Pembrolizumab-induced Acute Tubulointerstitial Nephritis Accompanying Fanconi Syndrome and Type 1 Renal Tubular Acidosis.

Pembrolizumab, an immune checkpoint inhibitor, is used to treat a variety of refractory malignancies. However, these agents are sometimes associated with immune-related adverse events. A 71-year-old woman received pembrolizumab-integrated chemotherapy to treat her recurrent mandibular gingival cancer. Five months after stopping pembrolizumab, she developed acute tubulointerstitial nephritis associated with Fanconi syndrome and type 1 renal tubular acidosis, which resolved with steroid therapy. We experienced a case of pembrolizumab-induced Fanconi syndrome and type 1 renal acidosis. We recommend follow-up of the tubular function in addition to the renal function even after discontinuation of pembrolizumab.

Pituitary apoplexy in endocrinologically silent adenoma during somatostatin analog administration for pancreatic neuroendocrine tumor: A case report.

A dopamine agonist administered for prolactinoma treatment and pituitary stimulation tests are reported as risk factors for pituitary apoplexy. We report a case of an 82-year-old patient who suffered from pituitary apoplexy in an endocrinologically silent adenoma during lanreotide administration. The patient was diagnosed with a pancreatic neuroendocrine tumor with lymph node metastasis and treated with lanreotide for two years. An endoscopic endonasal transsphenoidal approach was used for tumor and hematoma removal. The specimen showed growth hormone and prolactin positivity and was diagnosed as pit1-lineage plurihormonal adenoma. The tumor also showed positivity for somatostatin receptor 2. Thus, lanreotide treatment is a risk factor for pituitary apoplexy even in silent adenoma.

Sebaceous adenoma occurring within an intracranial dermoid cyst.

Among intracranial cystic lesions, dermoid cysts and epidermoid cysts are relatively common benign tumors. In a small number of these tumors, it is known that squamous cell carcinomas arise in the lining epithelium of the cysts. Among tumors derived from the appendage, only one case of hidradenoma within a dermoid cyst and no cases of sebaceous tumor have been reported previously. In the present case, a protruding lesion was present in the cystic wall, and it was composed of two cell types: sebaceous cells (sebocytes) and basaloid/germinated cells, being characteristic of this tumor. It is essential to distinguish it from other sebaceous lesions such as hyperplasia, sebaceoma, sebaceous carcinoma, and basal cell carcinoma with sebaceous differentiation derived from the epidermis. The critical distinguishing points in making a differential diagnosis among these lesions are the ratio of the two cell types and the presence or absence of other components such as hair sacs, invasion or cellular atypia. Immunohistochemical examination revealed that the tumor cells were positive for the epithelial markers, such as cytokeratin (CK)14, p63, p40, high-molecular CK, and adipophilin; these findings are peculiar to sebaceous adenoma. Although there have been several similar case reports of sebaceous tumors associated with dermmoid cysts in the ovaries, most of the intracranial lesions were squamous cell carcinomas that developed within the cysts, and there has been no precedent showing an association with a sebaceous tumor. The present report describes the first case of sebaceous adenoma that occurred in an intracranial dermoid cyst.

A Case of Dedifferentiated Melanoma With Lymph Node Metastasis Where Molecular Biological Tests Were Useful for Diagnosis.

Malignant melanoma is known to have an altered phenotype and loss of differentiation markers for melanoma due to metastasis. Here, we report a case in which the expression of the immunohistochemical markers for melanoma was changed due to lymph node metastasis of primary cutaneous malignant melanoma. The patient, a male in his 60s, was diagnosed with malignant melanoma after undergoing excision of a skin mass. The additional excision specimen showed a small number of tumor cell clusters infiltrating the dermis. The biopsied lymph node showed completely different histological findings from those of the skin lesion and consisted of spindle-shaped tumor cells. An immunohistochemical study revealed no significant positive reactions in the lymph node tissue indicative of melanoma. The additional genetic study revealed BRAF V600e mutations in both the primary tumor and a lymph node. Together with the histological findings, the diagnosis was of metastasis of dedifferentiated melanoma to a lymph node. In summary, there is a risk of underestimation or misdiagnosis of melanoma as undifferentiated sarcoma or other tumors when melanoma metastasizes to lymph nodes and findings show a dedifferentiated or undifferentiated tumor. Therefore, as in this case, it is necessary to add a genetic study in order to make a comprehensive judgment.

