[A case of mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) diagnosed by re-biopsy of the enlarged primary tumor during chemotherapy for gastric adenocarcinoma].

Gastric mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) is an extremely rare form of gastric neoplasm, and its prognosis is often poor. This is a case report wherein the primary site increased during chemotherapy against gastric adenocarcinoma and was diagnosed with gastric MiNEN after total gastrectomy. A 71-year-old man was diagnosed with gastric adenocarcinoma complicated with liver and para-aortic lymph node metastasis. Chemotherapy with S-1, oxaliplatin, and trastuzumab was initiated. Although the size of metastatic lesions was reduced after six courses of treatment, a part of the primary site of gastric tumor rapidly. Pathological rebiopsy of the primary site suggested a neuroendocrine carcinoma, and he was finally diagnosed with gastric MiNEN after total gastrectomy. Thus, second-line chemotherapy was then initiated showing good response. We herein report a case of MiNEN with a rare diagnostic process.

Case Report: Response to Intra-arterial Cisplatin and Concurrent Radiotherapy Followed by Salvage Surgery in a Patient With Advanced Primary Sinonasal Low-Grade Non-intestinal Adenocarcinoma.

Background: The clinical usefulness of concurrent chemoradiotherapy before surgery in the treatment of primary, locally advanced sinonasal low-grade, non-intestinal type adenocarcinoma (LG non-ITAC) is unclear. Methods: We present the first case report of the efficacy of super-selective intra-arterial cisplatin (CDDP) infusion concurrent with conventional fractionated radiotherapy (RT) for LG non-ITAC in a Japanese patient. Results: A white, rugged-marginal mass that was histopathologically diagnosed as LG non-ITAC occupied the right nasal cavity. Based on the imaging findings, including computed tomography, magnetic resonance imaging, and positron emission tomography, the tumor was diagnosed as T4aN0M0, stage IVa. After treatment, the nasal tumor disappeared leaving only a small bulge in the medial wall of the middle turbinate. The patient also underwent right transnasal ethmoidectomy performed as salvage surgery. A histopathological examination revealed that the lesion was replaced by granulation tissue with lymphocytic infiltration and hemosiderin-laden macrophages, and no viable tumor cells remained. In the seven years after treatment, the patient has not experienced any local recurrence or regional or distant metastasis. Conclusions: Super-selective intra-arterial CDDP infusion concurrent with conventional fractionated RT followed by salvage surgery might be useful for the management of sinonasal LG non-ITAC.

Gene networks in basal cell carcinoma of the eyelid, analyzed using gene expression profiling.

Basal cell carcinoma (BCC) is the most frequent malignant tumor of the eyelid; it progresses slowly and rarely metastasizes. However, BCC of the eyelid is partially invasive and can extend to the surrounding ocular adnexa even if appropriate treatment is performed. To understand the molecular mechanism underlying its pathogenesis, global gene expression analysis of surgical tissue samples of BCC of the eyelid (n=2) and normal human epidermal keratinocytes was performed using a GeneChip® system. The histopathological examination of surgically removed eyelid tissues showed the tumor nest composed with small basaloid. In the samples from patients 1 and 2, 687 and 713 genes were identified, respectively, demonstrating ≥5.0-fold higher expression than that noted in normal human epidermal keratinocytes. For the 640 genes with upregulated expression in both patient samples, Ingenuity® pathway analysis showed that the gene network in BCC of the eyelid included many BCC-associated genes, such as the following: BCL2 apoptosis regulator; Patched-1; and SRY-box 9. In addition, unique gene networks related to cancer cell growth, tumorigenesis, and cell survival were identified. These results of integrating microarray analyses provide further insights into the molecular mechanisms involved in BCC of the eyelid and may provide a therapeutic approach for this disease.

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.

Conventional osteosarcoma of the mandible successfully treated with radical surgery and adjuvant chemotherapy after responding poorly to neoadjuvant chemotherapy: a case report.

