Ikumi Kitazono

Mucin expression in endoscopic ultrasound-guided fine-needle aspiration specimens is a useful prognostic factor in pancreatic ductal adenocarcinoma.

Objectives The aim of this study was to further examine the utility of mucin (MUC) expression profiles as prognostic factors in pancreatic ductal adenocarcinoma (PDAC). Methods Mucin expression was examined by immunohistochemistry analysis in endoscopic ultrasound-guided fine-needle aspiration specimens obtained from 114 patients with PDAC. The rate of expression of each MUC was compared with clinicopathologic features. Results The expression rates of MUCs in cancer lesions were MUC1, 87.7%; MUC2, 0.8%; MUC4, 93.0%; MUC5AC, 78.9%; MUC6, 24.6%; and MUC16, 67.5%. MUC1 and MUC4 were positive, and MUC2 was negative in most PDACs. Patients with advanced stage of PDAC with MUC5AC expression had a significantly better outcome than those who were MUC5AC-negative (P = 0.002). With increasing clinical stage, total MUC6 expression decreased (P for trend = 0.001) and MUC16 cytoplasmic expression increased (P for trend = 0.02). The prognosis of patients with MUC16 cytoplasmic expression was significantly poorer than those without this expression. Multivariate survival analysis revealed that MUC16 cytoplasmic expression was a significant independent predictor of a poor prognosis after adjusting for the effects of other prognostic factors (P = 0.002). Conclusions Mucin expression profiles in ultrasound-guided fine-needle aspiration specimens have excellent diagnostic utility and are useful predictors of outcome in patients with PDAC.

Aberrant methylation of MUC1 and MUC4 promoters are potential prognostic biomarkers for pancreatic ductal adenocarcinomas

Pancreatic cancer is still a disease of high mortality despite availability of diagnostic techniques. Mucins (MUC) play crucial roles in carcinogenesis and tumor invasion in pancreatic neoplasms. MUC1 and MUC4 are high molecular weight transmembrane mucins. These are overexpressed in many carcinomas, and high expression of these molecules is a risk factor associated with poor prognosis. We evaluated the methylation status of MUC1 and MUC4 promoter regions in pancreatic tissue samples from 169 patients with various pancreatic lesions by the methylation specific electrophoresis (MSE) method. These results were compared with expression of MUC1 and MUC4, several DNA methylation/demethylation factors (e.g. ten-eleven translocation or TET, and activation-induced cytidine deaminase or AID) and CAIX (carbonic anhydrase IX, as a hypoxia biomarker). These results were also analyzed with clinicopathological features including time of overall survival of PDAC patients. We show that the DNA methylation status of the promoters of MUC1 and MUC4 in pancreatic tissue correlates with the expression of MUC1 and MUC4 mRNA. In addition, the expression of several DNA methylation/demethylation factors show a significant correlation with MUC1 and MUC4 methylation status. Furthermore, CAIX expression significantly correlates with the expression of MUC1 and MUC4. Interestingly, our results indicate that low methylation of MUC1 and/or MUC4 promoters correlates with decreased overall survival. This is the first report to show a relationship between MUC1 and/or MUC4 methylation status and prognosis. Analysis of epigenetic changes in mucin genes may be of diagnostic utility and one of the prognostic predictors for patients with PDAC.

TET1-mediated DNA hypomethylation regulates the expression of MUC4 in lung cancer

Lung cancer remains a disease of high mortality, despite advanced diagnostic techniques. Mucins (MUC) play crucial roles in carcinogenesis and tumor invasion in lung neoplasms. Our immunohistochemistry (IHC) studies have shown that high MUC4 expression correlates with a poor outcome. We have also shown that the expression of several mucin genes in cancer cell lines is regulated by DNA methylation. We evaluated the expression level of MUC4, mRNA and several DNA hypomethylation factors in lung tissue samples from 33 patients with various lung lesions. The results indicated that the DNA methylation status of MUC4 matched the expression level of mRNA. In addition, the TET1 (Ten-Eleven Translocation) mRNA showed a significant correlation with the status of DNA methylation of MUC4. Furthermore, the treatment of a lung cancer cell line with TET1 siRNA caused a reduction in MUC4 mRNA expression. Thus, we suggest that TET1 mediated DNA hypomethylation plays a key role in the expression of MUC4. This is the first report that TET1 mediated DNA hypomethylation regulates the expression of MUC4 in lung cancer. The analysis of these epigenetic changes may be useful for diagnosing carcinogenic risk.

