Neoadjuvant nivolumab plus chemotherapy followed by resection for superior sulcus tumour with high PD-L1 expression: A case report.

The standard treatment for resectable non-small cell lung cancer (NSCLC) located in the superior sulcus is neoadjuvant chemoradiotherapy followed by highly invasive resection. Based on the results of the CheckMate 816 trial, which showed a marked improvement in the efficacy of neoadjuvant chemo-immunotherapy, we report a case of minimally invasive resection after neoadjuvant nivolumab plus chemotherapy for superior sulcus NSCLC, resulting in a pathologic complete response. The patient was a 76-year-old man with a 65-mm right superior sulcus tumour diagnosed as squamous cell carcinoma with 95% PD-L1. After two courses of neoadjuvant nivolumab plus chemotherapy, the tumour was completely resected through an 11-cm right lateral thoracotomy with second rib resection and first rib preservation. No residual tumour cells were observed in the specimen, and the patient had a pathologic complete response. This report represents a new treatment option for superior sulcus tumours.

Artificial Intelligence Detected the Relationship Between Nuclear Morphological Features and Molecular Abnormalities of Papillary Thyroid Carcinoma.

Papillary thyroid carcinoma (PTC) is the most common type of thyroid carcinoma and has characteristic nuclear features. Genetic abnormalities of PTC affect recent molecular target therapeutic strategy towards RET-altered cases, and they affect clinical prognosis and progression. However, there has been insufficient objective analysis of the correlation between genetic abnormalities and nuclear features. Using our newly developed methods, we studied the correlation between nuclear morphology and molecular abnormalities of PTC with the aim of predicting genetic abnormalities of PTC. We studied 72 cases of PTC and performed genetic analysis to detect BRAF p.V600E mutation and RET fusions. Nuclear features of PTC, such as nuclear grooves, pseudo-nuclear inclusions, and glassy nuclei, were also automatically detected by deep learning models. After analyzing the correlation between genetic abnormalities and nuclear features of PTC, logistic regression models could be used to predict gene abnormalities. Nuclear features were accurately detected with over 0.90 of AUCs in every class. The ratio of glassy nuclei to nuclear groove and the ratio of pseudo-nuclear inclusion to glassy nuclei were significantly higher in cases that were positive for RET fusions (p = 0.027, p = 0.043, respectively) than in cases that were negative for RET fusions. RET fusions were significantly predicted by glassy nuclei/nuclear grooves, pseudo-nuclear inclusions/glassy nuclei, and age (p = 0.023). Our deep learning models could accurately detect nuclear features. Genetic abnormalities had a correlation with nuclear features of PTC. Furthermore, our artificial intelligence model could significantly predict RET fusions of classic PTC.

Double Negativity of MRI-Detected and Pathologically-Diagnosed Extramural Venous Invasion is a Favorable Prognostic Factor for Rectal Cancer.

BACKGROUND: Extramural venous invasion (EMVI) is a prognostic factor in rectal cancer. There are two types: EMVI detected by magnetic resonance imaging (MRI) (mr-EMVI) and EMVI detected by pathology (p-EMVI). They have been separately evaluated, but they have not yet been concurrently evaluated. We therefore evaluate both mr-EMVI and p-EMVI in rectal cancer at the same time and clarify their association with prognosis. PATIENTS AND METHODS: Included were the 186 consecutive patients who underwent complete radical resection of tumors ≤ stage III at Wakayama Medical University Hospital, Japan, between 2010 and 2018. All underwent preoperative MRI examination, and were reassessed for EMVI by a radiologist. Surgically resected specimens were then reassessed for EMVI by a pathologist. We assessed the correlation between positivity of mr-EMVI and p-EMVI and prognosis, and the clinicopathological background behind them. RESULTS: Patients with double negativity for mr-EMVI and p-EMVI had better prognosis than patients with mr-EMVI or p-EMVI positivity (p < 0.0001). Positivity for mr-EMVI or p-EMVI was a poor independent prognostic factor in multivariate analysis. CONCLUSIONS: Combined analysis of mr-EMVI and p-EMVI may enable prediction of postoperative prognosis of rectal cancer. Patients with double negativity of mr-EMVI and p-EMVI had better prognosis than patients with some form of positivity. Stated differently, patients with positivity of mr-EMVI, p-EMVI, or both had a poorer prognosis than those with double negativity. Postoperative adjuvant chemotherapy may improve poor prognosis. Combined evaluation of mr-EMVI and p-EMVI may be used to predict clinical outcomes and may be an effective prognostic predictor of rectal cancer.