BACKGROUND: Osteosarcoma, the most common primary bone malignancy, has an extremely poor prognosis and a high rate of local recurrence and distal metastases. Because osteosarcomas of the head and neck region are rare, accounting for less than 10% of all osteosarcoma cases, limited information is available about their treatment and prognosis. Because of the high rate of distal metastases associated with extragnathic osteosarcoma, surgery combined with chemotherapy is currently considered essential in its treatment. However, the role of chemotherapy has not been well elucidated in the treatment of head and neck osteosarcoma because of the rarity of this condition. CASE PRESENTATION: In this report, we present the case of a 58-year-old Japanese woman with osteosarcoma of the mandible that was treated with radical surgery combined with neoadjuvant and adjuvant chemotherapy. Because the tumor showed rapid growth during neoadjuvant chemotherapy, neoadjuvant chemotherapy was suspended and surgical resection was performed, followed by adjuvant chemotherapy. No evidence of local recurrence and distal metastasis was found 14 months after initial treatment. Local control is considered a principal prognostic factor for head and neck osteosarcoma. CONCLUSIONS: Wide surgical excision should be considered a primary goal even during neoadjuvant chemotherapy, especially in cases that respond poorly to neoadjuvant chemotherapy.

Hepatic Sinusoidal Obstruction Syndrome Induced by Non-transplant Chemotherapy for Non-Hodgkin Lymphoma.

Hepatic sinusoidal obstruction syndrome (SOS), a serious complication that mainly occurs after hematopoietic-stem cell transplantation (HSCT), is caused by damage to the sinusoidal endothelial cells after the obstruction of the sinusoid. Recently, hepatic SOS was reported to occur after non-HSCT chemotherapies. This report describes a patient who experienced hepatic SOS after non-HSCT chemotherapy for non-Hodgkin lymphoma. A liver biopsy showed the slight dilatation of the hepatic sinusoid, which may be indicative of hepatic SOS. Hepatic SOS should be included in the differential diagnosis of patients with severe liver injury following the administration of chemotherapy regimens that are toxic to the vascular endothelial cells.

Trousseau's syndrome caused by bladder cancer producing granulocyte colony-stimulating factor and parathyroid hormone-related protein: A case report.

The present study reports a rare case of bladder cancer that caused Trousseau's syndrome, a malignancy-associated hypercoagulative state leading to venous or arterial thrombosis. A 38-year-old Japanese female patient experienced a sudden onset of visual field defects and lower limb weakness. Cerebral magnetic resonance imaging revealed multi-regional hypointense areas compatible with acute cerebral infarction. Despite the repeated administration of anticoagulant treatment with heparin, the condition could not be adequately controlled and thromboembolic events occasionally recurred. Several tumor markers, including carbohydrate antigen 19-9, cancer antigen 125, carcinoembryonic antigen, cytokeratin 19 fragment and squamous cell carcinoma antigen levels, were elevated. Consequently, computed tomography scans were performed, which revealed a massive bladder tumor with multiple bone and lymph node metastases. The patient also exhibited other paraneoplastic disorders, including leukocytosis due to granulocyte colony-stimulating factor (G-CSF) production, and hypercalcemia due to parathyroid hormone-related protein (PTHrP) production. Transurethral resection of the bladder tumor was performed, and the tumor was pathologically confirmed as urothelial cell carcinoma. Immunohistochemical testing revealed positive staining for G-CSF and PTHrP. Despite undergoing gemcitabine/cisplatin-based systemic chemotherapy, the disease developed rapidly and the patient succumbed to the disease within 3 months of initial symptoms. The present case indicates that occult visceral malignancy should be considered in patients with unexplained thromboembolism.

Aberrant iron metabolism might have an impact on progression of diseases in Tsumura Suzuki obese diabetes mice, a model of spontaneous metabolic syndrome.

Tsumura Suzuki obese diabetes (TSOD) mice spontaneously develop obesity and type 2 diabetes with aberrant accumulation of excessive iron in the spleen. Aberrantly accumulated iron may cause oxidative stress and result in various symptoms of metabolic syndrome in the mice. We investigated iron metabolism and oxidative stress in TSOD mice. Male TSOD and control mice were killed at 2, 3, 6, and 8 months of age, and blood and tissue samples were collected. The serum levels of ferritin and oxidized low-density lipoprotein (OxLDL) were measured. Total glutathione concentrations of liver and spleen were also measured. Serum ferritin and OxLDL were higher in TSOD mice than in control mice at 2 and 6 months. In addition, the glutathione concentrations in TSOD mice were lower in the liver and higher in the spleen at 3 and 6 months than those in control mice. These results suggest that abnormal iron metabolism and imbalanced oxidative stress occurs in young and old TSOD mice. We propose herein that TSOD mice might be a unique and valuable model for investigating the role of iron metabolism in pathogenesis of metabolic syndrome.