The potential diagnostic significance of crypt differentiation in gastric dysplasia.

AIMS: This study investigated the relationship between the differentiation of tumour cells into crypts, which is determined by cell differentiation into Paneth and neuroendocrine cells, and tumour infiltration in gastric dysplasia. METHODS AND RESULTS: The lesions were endoscopically biopsied low-grade dysplasia (LGD), endoscopically resected high-grade dysplasia (HGD) or cancer with submucosal invasion. LGD (n = 32) displayed crypt differentiation across the entire width of the tumour in all cases. Crypt differentiation was identified as a characteristic of tumours with low biological malignancy. HGD (n = 40) included tumours with a mixture of areas with and without crypt differentiation (n = 25) and tumours with crypt differentiation throughout the entire width (n = 15). Of the cancers with submucosal invasion (n = 30), the morphological progression of the HGD area with crypt differentiation, the HGD area without crypt differentiation and invasive cancer without crypt differentiation was confirmed for 23 samples. In two lesions, invasive cancer without crypt differentiation developed from HGD without crypt differentiation throughout the tumour width. In five samples, well-differentiated tubular adenocarcinoma with crypt differentiation developed from HGD with crypt differentiation and invaded with lamina propria-like stroma. CONCLUSIONS: Loss of crypt differentiation could be an objective indicator of infiltration in the progression of HGD to invasive cancer. The invasive potential of dysplasia depends upon the presence or absence of crypt differentiation.

Protein-losing Enteropathy Complicated with Primary Intestinal Follicular Lymphoma.

Protein-losing enteropathy (PLE) is a rare syndrome characterized by hypoproteinemia due to gastrointestinal (GI) protein loss. Primary intestinal follicular lymphoma (PIFL), a specific variant of follicular lymphoma with essential only GI involvement, has not been reported as an etiology of PLE. We herein report a case of PLE complicated with PIFL that was successfully treated with rituximab, resulting in rapid improvement of PLE and a complete response of PIFL. Macroscopic findings of ulcerative lesions with diffuse involvement, which were precisely described by capsule and double-balloon enteroscopy at the diagnosis, also improved following the treatment. This case provides a clue suggesting factors that promote PLE in PIFL.

Interleukin-32 regulates downstream molecules and promotes the invasion of pancreatic cancer cells.

Pancreatic cancer is a malignant neoplasm with high invasiveness and poor prognosis. In a previous study, a highly invasive pancreatic cancer cell line was established and found to feature enhanced interleukin-32 (IL-32) expression. However, whether IL-32 promotes the invasiveness by enhancing or suppressing the expression of IL-32 through regulating downstream molecules was unclear. To investigate the effect of IL-32, cells were established with high levels of expression or downregulated IL-32; their invasive ability was measured using a real-time measurement system and the expression of some candidate downstream molecules involved in invasion was evaluated in the two cell types. The morphological changes in both cell types and the localization of IL-32 expression in pancreatic cancer tissues were studied using immunohistochemistry. Among the several splice variants of IL-32, cells transfected with the ε isoform had increased invasiveness, whereas the IL-32-suppressed cells had reduced invasiveness. Several downstream molecules, whose expression was changed in the two cell types, were monitored. Notably, changes of E-cadherin, CLDN1, CD44, CTGF and Wnt were documented. The morphologies of the two cell types differed from the original cell line. Immunohistochemically, the expression of IL-32 was observed only in tumor cells and not in normal pancreatic cells. In conclusion, IL-32 was found to promote the invasiveness of pancreatic cancer cells by regulating downstream molecules.

