Gallbladder microbiota composition is associated with pancreaticobiliary and gallbladder cancer prognosis.

BACKGROUND: The microbial population of the intestinal tract and its relationship to specific diseases has been extensively studied during the past decade. However, reports characterizing the bile microbiota are rare. This study aims to investigate the microbiota composition in patients with pancreaticobiliary cancers and benign diseases by 16S rRNA gene amplicon sequencing and to evaluate its potential value as a biomarker for the cancer of the bile duct, pancreas, and gallbladder. RESULTS: We enrolled patients who were diagnosed with cancer, cystic lesions, and inflammation of the pancreaticobiliary tract. The study cohort comprised 244 patients. We extracted microbiome-derived DNA from the bile juice in surgically resected gallbladders. The microbiome composition was not significantly different according to lesion position and cancer type in terms of alpha and beta diversity. We found a significant difference in the relative abundance of Campylobacter, Citrobacter, Leptotrichia, Enterobacter, Hungatella, Mycolicibacterium, Phyllobacterium and Sphingomonas between patients without and with lymph node metastasis. CONCLUSIONS: There was a significant association between the relative abundance of certain microbes and overall survival prognosis. These microbes showed association with good prognosis in cholangiocarcinoma, but with poor prognosis in pancreatic adenocarcinoma, and vice versa. Our findings suggest that pancreaticobiliary tract cancer patients have an altered microbiome composition, which might be a biomarker for distinguishing malignancy.

Respiratory epithelial adenomatoid hamartomas of the sinonasal tract: A histopathological analysis of 50 patients.

Respiratory epithelial adenomatoid hamartoma (REAH) is a benign lesion of the nasal cavity and paranasal sinuses. Here, we report the clinicopathological characteristics of REAH identified in 2065 cases with nasal/paranasal polypoid lesions treated with endoscopic sinus surgery (ESS) at our hospital from 2008 to 2021. Cases including the olfactory area were reviewed and 50 patients of REAH were identified pathologically (50/2065, 2.4%). The average age was 58.9 years old and the male/female ratio was 45/5. Grossly, REAH showed a whitish surface and elastic firm consistency. The histopathological characteristics included proliferation of small to medium-sized glands composed of ciliated respiratory epithelium containing goblet cells; thickening of the basement membrane compared to that for inverted papilloma (9.6 ± 2.4 vs. 1.3 ± 1.6 µm, p < 0.001); and no intra-epithelial neutrophilic infiltration. Among the REAH cases, 81% were associated with sinonasal inflammatory polyps. Many olfactory cleft polyps were REAH (38/98, 39%). The rate of REAH found in ESS in the last 7 years was higher than that in the first 7 years (3.17% vs. 1.62%, p = 0.032). Our results in Japanese patients are similar to those found in other countries, including male predominance. REAH is relatively common and that 39% of polyps taken from olfactory clefts are REAH.

Effect of Recent Antirheumatic Drug on Features of Rheumatoid Arthritis-Associated Lymphoproliferative Disorders.

OBJECTIVE: In this study, we examine how advancements in novel antirheumatic drugs affect the clinicopathologic features of lymphoproliferative disorder (LPD) in patients with rheumatoid arthritis (RA). METHODS: In this multicenter study across 53 hospitals in Japan, we characterized patients with RA who developed LPDs and visited the hospitals between January 1999 and March 2021. The statistical tools used included Fisher's exact test, the Mann-Whitney U-test, the log-rank test, logistic regression analysis, and Cox proportional hazards models. RESULTS: Overall, 752 patients with RA-associated LPD (RA-LPD) and 770 with sporadic LPD were included in the study. We observed significant differences in the clinicopathologic features between patients with RA-LPD and those with sporadic LPD. Histopathological analysis revealed a high frequency of LPD-associated immunosuppressive conditions. Furthermore, patients with RA-LPD were evaluated based on the antirheumatic drugs administered. The methotrexate (MTX) plus tacrolimus and MTX plus tumor necrosis factor inhibitor (TNFi) groups had different affected site frequencies and histologic subtypes than the MTX-only group. Moreover, MTX and TNFi may synergistically affect susceptibility to Epstein-Barr virus infection. In case of antirheumatic drugs administered after LPD onset, tocilizumab (TCZ)-only therapy was associated with lower frequency of regrowth after spontaneous regression than other regimens. CONCLUSION: Antirheumatic drugs administered before LPD onset may influence the clinicopathologic features of RA-LPD, with patterns changing over time. Furthermore, TCZ-only regimens are recommended after LPD onset.