Three cases of systemic amyloidosis successfully diagnosed by subcutaneous fat tissue biopsy of the hip.

Fine-needle aspiration biopsy of the abdominal fat pad is considered to be a minimally invasive procedure for diagnosing systemic amyloidosis. However, this procedure is sometimes difficult and can be dangerous for elderly patients whose abdominal fat layer is thin because of malnutrition. In such cases, alternative diagnostic methods are required. We report three elderly patients with heart failure complicated by malnutrition. In all cases, electrocardiogram showed low voltage in the limb leads and a pseudoinfarct pattern in the chest leads, and echocardiography showed left ventricular wall thickening with granular sparkling appearance. These patients were suspected of having amyloid cardiomyopathy but could not undergo myocardial biopsies because of their poor conditions. After failed attempts at biopsy of the abdominal fat pad or the other organs, subcutaneous fat tissue biopsy over the hip led to the diagnosis of systemic amyloidosis with cardiomyopathy. The resultant diagnosis guided us to choose the appropriate treatment for the patients. This article illustrates that subcutaneous fat tissue biopsy of the hip could be a useful procedure for diagnosing systemic amyloidosis in elderly patients, particularly when a fat tissue biopsy of the abdomen is associated with a high risk of complications because of malnutrition.

Invasive micropapillary salivary duct carcinoma mixed with mucin-rich salivary duct carcinoma in minor salivary gland: a rare case report.

BACKGROUND: Invasive micropapillary salivary duct carcinoma (SDC) is a rare variant of SDC. Although several cases involving major salivary glands have been reported, no cases arising de novo in minor salivary glands have been reported to date. Here we report the first case of invasive micropapillary SDC that arose in a minor salivary gland of the parapharyngeal space. METHODS: A 72-year-old male patient presented with an enlarging mass in the left parapharyngeal region along with trismus and swollen lymph nodes. Clinical examinations and biopsy findings were suggestive of a salivary gland malignant tumor with regional lymph node metastases. The tumor, therefore, was excised with partial mandibulectomy with unilateral radical neck dissection. RESULTS: Histologically, the tumor consisted of an invasive micropapillary growth pattern of SDC and mixed with mucinous component of SDC. Local recurrence and lung metastasis developed, and the patient died of disease 13 months after the initial treatment. CONCLUSIONS: We describe the clinical and histologic features of this extremely rare case of minor salivary gland SDC that was histologically characterized by the presence of both invasive micropapillary growth pattern and mucinous component.

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.

Perforation of intramural gastric metastasis during preoperative chemotherapy in a patient with thoracic esophageal squamous cell carcinoma.

INTRODUCTION: Perforation of intramural metastasis to the stomach (IMS) from esophageal cancer during chemotherapy has not been reported. PRESENTATION OF CASE: A 68-year-old male consulted our hospital due to appetite loss. He was diagnosed with advanced esophageal squamous cell carcinoma in the lower thoracic esophagus along with a large IMS in the upper stomach. The patient received preoperative chemotherapy of docetaxel, cisplatin, and 5-fluorouracil (DCF). During the second cycle of DCF, he had upper abdominal pain and was diagnosed with gastric perforation. Omental implantation repair for the perforation, peritoneal drainage, tube-gastrostomy, and tube-jejunostomy were performed. At 24 days after emergency surgery, he underwent thoracoscopic radical esophagectomy with total gastrectomy and reconstruction with colonic interposition. Pathological findings in the esophagus demonstrated complete replacement of the tumor by fibrosis. The gastric tumor was replaced by scar tissue with multinucleated giant cells along with a small amount of viable cancer cells. The patient was alive and healthy at 14 months after the radical operation, without tumor recurrence. DISCUSSION: The gastric perforation occurred due to rapid regression of the IMS which had involved the whole gastric wall before chemotherapy. Close monitoring to detect rapid tumor shrinkage during chemotherapy in patients with IMS may be warranted. A two-step operation was proposed to achieve safe curative treatment in patients with perforation of IMS during preoperative chemotherapy. CONCLUSION: We describe the first reported case of a patient with esophageal squamous cell carcinoma who showed perforation of IMS during preoperative chemotherapy.

Bone metastasis in gastrointestinal stromal tumors preferentially occurs in patients with original tumors in sites other than the stomach.