Utility of Ethylene-Diamine-Tetraacetic Acid Buffer Solution With Boric Acid for Immunostaining of Specimens Stored for an Extended Period.

Antigen modification and denaturation are recognized causes of false negatives in immunostaining. Specimens that have been stored for an extended period at room temperature show decreased immunoreactivity and may mislead the diagnosis. Studies of the molecular targeting of drugs often involve immunostaining of previous samples and, in some situations, only unstained specimens can be used. The present study aimed to develop an effective staining method to recover antigen activation in unstained specimens stored for an extended period by using ethylene-diamine-tetraacetic acid (EDTA) buffer solution with boric acid. We compared several commonly used antigen retrieval solutions and found that Tris-borate-EDTA (TBE) buffer solution with a pH ≥8.3 provided sufficient antigen retrieval. However, pH values higher than 8.3 (9.0, 10.0, and 11.0) frequently caused severe tissue damage. Thus, TBE with pH 8.3 was the most suitable antigen retrieval solution for recovering the antigenicity of specimens stored for an extended period. This procedure may allow useful immunohistochemical information, even from sections that have been stored for an extended period.

Effect of Continuous Feeding of Ayu-Narezushi on Lipid Metabolism in a Mouse Model of Metabolic Syndrome.

Ayu-narezushi, a traditional Japanese fermented food, comprises abundant levels of lactic acid bacteria (LAB) and free amino acids. This study aimed to examine the potential beneficial effects of ayu-narezushi and investigated whether ayu-narezushi led to improvements in the Tsumura Suzuki obese diabetes (TSOD) mice model of spontaneous metabolic syndrome because useful LAB are known as probiotics that regulate intestinal function. In the present study, the increased body weight of the TSOD mice was attenuated in those fed the ayu-narezushi-comprised chow (ayu-narezushi group) compared with those fed the normal rodent chow (control group). Serum triglyceride and cholesterol levels were significantly lower in the Ayu-narezushi group than in the control group at 24 weeks of age. Furthermore, hepatic mRNA levels of carnitine-palmitoyl transferase 1 and acyl-CoA oxidase, which related to fatty acid oxidation, were significantly increased in the ayu-narezushi group than in the control group at 24 weeks of age. In conclusion, these results suggested that continuous feeding with ayu-narezushi improved obesity and dyslipidemia in the TSOD mice and that the activation of fatty acid oxidation in the liver might contribute to these improvements.

Renal Cell Carcinoma on the Native Kidney Following Kidney Transplantation.

A 48-year-old man with histories of IgA nephropathy for 33 years, hemodialysis for 29 years, and a kidney transplant from a deceased donor 5 years ago was admitted to our institute complaining of high fever and back pain. Although repeated follow-up of computed tomography failed to detect any de novo issues, he was eventually diagnosed as a renal cell carcinoma with multiple metastases, developing from his native-acquired cystic disease kidney with multiple cysts using a positron emission tomography. We should be cautious of de novo renal cell carcinoma in kidney transplantation recipients, and careful follow-up might be helpful to detect it.

Diagnosis by molecular pathology of an early and atypical histoplasmosis lesion in the duodenum of an immunocompromised patient: A case report.

Histoplasmosis is a fungal infection caused by Histoplasma capsulatum (HC), which can occasionally be aggressive resulting in the formation of granulomatous lesions. These are usually located in the lungs; however, immunocompromised patients may occasionally develop disseminated lesions in other organs as well. Human immunodeficiency virus (HIV) primarily infects cells of the immune system expressing CD4 molecules. Not only does HIV multiply within these cells, but it can also kill them or otherwise cause loss of cellular function, leading to an immunocompromised state. As a result, in an immunocompromised patient, infection with HC can have serious implications, often the development of visceral histoplasmosis in different organs. Although several types of lesions are formed in HC-infected organs, it may be difficult to distinguish the causative organism from other pathogens based on morphology alone. The present case report describes the case of a 57-year-old woman, from South America, who may have been infected with HC >20 years previously, remaining asymptomatic over the years. She later developed a lesion in the duodenum associated with immunodeficiency caused by HIV infection. The differential diagnosis of this case was made on the basis of several specific morphological findings using histopathological analysis and molecular pathological techniques. The pathogenesis of characteristic lesions caused by HC in the presence of HIV infection was also reviewed.