Clinicopathological and molecular features of renal cell carcinomas with haemangioblastoma-like features distinct from clear cell renal cell carcinoma.

AIMS: Haemangioblastomas arise in the central nervous system. Rarely, haemangioblastomas may develop in extra-neural sites, such as the kidneys. A few reported cases of renal cell carcinomas (RCCs) with haemangioblastoma-like features have exhibited both clear cell renal cell carcinoma (CCRCC)- and haemangioblastoma-like components. The clinicopathological and molecular characteristics of RCCs with haemangioblastoma-like features were analysed, focusing on VHL alterations, in comparison with CCRCCs partially resembling haemangioblastoma. METHODS AND RESULTS: Four RCCs with haemangioblastoma-like features and five CCRCCs partially resembling haemangioblastoma were included. The RCCs with haemangioblastoma-like features were indolent and lacked adverse prognostic factors. All RCCs with haemangioblastoma-like features had a well-circumscribed appearance and a thick fibromuscular capsule, with fibromuscular bundles extending into the tumour to varying degrees in the three tumours. Each RCC with haemangioblastoma-like features exhibited CCRCC-like areas with indistinct tubular structures and foci of haemangioblastoma-like areas, in which vessels and short spindle cells overwhelmed tumour cells. Whereas haemangioblastoma-like areas in the CCRCCs partially resembling haemangioblastoma exhibited sparse vessels and spindle cells and distinct clear cells. The RCCs with haemangioblastoma-like features exhibited a unique immunohistochemical profile, with positive staining for inhibin-α, S100, carbonic-anhydrase-9, keratin7, and high molecular weight keratin and negative staining for (alpha-methylacyl-CoA racemase) AMACR. RCC with haemangioblastoma-like features did not display any VHL alterations, including VHL mutation, 3p LOH, and methylation of the VHL promoter region, and the two tumours harboured a likely oncogenic missense variant of MTOR (c.7280T>G). CONCLUSION: The histopathological, immunohistochemical, and molecular findings suggest that RCC with haemangioblastoma-like features is a distinct entity from CCRCC.

Overlapping Atypical Hemolytic Uremic Syndrome and C3 Glomerulopathy with Mutation in CFI in a Japanese Patient: A Case Report.

A 34-year-old Japanese man presented with blurred vision, headache, nausea, anemia, thrombocytopenia, and severe renal dysfunction. Thrombotic microangiopathy was initially suspected to have been caused by malignant hypertension. Antihypertensive medications did not improve his thrombocytopenia or renal dysfunction, and other diseases causing thrombotic microangiopathy were ruled out. Therefore, the patient was diagnosed with atypical hemolytic uremic syndrome. A renal biopsy revealed an overlap of thrombotic microangiopathy and C3 glomerulopathy. Genetic testing revealed c.848A>G (p.Asp283Gly), a missense heterozygous variant in the gene encoding complement factor I. Overlapping atypical hemolytic uremic syndrome and C3 glomerulopathy with complement factor I mutation is very rare, especially in Japan.

Utility of contrast-enhanced harmonic endoscopic ultrasonography for prediction of pathological response after neoadjuvant chemotherapy in patients with pancreatic cancer.

OBJECTIVES: Contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) plays an important role in the diagnosis of pancreatic lesions. The aim of this study was to evaluate whether CH-EUS is useful for predicting the treatment efficacy of neoadjuvant chemotherapy (NAC) determined by pathological response. METHODS: Patients who underwent CH-EUS before chemotherapy and surgical resection were divided into two groups according to poor (group-P) or rich tumor vascularity (group-R) determined by enhancement pattern on early- and late-phase CH-EUS. The pathological response to chemotherapy was categorized according to Evans' classification. Pathological analysis showing tumor cell destruction (>50 %) defined a good response. RESULTS: Early-phase CH-EUS classified 44 patients into group-R and 50 into group-P, whereas late-phase CH-EUS classified 10 into group-R and 84 into group-P. Early-phase CH-EUS classification resulted in significantly higher numbers of patients with a good response in the rich group (n = 19) than in the poor group (n = 4; P = 0.0015). Multivariate analysis showed that assignment to the rich group was the strongest independent factor associated with chemosensitivity (P = 0.006, hazard ratio = 5.66, 95 % confidence interval: 1.17-19.27). In resectable patients, the enhancement pattern was the only independent factor associated with chemosensitivity (group-P vs. group-R, P = 0.003; HR [95 % CI], 14.59 [1.38-154.38]). Late-phase CH-EUS did not reveal a significant difference between group-P and group-R. CONCLUSIONS: Evaluation of vascular pattern on CH-EUS could be useful for predicting the efficacy of NAC in patients with pancreatic cancer. The enhancement pattern on CH-EUS could be a one of the useful features for determining NAC indications in resectable pancreatic cancer patients.