Uterine cervical carcinomas associated with lobular endocervical glandular hyperplasia.

AIMS: To investigate the clinicopathological features of cervical uterine carcinoma associated with lobular endocervical glandular hyperplasia (LEGH). METHODS AND RESULTS: Subjects comprised 12 patients with cervical carcinoma associated with LEGH. Carcinoma included nine invasive adenocarcinomas, two adenocarcinoma in-situ (AIS) and one microinvasive squamous cell carcinoma (SCC). Baseline characteristics, cervical cytology, human papilloma virus (HPV) status, immunohistochemistry, surgical procedures and clinical outcomes were investigated. There was a pair of adenocarcinoma cases in a mother and daughter unrelated to Peutz-Jeghers syndrome. In all patients, atypical cells were seen on cervical cytology (adenocarcinoma cells in 11 cases and SCC cells in one). All the 12 patients were positive for mucin antigen 6 (MUC6) in the LEGH component, while seven patients were positive for gastric mucin (HIK1083). HPV was detected only in the SCC component. One patient with adenocarcinoma stage Ib died of disease 4 years after radical hysterectomy. The others are currently alive 2-16 years postoperatively. CONCLUSIONS: The diagnosis of adenocarcinoma with LEGH is not always difficult. The prognosis of adenocarcinoma associated with LEGH may be better than previously expected. Adenocarcinoma with a LEGH component does not always develop into a highly aggressive minimal deviation adenocarcinoma.

PCP4/PEP19 and HER2 Are Novel Prognostic Markers in Mucoepidermoid Carcinoma of the Salivary Gland.

Mucoepidermoid carcinoma (MEC) is one of the most common malignant salivary gland carcinomas, but no effective treatment strategy has been established other than surgical resection. Purkinje cell protein (PCP) 4/peptide (PEP) 19 is a calmodulin-binding antiapoptotic peptide that is expressed and inhibits apoptosis in human breast cancer cells. Human epidermal growth factor receptor 2 (HER2) is an epidermal growth factor that has been implicated in the pathogenesis of many carcinomas, particularly breast and gastric carcinomas. In the present study, we performed immunohistochemical analyses of samples from 73 patients who underwent surgical resection for MEC of the salivary gland using antibodies against PCP4/PEP19 and HER2. PCP4/PEP19 expression was related to better prognosis, while HER2 expression was associated with worse prognosis. Patients that were PCP4/PEP19-positive and HER2-negative showed similar outcomes to PCP4/PEP19 and HER2 alone. Therefore, PCP4/PEP19 and HER2 are predicted to play important roles in the pathogenesis and progression of MEC.

Expression of mucin antigens (MUC1 and MUC16) as a prognostic factor for mucinous adenocarcinoma of the uterine cervix.

AIM: Only limited data are available regarding mucin antigen expression in adenocarcinoma of the uterine cervix. METHODS: Fifty-two patients with mucinous adenocarcinoma of the endocervical type were enrolled for making clear implication of the mucin antigens. The expression of mucin antigens in hysterectomized specimens were determined immunohistochemically. Clinicopathological characteristics and prognosis included International Federation of Gynecology and Obstetrics (FIGO) stage, histological grade, nodal and ovarian metastases, overall and disease-free survivals. The relationships of the expression of mucin antigens to various variables were investigated using uni- and multivariate analyses. RESULTS: The majority of mucinous adenocarcinoma showed overexpression of MUC1 and MUC16. Overexpression of both MUC1 and MUC16 was associated with lower survival rates. Particularly, overexpression of MUC1 was associated with a lower disease-free survival rate and lymph node metastasis. However, absence of expression of MUC1 and/or MUC16 was associated with longer overall and disease-free survival. In cases classified as FIGO stage Ib (n = 35), after adjusting for patient age at diagnosis and stratifying by histological grade, MUC1 and/or MUC 16 overexpression was an independent prognostic factor for overall survival (hazard ratio [HR] = 6.16, 95% confidence interval [CI] = 1.01-118.5, P < 0.05). After stratifying by ovarian metastasis, MUC1 and/or MUC 16 overexpression was also an independent prognostic factor for disease-free survival (HR = 5.50, 95% CI = 0.82-87.4, P < 0.05). CONCLUSION: The expressions of MUC1 and/or MUC16 may be available as independent prognostic factors for the endocervical type of mucinous adenocarcinoma.

Expression profiles of MUC1, MUC2, and MUC4 mucins in human neoplasms and their relationship with biological behavior.