Establishment of highly invasive pancreatic cancer cell lines and the expression of IL-32.

Compared to tumors of other organs, pancreatic cancer is highly aggressive; with one of its biological features being that, despite a prominent fibrotic stroma, there is remarkable infiltration of tumor cells. This characteristic is considered to be the main reason for the poor prognosis of patients with pancreatic cancer. Therefore, in order to elucidate the factors that contribute to this high invasiveness, a selective invasion method was used to establish four highly invasive subclones from six human pancreatic cancer cell lines. The results demonstrated that two cell lines did not exhibit enhanced invasiveness. Microarray analysis revealed that, in the highly invasive cell lines, several genes were expressed at high levels, compared with the original cell lines. These highly expressed genes were recognized only in highly invasive cells. Among them, IL-32 was most strongly upregulated in the highly invasive cells, compared with cells with a low invasive potential, as well as the original cells. RT-qPCR and western blot analysis confirmed the high levels of expression of IL-32 in highly invasive cells at the RNA and protein levels. In addition, immunohistochemical analysis of resected surgical materials revealed that the tumor cells expressed IL-32 and, in particular, many IL-32 positive cells were seen at the invasive front of the tumor tissue. IL-32 is a cytokine that is widely involved in the development of cancer and has recently received considerable attention. This cytokine has multiple splice variants and shows a wide variety of behaviors, depending on the tumor type and primary organ. Although some hypotheses have been proposed to explain the activity of IL-32, a unified view has not been agreed. In the present study, through the establishment of highly invasive cells from pancreatic cancer and a comprehensive gene analysis, it is suggested that IL-32 may serve an important role as a molecule involved in the invasiveness of this neoplasm.

Risk factors for spontaneous miscarriage above 12 weeks or premature delivery in patients undergoing cervical polypectomy during pregnancy.

BACKGROUND: It currently remains unknown whether the resection of cervical polyps during pregnancy leads to miscarriage and/or preterm birth. This study evaluated the risk of spontaneous PTB below 34 or 37 weeks and miscarriage above 12 weeks in patients undergoing cervical polypectomy during pregnancy. METHODS: This was a retrospective monocentric cohort study of patients undergoing cervical polypectomy for clinical indication. Seventy-three pregnant women who underwent polypectomy were selected, and risk factors associated with miscarriage above 12 weeks or premature delivery below 34 or 37 weeks were investigated. A multivariable regression looking for predictors of spontaneous miscarriage > 12 weeks and PTB < 34 or 37 weeks were performed. RESULTS: Sixteen patients (21.9%, 16/73) had spontaneous delivery at < 34 weeks or miscarriage above 12 weeks. A univariate analysis showed that bleeding before polypectomy [odds ratio (OR) 7.7, 95% confidence interval (CI) 1.6-37.3, p = 0.004], polyp width ≥ 12 mm (OR 4.0, 95% CI 1.2-13.1, p = 0.005), the proportion of decidual polyps (OR 8.1, 95% CI 1.00-65.9, p = 0.024), and polypectomy at ≤10 weeks (OR 5.2, 95% CI 1.3-20.3, p = 0.01) were significantly higher in delivery at < 34 weeks than at ≥34 weeks. A logistic regression analysis identified polyp width ≥ 12 mm (OR 11.8, 95% CI 2.8-77.5, p = 0.001), genital bleeding before polypectomy (OR 6.5, 95% CI 1.2-55.7, p = 0.025), and polypectomy at ≤10 weeks (OR 5.9, 95% CI 1.2-45.0, p = 0.028) as independent risk factors for predicting delivery at < 34 weeks. Polyp width ≥ 12 mm and bleeding before polypectomy are risk factors for PTB < 37 wks. CONCLUSIONS: Our cohort of patients undergoing polypectomy in pregnancy have high risks of miscarriage or spontaneous premature delivery. It is unclear whether these risks are given by the underlying disease, by surgical treatment or both. This study establishes clinically relevant predictors of PTB are polyp size> 12 mm, bleeding and first trimester polypectomy. PTB risks should be exposed to patients and extensively discussed with balancing against the benefits of intervention in pregnancy.