Bone metastases are rare in gastrointestinal stromal tumors (GISTs) and data on the clinicopathological profiles are lacking. The purpose of this report was to identify the clinicopathological profiles of this rare clinical setting by evaluating 23 cases, four of which were our own and the additional 19 were from the relevant English literature. In 18 cases, the primary GISTs occurred in sites other than the stomach, although a high proportion of these tumors do arise in the stomach. All tumors at the disease presentation had more than a low risk of recurrence, with most tumors either at a high risk or initially malignant with liver metastasis. In four cases, bone metastasis was the primary metastatic manifestation. Although rare in GISTs, bone metastasis should be considered in patients with primary tumors at a high risk for recurrence or in initially malignant tumors with liver metastasis, especially with primary tumors in sites other than the stomach.

Primary non-gestational pure choriocarcinoma arising in the ovary: A case report and literature review.

Pure non-gestational choriocarcinoma is a primary germ cell neoplasm that has been defined as a tumor without other germ cell elements. The current study presents an extremely rare case of non-gestational pure choriocarcinoma in a postmenarcheal young female and describes details of the tumor, including the clinicopathological findings. The patient was a 10-year-old female who underwent salpingo-oophorectomy. Histologically, the extensive hemorrhagic tumor was composed of choriocarcinoma without additional germ cell tumor components. The tumor cells were immunohistochemically positive for epithelial markers, including cytokeratins and epithelial membrane antigens, and there was a positive cytoplasmic reaction for ß-human chorionic gonadotropin in the syncytiotrophoblasts. Furthermore, numerous tumor cells were immunohistochemically positive for the ß2-microglobulin antibody. The patient received adjuvant cisplatin, etoposide and bleomycin chemotherapy, and is currently disease-free without evidence of recurrence or metastasis subsequent to 62 months of follow-up.

Immune-mediated protein-losing enteropathy with Down syndrome.

A 28-year-old woman previously diagnosed to have Down syndrome presented with a one-month history of severe hypoalbuminemia, lower extremity edema, and diarrhea. Her urine was negative for protein. She was diagnosed with immune-mediated protein-losing enteropathy (PLE) based on clinical findings, protein loss evident on (99m)Technetium-labeled human serum albumin scintigraphy, and IgM and complement C3 deposition in the duodenum. She did not exhibit any manifestations of collagen diseases. A dramatic remission was achieved and maintained with corticosteroid administration. This is the first report of immune-mediated PLE in a patient with Down syndrome.

Neonatal monosodium glutamate treatment causes obesity, diabetes, and macrovesicular steatohepatitis with liver nodules in DIAR mice.

BACKGROUND AND AIM: Non-alcoholic steatohepatitis (NASH) is the hepatic manifestation of metabolic syndrome (MS). Monosodium glutamate (MSG)-treated ICR mice is a useful model of MS and NASH, but it shows the different patterns of steatosis from human NASH. Because inbred aged DIAR (ddY, Institute for Animal Reproduction) mice spontaneously show the similar pattern of steatosis as NASH, we analyzed their liver pathology after administering MSG. METHODS: MSG-treated DIAR mice (DIAR-MSG) and untreated DIAR mice (DIAR-controls) were sacrificed and assessed histopathologically at 29, 32, 40, 48, and 54 weeks of age. The NASH activity score, body mass index, blood glucose level, and oral glucose tolerance test were also assessed. RESULTS: The body mass index and blood glucose levels of DIAR-MSG were significantly higher than controls. The oral glucose tolerance test revealed a type 2 diabetes pattern in DIAR-MSG. The livers of DIAR-MSG mice showed macrovesicular steatosis, lobular inflammation with neutrophils, and ballooning degeneration after 29 weeks. At 54 weeks, mild fibrosis was observed in 5/6 DIAR-MSG and 2/5 DIAR-control mice. In imaging mass spectrometry analysis, cholesterol as well as triglyceride accumulated in the liver of DIAR-MSG mice. Atypical liver nodules were also observed after 32 weeks in DIAR-MSG, some with cellular and structural atypia mimicking human hepatocellular carcinoma. The NASH activity score of DIAR-MSG after 29 weeks was higher than that of control mice, suggesting the development of NASH. CONCLUSIONS: DIAR-MSG had NASH-like liver pathology and liver nodules typically associated with MS symptoms. DIAR-MSG provides a valuable animal model to analyze NASH pathogenesis and carcinogenesis.

Malignant transformation of hyperplastic gastric polyps: An immunohistochemical and pathological study of the changes of neoplastic phenotype.