Mucins are high molecular weight glycoproteins that play important roles in carcinogenesis or tumor invasion. To clarify the relationship of the expression patterns of mucins in human neoplasms with their biological behavior, we examined the expression profiles of MUC1, MUC2, and MUC4 mucins in various human neoplasms using immunohistochemistry and in situ hybridization, and compared them with clinicopathologic factors including outcome of the patients. MUC1 or MUC4 expression is related with the aggressive behavior of human neoplasms and a poor outcome of the patients. In contrast, MUC2 expression tends to be related with the indolent behavior of human neoplasms and a favorable outcome of the patients, although indolent pancreatobiliary neoplasms sometimes show invasive growth with MUC1 expression in the invasive areas. The expression of MUC2 mucin in indolent pancreatobiliary neoplasms coincided with expression of MUC2 mRNA. Our recent studies to clarify the MUC2 gene regulation mechanism disclosed that DNA methylation and histone modification in the 5' flanking region of the MUC2 promoter may play an important role. Further studies of the epigenetics also in MUC1 and MUC4 gene expression may be needed to understand the relationship between the expression of mucins in human neoplasms with their biological behavior.

Immunohistochemical expression profiles of mucin antigens in salivary gland mucoepidermoid carcinoma: MUC4- and MUC6-negative expression predicts a shortened survival in the early postoperative phase.

In mucoepidermoid carcinoma (MEC), the most common salivary gland carcinoma, there is a lack of novel prognostic markers, but post-operative early recurrence strongly affects the clinical course and a poor outcome. It is critical to predict which MEC patients are prone to develop recurrence/metastases. Mucins play pivotal roles in influencing cancer biology, thus affecting cell differentiation, adhesion, carcinoma invasion, aggressiveness and/or metastatic potential. Our aim is to elucidate the significance of expression profiles for mucins, particularly MUC4 and MUC6, and their correlations with various clinicopathological features and recurrence in salivary gland MECs. We performed immunohistochemical analyses on patients with surgically resected primary MEC using antibodies against mucin core proteins MUC4/8G7 and MUC6/CLH5 in 73 paraffin-embedded samples. Recurrence was noted in 15 of 73 (20.5%) patients. MUC4 or MUC6 expression was considered to be negative when <30% or 0% of the MEC cells showed positive staining, respectively. MUC4- and/or MUC6-negative expression respectively and variably showed a significant relationship to pathological tumor high-grade, the presence of lymphovascular invasion, lymph node metastasis and/or tumor-related death. In addition, MUC4 showed significantly negative co-expression with MUC6. Kaplan-Meier analyses revealed that not only single MUC4/6-negative expression but also the combination of both predicted significantly shorter disease-free and disease-specific survivals in MECs, especially within the first two years postoperatively. Therefore, each mucin plays a pivotal role in the pathogenesis of MEC progression. The detection of MUC4 and/or MUC6 might be a powerful parameter in the clinical management of MECs in the early postsurgical phase.

Mycobacterium leprae in neurons of the medulla oblongata and spinal cord in leprosy.

Peripheral neuropathy has been extensively studied in leprosy, a chronic disease caused by Mycobacterium leprae, but the central nervous system (CNS) is thought to be free from bacilli. Involvement of the CNS was explored in autopsy cases of clinically cured lepromatous leprosy (n = 67) and in non-leprosy cases (n = 15). Paraffin sections of the medulla oblongata and spinal cord were subjected to hematoxylin and eosin staining, Fite acid-fast staining, and anti-phenolic glycolipid-I (PGL-I) immunostaining. PGL-I-positive areas were microdissected from selected cases and nested polymerase chain reaction (PCR) targeting the M. leprae-specific repetitive sequence was performed. Of the 67 cases of leprosy, 44 (67%) had vacuolar changes of motor neurons either in medulla oblongata (nucleus ambiguous or hypoglossal nucleus) or spinal cord. Fite staining was negative, but PGL-I was positive in vacuolated areas. PCR revealed M. leprae-specific genomic DNA in 18 of 19 cases (95%) with vacuolated changes and 5 of 8 (63%) without vacuolated changes. All of above findings were negative in control cases. Terminal deoxynucleotidyl transferase dUTP nick-end labeling staining did not show a significant increase of apoptosis in the neurons. The PCR positivity had a significant correlation with PGL-I immunostaining (p < 0.05). The presence of vacuolar changes in the spinal cord was correlated with hand and feet deformity grades (p = 0.04). This study provides significant additional evidence to indicate that M. leprae is present in the CNS in a subset of patients. Further investigation is required to correlate this finding to motor dysfunction and silent neuropathy in leprosy.