A rare case of internal jugular vein aneurysm with massive hemorrhage in neurofibromatosis type 1.

Neurofibromatosis Type 1 (NF1) is a relatively common autosomal dominant disorder. Vascular involvement is a well-recognized manifestation of NF1, but venous aneurysm associated with NF1 is extremely rare. We present a case of an NF1 patient with a left internal jugular vein aneurysm with massive hemorrhage occurring during surgery. Due to the extreme fragility of both the aneurismal wall and the surrounding tissue, the patient developed severe intraoperative bleeding. Pathological examination confirmed aneurismal wall infiltration of the neurofibromatosis. Physicians should be aware that hemorrhagic complication in NF1 can occur and be fatal.

Mature posterior fossa teratoma mimicking dermoid cyst

We describe a very rare case of mature posterior fossa teratoma in an adult who presented with clinico-radiological findings consistent with a dermoid cyst. A computed tomography scan showed a hypodense mass in the cistern magna with calcification and a sinus tract in the occipital bone. Magnetic resonance imaging revealed a hypo- to hyperintense mass without contrast enhancement. The intraoperative picture showed a dermal sinus and a cyst containing lipid, keratin and hair. Histopathological examination showed a tumor with components of all the three germ layers; thereby, a diagnosis of mature teratoma was made. The histopathological differentiation between teratoma and dermoid cyst is very valuable for ruling out the presence of immature/malignant or germinomatous components that would require further adjuvant therapies. Thus, we here present a rare case of posterior fossa teratoma mimicking dermoid cyst and emphasize the importance of histopathological differentiation between these entities.

The First Case of Pulmonary Alveolar Proteinosis With Small Cell Lung Carcinoma

Pulmonary alveolar proteinosis (PAP) is a rare pulmonary disease characterized by alveolar accumulation of surfactant lipids and proteins. It is usually autoimmune and secondary to hematologic malignancy or infection. To date, only 5 case reports of PAP associated with lung cancers, including 2 cases of squamous cell carcinoma and 3 cases of adenocarcinoma, have been published. To the best of our knowledge, no case of PAP with small cell lung carcinoma has been reported thus far. We herein report the first case of PAP associated with small cell lung carcinoma.

Immunohistochemical expression of mucin antigens in gallbladder adenocarcinoma: MUC1-positive and MUC2-negative expression is associated with vessel invasion and shortened survival

Mucins play pivotal roles in influencing cancer biology, for example affecting carcinoma invasion, aggressiveness and/or metastatic potential. Our aim is to investigate the significance of expression profiles of two mucins in particular, MUC1 and MUC2, their correlations with various clinicopathological features, and prognosis in gallbladder adenocarcinoma (GBAC). We performed immunohistochemistry from patients with surgically resected GBAC, using antibodies against mucin core proteins MUC1/DF3 and MUC2/Ccp58 in 81 paraffin-embedded tumor samples. MUC1 or MUC2 expression was considered to be high when ≥ 20% or 10% of the GBAC cells showed positive staining, respectively. High MUC1 expression was revealed to have a significant relationship to the presence of pathologically lymphatic and vascular invasion, and regional lymph node metastasis. By contrast, high MUC2 expression showed a significant correlation with pathologically perineural invasion, T stage ≥ 3, and post-operative recurrence. Moreover, MUC1 showed significantly positive co-expression and potentially complementary correlations with MUC2. Multivariate analyses demonstrated that the high MUC1 expression group had significantly shorter disease-specific survival times. However, the combination of both high MUC1 and MUC2 expression did not predict worse outcome in GBACs. Therefore, although each mucin has a somewhat important role in the pathogenesis of GBAC progression, MUC1 can independently predict vessel invasion and poor prognosis in patients with GBAC. The detection of MUC1 might well offer a useful parameter for providing clinical management and treatment against postsurgical GBACs.