Current Knowledge and Prospects for Renal Hemangioblastoma and Renal Cell Carcinoma with Hemangioblastoma-like Features.

Tumors exhibiting histopathological findings similar to those of hemangioblastoma of the central nervous system (CNS-HB) rarely develop in the kidneys. Currently, renal hemangioblastoma (RHB) is considered analogous to CNS-HB; however, they differ in gross appearance, as well as immunohistochemical and molecular findings. In contrast, some renal cell carcinomas reportedly comprise distinct, clear cell renal cell carcinoma (CCRCC)- and hemangioblastoma (HB)-like areas. Initially, renal cell carcinomas with HB-like features (RCC-HBs) were considered a morphological variant of CCRCC owing to their diverse histological findings. However, the immunohistochemical and molecular findings of RCC-HBs suggest that RCC-HB is distinct from CCRCC. Additionally, one of the RCC-HBs had a focal leiomyomatous stroma and TSC2 variant, suggesting that RCC-HB and RCC with fibromyomatous stroma (RCC-FMS) might belong to the same disease entity. Therefore, we comprehensively reviewed the clinical, pathological, and molecular features of RHB, RCC-HB, and the related tumors and discussed the similarities, differences, and relationships between them. We believe that our review would serve as a foundation for further investigation on elucidating the relationship between CNS-HB, RHB, RCC-HB, and RCC-FMS.

Chondroma Arising from the Temporomandibular Joint: A Case Report.

Periarticular chondromas are common in the humerus and femur but rarely occur in the temporomandibular joint. We report a case of a chondroma in the anterior part of the ear. One year prior to his visit, a 53-year-old man became aware of swelling in the right cheek region which gradually increased in size. In the anterior part of the right ear, there was a palpable 25 mm tumor, elastic and hard, with poor mobility and without tenderness. A contrast-enhanced computed tomography CT showed a mass lesion with diffuse calcification or ossification in the upper pole of the parotid gland and areas of poor contrast within. A magnetic resonance imaging showed a low-signal mass lesion at the parotid gland with some high signals in both T1 and T2. Fine-needle aspiration cytology did not lead to diagnosis. Using a nerve monitoring system, the tumor was resected with normal tissue of the upper pole of the parotid gland in the same way as for a benign parotid tumor. Distinguishing between pleomorphic adenoma, including diffuse microcalcification of the parotid gland and cartilaginous tumors of the temporomandibular joint, may be sometimes difficult. In such cases, surgical resection may be a beneficial treatment option.

Papillary thyroid carcinoma with aggressive fused follicular and solid growth pattern: A unique histological subtype with high-grade malignancy?

Papillary thyroid carcinoma (PTC) is usually indolent; however, some rare subtypes of PTCs, such as columnar cell and hobnail subtypes, carry poor prognosis as an intermediate malignancy between differentiated carcinoma and anaplastic carcinoma. We present the case of a 56-year-old Japanese woman having PTC with aggressive behavior showing characteristic histological features of a predominantly fused follicular and focally solid (FFS) pattern. The fused follicular pattern is cribriform-like without intermingled vessels. This PTC with FFS pattern included frequent mitotic figures, necrosis, lymphovascular invasion, and metastases with high clinical stage. The tumor cells were broadly positive for antibodies to TTF-1, PAX8, and bcl-2, and negative for cyclin D1. Ki-67 labeling index was approximately 10%, and there was occasional positivity of p53. Targeted next generation sequencing analysis only detected a NRAS mutation (Q61K); there was no mutation and no translocation of other genes including BRAF and RET/PTC. To our knowledge, this is first report that PTC shows aggressive FFS growth pattern. The tumor is possibly included in the new category of differentiated high-grade thyroid carcinoma in the World Health Organization 2022 classification, or in a novel subtype of PTC owing to its characteristic histological feature and intermediate malignancy between differentiated carcinoma and anaplastic carcinoma.

Targeted Next-Generation Sequencing of Flat Urothelial Lesions Reveals Putative Pathobiological Pathways, Potential Biomarkers, and Rational Therapeutic Targets.

