights reserved.)

Sustained expression of FOXM1 is a hallmark of nearly all human cancers including squamous cell carcinomas of the head and neck (HNSCC). HNSCCs partially preserve the epithelial differentiation program, which recapitulates fetal and adult traits of the tissue of tumor origin but is deregulated by genetic alterations and tumor‐supporting pathways. Using shRNA‐mediated knockdown, we demonstrate a minimal impact of FOXM1 on proliferation and migration of HNSCC cell lines under standard cell culture conditions. However, FOXM1 knockdown in three‐dimensional (3D) culture and xenograft tumor models resulted in reduced proliferation, decreased invasion, and a more differentiated‐like phenotype, indicating a context‐dependent modulation of FOXM1 activity in HNSCC cells. By ectopic overexpression of FOXM1 in HNSCC cell lines, we demonstrate a reduced expression of cutaneous‐type keratin K1 and involucrin as a marker of squamous differentiation, supporting the role of FOXM1 in modulation of aberrant differentiation in HNSCC. Thus, our data provide a strong rationale for targeting FOXM1 in HNSCC. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Arsenic is an environmental toxicant with long-term exposure associated with the development of urothelial carcinomas. Our lab has developed an in-vitro model of urothelial carcinoma by exposing the immortal, but non-tumorigenic bladder cell line, the UROtsa, to arsenite (As3+). These transformed cells form tumors in immune-compromised mice, which resemble urothelial carcinomas with components of the tumor exhibiting squamous differentiation. The goal of the present study was to determine the differences in global gene expression patterns between the As3+-transformed UROtsa cells and the urospheres (spheroids containing putative cancer initiating cells) isolated from these cell lines and to determine if the genes involved in the development of squamous differentiation were enriched in the urospheres. The results obtained in this study show an enrichment of genes such as KRT1, KRT5, KRT6A, KRT6B, KRT6C, KRT14 and KRT16 associated with squamous differentiation, a characteristic feature seen in aggressive basal subtypes of urothelial cell carcinoma (UCC) in the urospheres isolated from As3+-transformed UROtsa cells. In addition, there is increased expression of several of the small proline-rich proteins (SPRR) in the urospheres and overexpression of these genes occur in UCC's displaying squamous differentiation. In conclusion, the cancer initiating cells present in the urospheres are enriched with genes associated with squamous differentiation. • UROtsa cells transformed with arsenite show areas of squamous differentiation. • Urospheres are enriched in squamous differentiation and keratinization genes. • There is lack of stability in the urosphere gene expression pattern. • Epigenetic regulation does not play a role in maintaining urosphere gene expression. [ABSTRACT FROM AUTHOR]

Highlights • Cadmium is found in tobacco smoke and linked to smoke-related respiratory diseases. • Cadmium impaired cilia function in a human air-liquid-interface airway tissue model. • Cadmium induced aberrant mucins expression and secretion. • Cadmium induced oxidative stress, release of cytokines and matrix metalloproteinases. • Cadmium initiated squamous differentiation in this in vitro airway tissue model. Abstract Cadmium (Cd) is found at high concentrations in tobacco smoke due to its volatility when tobacco is burned. Inhaled Cd is linked to smoking-related respiratory diseases, such as chronic obstructive pulmonary disease and lung cancer. Alterations in mucociliary clearance, squamous metaplasia, and carcinoma are commonly observed in the respiratory tract of animals exposed to Cd. In vitro cell models widely used to study mechanisms underlying Cd toxicity are not suitable for studying its effects on mucociliary clearance and airway tissue remodeling. Herein we assess Cd-induced functional and structural changes in a well-differentiated human air-liquid-interface (ALI) airway tissue model. Acute treatments with Cd induced aberrant expression and secretion of mucins, impaired cilia functions, and squamous differentiation, and produced persistent oxidative stress and enhanced release of pro-inflammatory cytokines and matrix metalloproteinases. Accumulation of intracellular Cd was associated with sustained oxidative stress and inflammation, which, in turn, may have initiated squamous differentiation in ALI cultures. These observations demonstrate that ALI airway tissue models can recapitulate the functional and structural alterations in Cd-exposed animals, suggesting their potential application for studying tissue responses related to respiratory toxicants like those present in tobacco smoke. [ABSTRACT FROM AUTHOR]

Tumors of urinary origin are infrequently reported in non‐human primates. Urothelial carcinoma involving the urinary bladder was diagnosed in an adult female Japanese macaque that extended transmurally to the uterus and cervix. To our knowledge, this is the first report of a primary cystic urothelial carcinoma in a Japanese macaque. [ABSTRACT FROM AUTHOR]