Three cases of clear-cell adenocarcinoma arising from endometrioma during hormonal treatments.

Endometrioma is known to be an occurrence site of ovarian cancer, but there is no evidence on how to reduce the risk of canceration. Here, we report three cases of ovarian cancer arising from endometrioma during hormone therapies of GnRH analogue and tamoxifen, low-dose estrogen-progestin (LEP) and dienogest. In all cases, each hormonal treatment was effective in shrinking the size of the endometrioma. During hormonal treatments, solid parts inside endometrioma were observed, which was followed by surgery. The histology of the solid parts was clear-cell adenocarcinoma in all cases. An immunohistochemistry study demonstrated that the estrogen receptor (ER) and progesterone receptor (PR) were positive in the endometriosis part but negative in the cancer part, while the human EGF receptor (HER) 2 was negative or very weak in the benign part and positive in the malignant part in all three cases. Even though hormonal treatments seem to be effective to regulate endometrioma, careful observation is needed to follow-up patients with endometrioma.

Endoglin (CD105) and SMAD4 regulate spheroid formation and the suppression of the invasive ability of human pancreatic cancer cells.

In this study, we investigated the ability of pancreatic cancer cell lines to form spheroids with the aim of identifying factors involved in cell invasiveness, a property that leads to a poor prognosis in pancreatic cancer. For this purpose, 8 cell lines derived from human pancreatic cancer tissues were cultured in non-adherent culture conditions to form spheroids, as well as normal monolayers. The morphology of the cells was observed and spheroid diameters measured. mRNA expression was compared between cells cultured under both culture conditions. The gene knockdown of endoglin (ENG) and SMAD4, components of the transforming growth factor-ß (TGF-ß) signaling system, using siRNAs was conducted in spheroids in order to identify affected protein signaling factors, determine the morphological changes occurring over time and to measure the invasive capacity of the cells constituting spheroids. The cell lines exhibited differences in their spheroid-forming abilities. The expression of SMAD4 and ENG concomitantly increased in the cells that formed spheroids. SMAD4 was transported into the nucleus when spheroids were formed. The expression of ENG was decreased in the cells in which SMAD4 was knocked down; by contrast, the expression of BMP and activin membrane-bound inhibitor (BAMBI) and noggin (NOG), further components of the TGF-ß signaling system, increased. In the cells in which ENG was knocked down, the decreased mRNA expression of TGF-ß receptor type 2 (TGFBR2) and SMAD9 was observed, as well as a change in the expression of pSMAD1/5/9, and a tendency of spheroids to decrease in size. Spheroids cultured on Matrigel exhibited a tendency towards a reduction in size over time, as well as a tendency to invade into the Matrigel. In particular, the cells in which ENG was knocked down exhibited spheroids which were reduced in size, and also exhibited an increase in invasiveness, and a decrease in adhesiveness. Thus, our data indicate that in pancreatic cancer cells, the expression of ENG may be controlled by a pathway mediated by SMAD4. In addition, ENG was found to be related to the spheroid-forming ability of cells and to be involved in the invasive capacity of pancreatic cancer cells.

Primary peri-implant oral intra-epithelial neoplasia/carcinoma in situ: a case report considering risk factors for carcinogenesis.