Flat urothelial lesions are controversial diagnostic and prognostic urologic entities whose importance relies mainly on their ability to progress to muscle-invasive tumors via urothelial carcinoma in situ (CIS). However, the carcinogenetic progression of preneoplastic flat urothelial lesions is not well established. Moreover, predictive biomarkers and therapeutic targets of the highly recurrent and aggressive urothelial CIS lesion are lacking. Using a targeted next-generation sequencing (NGS) panel of 17 genes directly involved in bladder cancer pathogenesis, we investigated alterations of genes and pathways with clinical and carcinogenic implications on 119 samples of flat urothelium, including normal urothelium (n = 7), reactive atypia (n = 10), atypia of unknown significance ( n = 34), dysplasia ( n = 23), and CIS (n = 45). The majority of the flat lesions were tumor-associated but grossly/microscopically or temporally separated from the main tumor. Mutations were compared across flat lesions and concerning the concomitant urothelial tumor. Associations between genomic mutations and recurrence after intravesical bacillus Calmette-Guerin treatment were estimated with Cox regression analysis. TERT promoter mutations were highly prevalent in intraurothelial lesions but not in the normal or reactive urothelium, suggesting that it is a critical driver mutation in urothelial tumorigenesis. We found that synchronous atypia of unknown significance-dysplasia-CIS lesions without concomitant papillary urothelial carcinomas had a similar genomic profile that differed from atypia of unknown significance-dysplasia lesions associated with papillary urothelial carcinomas, which harbored significantly more FGFR3, ARID1A, and PIK3CA mutations. KRAS G12C and ERBB2 S310F/Y mutations were exclusively detected in CIS and were associated with recurrence after bacillus Calmette-Guerin treatment (P = .0006 and P = .01, respectively). This targeted NGS study revealed critical mutations involved in the carcinogenetic progression of flat lesions with putative pathobiological pathways. Importantly, KRAS G12C and ERBB2 S310F/Y mutations were identified as potential prognostic and therapeutic biomarkers for urothelial carcinoma.

Use of Artificial Intelligence for the Interpretable Prediction of the Pathologic Diagnosis and Molecular Abnormalities of Flat Urothelial Lesions.

Flat urothelial lesions are important because of their potential for carcinogenesis and development into invasive urothelial carcinomas. However, it is difficult for pathologists to detect early flat urothelial changes and accurately diagnose flat urothelial lesions. To predict the pathologic diagnosis and molecular abnormalities of flat urothelial lesions from pathologic images, artificial intelligence with an interpretable method was used. Next-generation sequencing on 110 hematoxylin and eosin-stained slides of normal urothelium and flat urothelial lesions, including atypical urothelium, dysplasia, and carcinoma in situ, detected 17 types of molecular abnormalities. To generate an interpretable prediction, a new method for segmenting urothelium and a new pathologic criteria-based artificial intelligence (PCB-AI) model was developed. κ Statistics and accuracy measurements were used to evaluate the ability of the model to predict the pathologic diagnosis. The likelihood ratio test was performed to evaluate the logistic regression models for predicting molecular abnormalities. The diagnostic prediction of the PCB-AI model was almost in perfect agreement with the pathologists' diagnoses (weighted κ = 0.98). PCB-AI significantly predicted some molecular abnormalities in an interpretable manner, including abnormalities of TP53 (P = 0.02), RB1 (P = 0.04), and ERCC2 (P = 0.04). Thus, this study developed a new method of obtaining accurate urothelial segmentation, interpretable prediction of pathologic diagnosis, and interpretable prediction of molecular abnormalities.

A rare case of Pseudomonas aeruginosa enteritis induced by pembrolizumab.

A 72-year-old male had pseudomonal enteritis related to pembrolizumab. Chemotherapy for hypopharyngeal carcinoma with lung metastasis comprised cisplatin, 5-FU, and pembrolizumab. On day 14 of chemotherapy treatment he had a sudden prominent abdominal bulge, decreased consciousness, and drop in blood pressure in septic shock. CT scan showed marked intestinal gas through to intrahepatic bile ducts. Pseudomonas aeruginosa was simultaneously detected in both blood and stool cultures. Intestinal endoscopy revealed ulcerative lesions from the transverse colon to the rectum. Pathological investigations indicated apoptosis of the villus. The patient was diagnosed with pseudomonal enteritis induced by immune-related adverse events from the use of pembrolizumab. Treatment by corticosteroid and meropenem were subsequently switched to cefepime and metronidazole, and this successfully improved his colitis. In this new era of biological-targeted drugs and as clinical experience grows, we recommend a high level of alertness for potential diagnosis of infectious complications.