In spite of the evidence that the malignant transformation of gastric hyperplastic polyps (HPs) is a rare event, it must always be taken into account during diagnosis. The aim of the current study was to clarify the mechanism of the malignant transformation of gastric hyperplasia polyps, with focus on phenotypic expression, cell proliferation and p53 overexpression. Immunohistochemistry for mucin phenotypic markers, including MUC1, MUC2, MUC5AC, MUC6, tight junction factors (claudin-3, -4 and -18), an intestinal phenotypic marker [caudal type homeobox 2 (Cdx2)], Ki-67 proliferative index and p53 overexpression, was performed on archival specimens of gastric polyps excised from six patients. Histologically, the intermingled components of several lesions were present in these polyps. Furthermore, the cancer components were predominantly differentiated adenocarcinoma. Immunohistochemically, all hyperplastic components expressed MUC5AC, but did not exhibit positivity for MUC2. Additionally, the majority of hyperplastic components were immunonegative for claudin-3, while claudin-3 positivity was observed in the majority of areas of dysplasia and carcinoma. Expression of claudin-4 was also observed in the majority of cases and claudin-18 was preserved in the hyperplastic, dysplastic and adenocarcinomatous lesions of all cases. Nuclear accumulation of Cdx2 was detected in almost all the samples with dysplasia and carcinoma, while nuclear p53 was detected in 24-80% of the dysplastic areas and >85% of the cancer components. The Ki-67 labeling index appeared to correlate with neoplastic progression. The observations provided evidence that the mechanism underlying malignant transformation of gastric HPs may occur by multistep carcinogenesis, such as the hyperplasia-adenoma (dysplasia)-adenocarcinoma sequence, and these neoplastic cells may acquire various phenotypes during this process.

A simple and rapid decalcification procedure of skeletal tissues for pathology using an ultrasonic cleaner with D-mannitol and formic acid.

Decalcification procedures are required in order to prepare histopathological preparations of hard tissues such as bone and teeth. Decalcification is usually performed by immersing the hard tissue in different decalcification fluids with various properties. These decalcification fluids typically include inorganic and organic acids, a neutral fluid containing a chelating agent, or a mixture of solutions. Unfortunately, there is no universal decalcification fluid that satisfies all the requirements of pathologists such as rapid decalcification, easy handling, and minimal tissue damage. Techniques involving use of microwaves (MW) or ultrasonic apparatus (US) have been shown to be useful for shortening the time for decalcification procedures. In the present study, we investigated a unique decalcification procedure that uses a common commercial ultrasonic cleaner and a decalcification fluid (formic acid) containing a free-radical scavenger (D-mannitol). The time required to complete the procedure is approximately half of that required to complete a standard decalcification procedure. In addition, tissue morphology and antigenicity is fairly well preserved after decalcification. The procedure is quick, easy to perform, and achieves decalcification of hard tissue with minimal tissue damage.

Introduction and utility of liquid-based cytology on aspiration biopsy of peripheral nodular lesions of the lung.

In the present study, aspiration biopsy cytology (ABC) was used for the diagnosis of peripheral nodular lesions in the lung (PNLL), and liquid-based cytology (LBC) was carried out on the material collected to evaluate it in comparison with the conventional method (CM). The subjects comprised 130 cases that underwent computed tomography (CT)-guided ABC for PNLL. A total of 73 cases received a tumor resection, with a diagnosis based on the pathology, while 57 cases were followed up, as the tumor showed no change on the radiological examinations. Biopsy samples from these patients and lavage fluid from the aspiration needles were used for analysis. Cellular material was obtained by centrifugation of the lavage fluid, and samples were prepared by two methods, direct smearing and LBC according to the ThinPrep method. The samples were categorized into three diagnoses: i) Benign, ii) suspicion of malignancy and iii) malignant. Appropriate samples were collected in 72% of cases by LBC, but only in 36% of cases by the CM. There was no marked difference in cellular images between the two methods, with the exception of a few specific cases. LBC on its own provided sensitivity at 68%, specificity at 61% and accuracy at 65%, while a combination of LBC and biopsy markedly improved these figures to 94, 81 and 84%, respectively. The introduction of LBC is considered useful for the cytopathological diagnosis of PNLL by CT-guided ABC. LBC enables the examination of appropriate samples rich in cellular components and supports a biopsy-based diagnosis. A combination of these two methods provides even higher diagnostic accuracy, and LBC is considered an excellent method to evaluate these pathological samples.