Unusual morphology of a pulmonary blastoma having an epithelial component with focally significant nuclear pleomorphism

To the Editor: Biphasic pulmonary tumors, consisting of adenocarcinoma and a mesenchymal component, comprise pulmonary blastoma and carcinosarcoma, including blastomatoid carcinosarcoma. They are very rare lung tumors; for example, only 0.5% of lung tumors are pulmonary blastomas. Pulmonary blastoma typically consists of low-grade fetal adenocarcinoma (L-GFAC) with morula formation and primitive mesenchymal stroma. Foci of differentiated sarcomatous elements such as rhabdomyosarcoma, chondrosarcoma, or osteosarcoma can be found. In contrast, carcinosarcoma is defined as a malignant tumor with a mix of differentiated carcinoma and sarcoma, which typically consists of non-small cell lung carcinoma (e.g., squamous cell carcinoma and adenocarcinoma) and true sarcoma containing differentiated elements. In contrast to conventional carcinosarcoma, high-grade fetal adenocarcinoma (HGFAC) as a carcinomatous component has sometimes been reported. In the literature, these cases have been referred to as blastomatoid carcinosarcoma. Here, we describe a unique case of pulmonary blastoma having an epithelial component with focally significant nuclear pleomorphism. A 52-year-old Japanese man was admitted to the hospital for a health check. He had a 72 pack-year smoking history and no significant past medical history. A chest computed tomography (CT) scan revealed a 30mm mass with pleural invasion in the left upper lobe. Follow-up CT after 1 month showed an increase in tumor size. The tumor was suspected to be malignant, and a left upper lobectomy was performed. Macroscopic examination revealed a 30 25 20mm tan-white tumor, with bullae adjacent to the tumor (Fig. 1a). The non-neoplastic lung was emphysematous with bullae. Microscopically, it was a biphasic tumor comprising both epithelial and mesenchymal components. The epithelial component, up to 60% of the vital tumor, comprised nonciliated columnar cells with round-to-oval and small-tomoderately sized nuclei, clear glycogen-rich cytoplasm, and supra/subnuclear vacuoles forming complex glandular structure (Fig. 1b). Some morulas were seen. These findings suggested L-GFAC. However, significant nuclear pleomorphism (enlarged vesicular nuclei and prominent nucleoli) was focally seen with sparse, large, bizarre nuclei, which resembled H-GFAC (Fig. 1c). The mesenchymal component comprised immature spindle cells forming sheets of solid nests with focal and small islands of neoplastic cartilage (Fig. 1d). The tumor stroma showed fibrous scarring with edematous and hyaline change with hemorrhage. Immunohistochemically, the tumor cells of the L-GFAClike component were positive for TTF-1 and beta-catenin, showing nuclear/cytoplasmic expression (Fig. 1b, inset). Moreover, CD56, synaptophysin, and AFP were focally positive. In contrast, the tumor cells resembling H-GFAC showed a membranous expression of beta-catenin (Fig. 1c, inset) but were negative for TTF-1 and AFP. Both types of tumor cells were negative for chromogranin A, napsin A, S-100 protein, and p53. The mesenchymal component was positive for S-100 protein and CD56 (Table S1). Because this was a biphasic tumor with both L-GFAC-like epithelial components and small foci of neoplastic cartilage, we made a diagnosis of pulmonary blastoma. The existence of an H-GFAC-resembling element in pulmonary blastoma was a unique histopathological finding. Carcinosarcoma is reported to develop in elderly men aged 50–80 years who are heavy smokers, whereas pulmonary blastoma develops in younger people with a peak incidence in the 40s and without a significant sex predilection. In our case, carcinosarcoma was suspected from the clinical presentation; however, the gross findings were unusual because both tumors are known to form a bulky mass in either the central/peribronchial areas or in the periphery of the lungs. The epithelial component of pulmonary blastoma is L-GFAC, which shows aberrant nuclear/cytoplasmic localization of beta-catenin, with frequent mutations of the betacatenin gene. Our case showed histological findings of a sarcomatous cartilaginous element and an epithelial component resembling L-GFAC (adenocarcinoma with clear glycogen-rich cytoplasm, mild-to-moderate nuclear atypia, and morula formation). Moreover, an epithelial element was also observed that resembled H-GFAC (adenocarcinoma with clear glycogen-rich cytoplasm, enlarged vesicular nuclei, and prominent nucleoli, and without morula formation). An immunohistochemical analysis of beta-catenin demonstrated the nuclear/cytoplasmic expression of the L-GFAC-like component and the membranous expression of the H-GFAC-like element. The results were consistent with L-GFAC and H-GFAC, histologically and immunohistochemically.