Pathologic Image Classification of Flat Urothelial Lesions Using Pathologic Criteria-Based Deep Learning.

OBJECTIVES: Pathologic diagnosis of flat urothelial lesions is subject to high interobserver variability. We expected that deep learning could improve the accuracy and consistency of such pathologic diagnosis, although the learning process is a black box. We therefore propose a new approach for pathologic image classification incorporating the diagnostic process of the pathologist into a deep learning method. METHODS: A total of 267 H&E-stained slides of normal urothelium and urothelial lesions from 127 cases were examined. Six independent convolutional neural networks were trained to classify pathologic images according to six pathologic criteria. We then used these networks in the main training for the final diagnosis. RESULTS: Compared with conventional manual analysis, our method significantly improved the classification accuracy of images of flat urothelial lesions. The automated classification showed almost perfect agreement (weighted κ = 0.98) with the consensus reading. In addition, our approach provides the advantages of reliable diagnosis corresponding to histologic interpretation. CONCLUSIONS: We used deep learning to establish an automated subtype classifier for flat urothelial lesions that successfully combines traditional morphologic approaches and complex deep learning to achieve a learning mechanism that seems plausible to the pathologist.

A novel missense mutation in the folliculin gene associated with the renal tumor-only phenotype of Birt-Hogg-Dubé syndrome.

Birt-Hogg-Dubé syndrome is an autosomal dominant disease caused by germline mutations in the folliculin gene (FLCN), characterized by skin fibrofolliculomas, pulmonary cysts, and multiple renal tumors. We report the case of a 51-year-old woman with multiple bilateral renal tumors resected by bilateral open partial nephrectomy. Following pathological diagnosis of hybrid oncocytic/chromophobe tumors, targeted next-generation sequencing of FLCN of the patient's blood revealed a novel missense mutation (c.602A>C, p.Gln201Pro) in exon 6. Sanger sequencing revealed that this mutation was heterozygous. In silico prediction programs consistently indicated the mutation as pathogenic. Western blot analysis and immunohistochemistry revealed suppressed FLCN expression and the upregulation of glycoprotein nonmetastatic B, a downstream target negatively regulated by FLCN, in the tumor tissue, suggesting that the mutation resulted in reduction of functional FLCN expression. Whole-genome sequencing of one of the tumors identified another frameshift mutation in exon 4, suggesting a "second hit" leading to tumorigenesis. We recommend that gene sequencing should be considered in patients with multiple renal tumors to identify their genetic predisposition to renal tumors.

Prognostic value of CD155/TIGIT expression in patients with colorectal cancer.

INTRODUCTION: The interaction of CD155 with its ligand, the T cell immunoreceptor with Ig and ITIM domains (TIGIT), is being studied owing to its potential to act as a target in the treatment of various solid tumors. However, the relationship between CD155 and TIGIT in colorectal cancer (CRC) prognosis is not known. We hypothesized that the TIGIT-CD155 pathway suppresses the attack of T cells on tumors, thereby affecting CRC prognosis. METHODS: We examined the expression of CD155 and TIGIT using immunohistochemical staining in 100 consecutive patients with CRC who underwent complete resection of ≤Stage III tumors at Wakayama Medical University Hospital between January and December 2013. We assessed the correlation between CD155 and TIGIT expressions and prognosis as well as the clinicopathological background of CD155 and TIGIT. RESULTS: Patients with high CD155 and TIGIT expressions showed worse prognosis than those with other levels of expression (p = 0.026). In multivariate analysis that also included the existing prognostic markers, high CD155 and TIGIT expressions were identified as independent poor prognostic factors. CONCLUSIONS: The interaction between CD155 and TIGIT possibly plays an important role in the immunological mechanism of CRC. Therefore, it may be possible to effectively predict the postoperative prognosis of CRC by evaluating the combined expression of CD155 and TIGIT. The study findings suggest that CD155 and TIGIT can predict clinical outcomes, thereby contributing to the personalized care of CRC.

Small cell variant of chromophobe renal cell carcinoma: Clinicopathologic and molecular-genetic analysis of 10 cases.