BACKGROUND: Major risk factors for oral squamous cell carcinoma (SCC) are tobacco smoking, a betel quid chewing habit, and heavy alcohol consumption. However, around 15% of oral SCCs cannot be explained by these risk factors. Although oral SCC associated with dental implants is quite rare, there has been a recent gradual accumulation of reports about it. Here, we report a case of primary peri-implant oral intra-epithelial neoplasia/carcinoma in situ (OIN/CIS) in a woman without the major risk factors for oral SCC. CASE PRESENTATION: A 65-year-old woman was referred to our clinic with a tumor in the right lower gingiva. She had no history of tobacco smoking and only drank socially. Ten years previously, mandibular right posterior teeth had been replaced with an implant-supported porcelain-fused-to-metal restoration in a dental clinic. About 7 years later, she noticed swelling on the lingual side of the gingiva around the implant-supported restoration, and was eventually referred to our clinic with the suspicion of a neoplasia around the dental implant. The upper part of the implant body was exposed on the implant corresponding to the first molar of the right side of the mandible; this was associated with painless, elastic soft, and relatively well circumscribed gingival swelling on the lingual site. A panoramic radiograph showed slight vertical bone resorption around the implants. An incisional biopsy was conducted under the suspicion of neoplasia. Pathological microscopic examination of the biopsy specimen revealed thickened squamous epithelia with slight nuclear atypism and disorders of the epithelial rete pegs. Immunohistochemical findings showed positive staining for keratin 17 and a negative staining mosaic pattern for keratin 13. High p53, p63, and Ki-67 reactivity was also observed. From these findings, OIN/CIS of the gingiva was pathologically diagnosed, and a wide local excision with rim resection of the mandible, including the implants, was performed. The pathological findings for the resected specimen were same as those for the biopsy specimen. After 1 year of follow-up, there was no evidence of recurrence. CONCLUSION: In this case, prolonged peri-implant mucositis or peri-implantitis may have been a plausible risk factor for carcinogenesis.

Complete Resolution of Pseudomalignant Erosion in a Reflux Gastroesophageal Polyp with Proton Pump Inhibitor.

Pseudomalignant erosion is a diagnostic pitfall for pathologists in the differential diagnosis of malignant neoplasms. Here, we present a challenging case of a biopsy specimen from the eroded head of a polyp at the esophagogastric junction. A malignant neoplasm could not be ruled out due to the presence of bizarre stromal cells. A second biopsy performed after the administration of a proton pump inhibitor (PPI) for 4 weeks revealed endoscopic resolution of the polyp along with the complete histological resolution of the bizarre stromal cells and led to the diagnosis of pseudomalignant erosion in a reflux gastroesophageal polyp. In conclusion, histological and endoscopic response to PPI therapy is an important clue for the correct diagnosis of reflux gastroesophageal polyps with pseudomalignant erosion.

The liver in itai-itai disease (chronic cadmium poisoning): pathological features and metallothionein expression.

Cadmium (Cd) is a highly hepatotoxic heavy metal, which is widely dispersed in the environment. Acute Cd hepatotoxicity has been well studied in experimental animals; however, effects of prolonged exposure to Cd doses on the liver remain unclear. In the present study, to evaluate chronic Cd hepatotoxicity, we examined specimens from cases of itai-itai disease, the most severe form of chronic Cd poisoning. We compared 89 cases of itai-itai disease with 27 control cases to assess Cd concentration in organs. We also examined 80 cases of itai-itai disease and 70 control cases for histopathological evaluation. In addition, we performed immunohistochemistry for metallothionein, which binds and detoxifies Cd. Hepatic Cd concentration was higher than Cd concentration in all other organs measured in the itai-itai disease group, whereas it was second highest following renal concentration in the control group. In the liver in the itai-itai disease group, fibrosis was observed at a significantly higher rate than that in the control group. Metallothionein expression was significantly higher in the itai-itai disease group than that in the control group. Prolonged exposure to low doses of Cd leads to high hepatic accumulation, which can then cause fibrosis; however, it also causes high expression of metallothionein, which is thought to reduce Cd hepatotoxicity.