Anaplastic astrocytoma cells not detectable on autopsy following long‑term temozolomide treatment: A case report

We herein present an autopsy case of a glioma patient who received long-term treatment with temozolomide (TMZ). The patient, a 35-year-old man with a hypointense tumor of the left frontal lobe, without contrast enhancement following gadolinium (Gd) administration on T1-weighted images, underwent tumor removal surgery, after which the tumor was diagnosed as anaplastic astrocytoma. By the third round of surgery, the tumor had progressed to anaplastic astrocytoma with contrast enhancement following Gd administration, and the patient received 60 Gy of external beam radiotherapy and nimustine hydrochloride (ACNU)-based chemotherapy. After the fifth tumor removal surgery, TMZ was substituted with ACNU chemotherapy, which suppressed tumor progression. Following the 41st TMZ treatment, hemorrhage was observed in the residual tumor, and the hematoma had been replaced by a hemangioma. The hemangioma and surrounding brain tissue was removed during the sixth surgery. The patient survived for 14 years and 9 months after the initial surgery, but succumbed to hydrocephalus due to bleeding from hemangiomas. The histopathological specimens of the first to the sixth surgeries revealed mutant isocitrate dehydrogenase 1 (IDH1; R132H point mutation) and p53-positive tumor cells, but cells positive for the R132H mutation or p53 could not be detected by immunohistochemistry in the autopsy specimens of the brain after 108 courses of TMZ treatment. Mutant IDH1 (R132H) cells were also not detected in the autopsy specimens of the brain by polymerase chain reaction analysis.

Aortic fibromuscular dysplasia complicated by dissection: a case report and review of literature

Fibromuscular dysplasia (FMD) is an idiopathic, segmental, nonatherosclerotic, non-inflammatory vascular disease, which is often complicated by the occurrence of dissection. Although it is known to occur in all arteries, aortic involvement is relatively rare. To date, 33 cases of aortic FMD have been reported in available English literature, among which only three cases have been complicated by the occurrence of dissection. We describe the case of a 40-year-old woman diagnosed with aortic FMD complicated by the occurrence of a type A aortic dissection. Non-invasive imaging revealed an ascending to descending thoracic aneurysm measuring 8 cm in diameter associated with dissection. Histopathologically, a segment of the wall of the aneurysm showed architectural disorganization of the aortic wall with loss of elastic fibers, collagen deposition, and irregular proliferation of smooth muscle cells in the intima and media-features suggesting FMD. No atheromatous plaque or medial cystic degeneration was observed in the aorta. Although aortic FMD is sometimes fatal, it is often very difficult to diagnose using imaging techniques. Therefore, performing a histopathological diagnosis is very important and should be emphasized.