Risk factors of gastric cancer specific for tumor location and histology in Cali, Colombia.

AIM: To examine histology- and tumor-location specific risk factors of gastric cancer (GC). METHODS: This was a case-control study. The study subjects were 216 GC patients newly diagnosed during the period 2000-2002 and 431 controls selected from non-cancer patients matching in age, gender, and hospital. We obtained information on lifestyles, dietary habits, and others by a questionnaire. RESULTS: The subjects who were not eldest among his/her siblings were at a slightly elevated GC risk (OR 1.3; 95% CI 0.8-2.0). Salting meals before tasting was related to an increased GC risk (OR 3.5; 95% CI 1.6- 7.3). Frequent consumptions of fruits (OR 0.3; 95% CI 0.1-1.0) and vegetables (OR 0.3; 95% CI 0.1-1.0) were related to decreased GC risks. On the other hand, frying foods (OR 1.9; 95% CI 1.0-3.6) and cooking with coal (OR 1.8; 95% CI 1.3-2.6) were related to increased GC risks. Neither Laurenos histological classification (intestinal and diffuse types) nor tumor location significantly affected those associations except birth order. The subjects who were not eldest among his/her siblings had an increased risk of GCs in the distal and middle thirds, and their ORs were 1.7 (95% CI 1.0-2.8) and 1.9 (95% CI 0.8-4.3), respectively. The corresponding OR in the upper third stomach was 0.3 (95% CI 0.1-0.9). The differences of those three ORs were statistically significant (P = 0.010). CONCLUSION: The present study shows that birth order, salt intake, consumption of fruits and vegetables, the type of cooking, and cigarette smoking are related to GC risk. In histology and tumor-location specific analyses, non-eldest person among their siblings is related to an increased GC risk in the distal and middle thirds of the stomach, and is related to a decreased GC risk in the cardia.

Mapping of the methylation pattern of the MUC2 promoter in pancreatic cancer cell lines, using bisulfite genomic sequencing.

Expression of the MUC2 gene is controlled by the methylation of CpG sites in the promoter region, but the detailed methylation status of this region has yet to be reported. We have mapped the complete methylation status of the MUC2 promoter from position -1989 to position +288 upstream, a region that contains 59 CpG sites, using bisulfite genomic sequencing in two pancreatic cancer cell lines (PANC1, BxPC3) and in isolated normal colon crypts as a control. The MUC2 promoter in PANC1, a cell line that does not express MUC2, was highly methylated (average 87%, complete methylation at 28 of the 59 CpG sites), while the promoter region in the MUC2-expressing BxPC3 cell line (average 43%, complete methylation at 2 of 59 CpG sites) and in MUC2-expressing normal colon crypts (average 33%, no CpG site was completely methylated) were only partially methylated (P<0.0001). 5-Aza-2'-deoxycytidine treatment of PANC1 cells reduced the methylation level (average 36%) and induced MUC2 mRNA expression. However, mRNA expression of AP2, SP1 and CDX2 was not affected by this treatment. Our data provide the first detailed methylation map of the MUC2 promoter region for the first time, using the conversion-specific bisulfite genomic sequencing. Previously unproven methylation sites were detected, and some AP2 and SP1 binding sites showed different methylation levels among PANC1, BxPC3 and colonic crypt cells. Our mapping data provide an essential basis for further studies of methylation-regulated MUC2 inactivation.

Polymorphisms of the CYP1B1 gene as risk factors for human renal cell cancer.

PURPOSE: CYP1B1 activates various environmental carcinogens in human tissues, including renal tissues. We hypothesize that certain polymorphisms of the CYP1B1 gene are risk factors for renal cell cancer. The rationale for this hypothesis is that chemical procarcinogenic compounds require metabolic activation by oxidative enzymes such as CYP1B1 to be transformed into potentially carcinogenic forms. To test this hypothesis, we investigated the genotypic distributions of six different loci on the CYP1B1 gene and their association with renal cell cancer. EXPERIMENTAL DESIGN: DNA from 211 cases of human renal cell cancer and 200 healthy controls was analyzed by sequence-specific PCR and direct DNA sequencing to determine the genotypic frequencies of six different polymorphic loci on the CYP1B1 gene. RESULTS: The results of this study demonstrate that the frequencies of genotype 119T/T and genotype 432G/G were significantly higher in renal cell cancer patients compared with healthy normal controls. The relative risks were calculated as 3.01 and 2.17 for genotypes 119T/T and 432G/G, respectively, in renal cell carcinoma patients. These genotypic distributions were also significantly different between male and female patients. The relative risks of genotype 119T/T were calculated as 3.95 in males and 1.92 in females, and the relative risks of genotype 432G/G were calculated as 2.81 in males and 1.35 in females. CONCLUSIONS: The present study demonstrates for the first time that the polymorphisms at codons 119 and 432 may be risk factors for renal cancer, especially in the male population.