The morphologic diversity of chromophobe renal cell carcinoma (ChRCC) is well-known. Aside from typical morphology, pigmented adenomatoid, multicystic and papillary patterns have been described. Ten cases of CHRCC composed of small cell population in various percentages were analysed, using morphologic parameters, immunohistochemistry and next-generation sequencing (NGS) testing. Patients were five males and five females, with age ranging from 40 to 78years. The size of tumors ranged from 2.2 cm to 11 cm (mean 5.17 cm). Small cell component comprised 10 to 80% of the tumor volume, while the remaining was formed by cells with classic ChRCC morphology. The immunohistochemical profile of the small cell component was consistent with typical ChRCC immunophenotype, with CD117 and CK7 positivity. Neuroendocrine markers were negative. Mutations of 13 genes were found: DCIER1, FGFR3, JAK3, SUFO, FAM46C, FANCG, MET, PLCG2, APC, POLE, EPICAM, MUTYH and AR. However, only the PLCG2 mutation is considered pathogenic.The small cell variant of ChRCC further highlights and expand upon existing morphologic heterogeneity spectrum. Recognition of small cell variant of CHRCC is not problematic in tumors, where the "classic" CHRCC component is present. However, in limited material (i.e., core biopsy), this may present a diagnostic challenge. Based on the limited follow-up data available, it appears that the small cell tumor component had no impact on prognosis, since there was no aggressive behavior documented.   Awareness of this unusual pattern and applying additional sections to find classic morphology of ChRCC, as well as excluding neuroendocrine nature by immunohistochemistry, may help resolve difficult cases.

Clinicopathological and Molecular Characteristics of Macroscopically Yellowish-Colored Chromophobe Renal Cell Carcinoma Compared to Non-Yellowish-Colored Chromophobe Renal Cell Carcinoma.

Each histological variant of renal cell tumors has a unique color. The yellowish color of clear cell renal cell carcinoma (CCRCC) is explained by the presence of intracytoplasmic lipid and glycogen accumulation. Color changes in CCRCC are correlated with clinicopathological and metabolic changes, as well as biological behavior. We analyzed and compared the clinical, histopathological, and immunohistochemical features and gene expression profiles, in lipid metabolism of yellowish-colored ChRCC (ChRCC-Y), non-yellowish-colored ChRCC (ChRCC-N), and CCRCC. Of 14 ChRCCs, we retrieved 6 ChRCC-Ys. Patients with ChRCC-Y are younger than those with ChRCC-N, and the tumor is not predominant in males. ChRCC-Ys are smaller than ChRRC-Ns. Three ChRCC-Ys exhibited individual discrete tubule formation. No ChRCC-Ns exhibited individual discrete tubule formation. Two of 6 ChRCC-Ys showed relatively diffuse adipophilin positivity. No ChRCC-Ns demonstrated diffuse positivity for adipophilin. The expression of SCD, FDFT1, and E2F1 showed a tendency to be lower in ChRCC-Y than in ChRCC-N. The expression of PDGFB showed a tendency to be higher in ChRCC-Y than in ChRCC-N. This study demonstrated ChRCC-Y did not indicate an increase in lipid and cholesterol metabolism and that ChRCC-Y did not have the common molecular alteration of CCRCC. The absence of such metabolic acceleration in ChRCC-Y might support the biological indolent behavior. Furthermore, we revealed that macroscopic color changes might be correlated with various clinicopathological features and immunohistochemical and molecular changes from different perspectives. We believe further characterization of RCC, including tumor heterogeneity, is needed to improve the management of patients with RCC.

Disseminated carcinomatosis of the bone marrow caused by prostate cancer diagnosed with only bone marrow biopsy.

INTRODUCTION: Disseminated carcinomatosis of the bone marrow caused by prostate cancer is a rare condition with poor prognosis. Diagnosis has mostly been by primary prostate biopsy. CASE PRESENTATION: A 60-year-old man had malaise, low platelet count (9000/µL), and high prostate-specific antigen (1382 ng/mL). Bone marrow biopsy showed strongly positive immunostaining NKX3.1, leading to diagnosis of prostate cancer bone marrow metastasis, cT3aN1M1b. Definitive diagnosis by prostate biopsy was difficult because of the sparsity of atypical glands. He had progression to castration-resistant prostate cancer after 3 months of hormonal therapy, and received 27 courses of docetaxel and six courses of cabazitaxel as chemotherapy, but finally died of respiratory failure 33 months after the start of treatment. CONCLUSION: Aggressive biopsy of the metastatic sites should be considered if a prostate biopsy at the primary site cannot be diagnosed definitively.

Detection of HPV infection in urothelial carcinoma using RNAscope: Clinicopathological characterization.

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.