Three cases of spontaneous superficial temporal artery aneurysm with literature review.

Spontaneous, nontraumatic, superficial temporal artery (STA) aneurysms have been rarely reported. We herewith report three cases of spontaneous and true STA aneurysms. All patients, a 65-year-old male, a 76-year-old female, and a 47-year-old female, had no history of head trauma that requires medical attention. Painless, pulsatile, and slowly growing calvarial lump was the symptom leading to image studies. All the lumps were preoperatively diagnosed as STA aneurysms by magnetic resonance angiography and/or three-dimensional computed tomographic angiography. One case was accompanied by anterior communicating aneurysm. And another case was associated with two more scalp aneurysms arising from occipital artery and contralateral STA. Pathologic studies showed that all three were true aneurysms, with intact media and adventitia but without organized hematoma. Literature review showed that 8% of all STA aneurysms comprised spontaneous STA aneurysms. We found 32 cases (19 males and 13 females) of well-described spontaneous STA aneurysms including ours. Twenty-eight cases (87.5%) were true aneurysms. Seven cases (21.9%) had coexisting vascular lesions. Five (15.6%) of these seven cases were diagnosed with cerebral or abdominal aneurysm. Multiple scalp aneurysms are quite rare; only two cases including ours have been reported. It seems important to know that spontaneous STA aneurysms may coexist with other vascular lesions including intracranial aneurysm.

Long-term survivor diagnosed with arrhythmogenic right ventricular cardiomyopathy/dysplasia.

The subject was a 70 year-old man who survived for 31 years after being diagnosed with right ventricular cardiomyopathy, having undergone right ventricular (RV) aneurysmectomy at the age of 39. His arrhythmia and syncopal attacks were effectively abolished after the original aneurysmectomy. Although he frequently suffered from right heart failure, hemodialysis improved his status. However, the patient died due to worsening anasarca caused by RV low output syndrome. Autopsy results indicated extensive replacement of the RV myocardium with fibrous and fatty tissues. This case suggests that patients with arrhythmogenic RV cardiomyopathy, but without left ventricular abnormalities and rapid ventricular arrhythmia, have a relatively favorable prognosis, although RV abnormalities may be progressive.

Primary leiomyosarcoma of the pulmonary artery: a case of a 20-month survivor after incomplete surgical resection.

We report a 53-year-old man who presented with dyspnea and low-grade fever. Cardiac ultrasound showed pulmonary hypertension and an ill-defined echogenic mass within the pulmonary trunk. Computed tomography scan revealed an inhomogeneous mass which filled the main pulmonary trunk with near-total occlusion, and extended into both pulmonary arteries. Anticoagulant therapy was administered based on a presumptive diagnosis of pulmonary thromboembolism. Positron-emission tomography scan was useful for differentiating the mass, which was determined as a pulmonary artery sarcoma by surgical resection. Although complete resection was impossible, the patient survived for 20 months with adjuvant chemotherapy and medical treatment.

FDG PET/CT and diffusion-weighted imaging of head and neck squamous cell carcinoma: comparison of prognostic significance between primary tumor standardized uptake value and apparent diffusion coefficient.

PURPOSE: To compare primary tumor (18)F-fluorodeoxyglucose (FDG) maximum standardized uptake value (SUV(max)) and diffusion-weighted imaging (DWI) apparent diffusion coefficient (ADC) obtained in the same patients with head and neck squamous cell carcinoma (HNSCC) to clarify the prognostic significance of both indexes. MATERIALS AND METHODS: The study population comprised 26 patients with HNSCC visible on both pretreatment FDG PET/CT and DWI. Correlation between SUV(max) and ADC (b values; 0 and 800 seconds/mm(2)) was analyzed by the Spearman's rank test. Disease-free survival (DFS) was calculated by the Kaplan-Meier method. Prognostic significance was assessed by the long-rank test and Cox proportional hazards analysis. RESULTS: SUV(max) and ADC correlated significantly and negatively (ρ = -0.566, P = 0.005). High (>12.1) SUV(max) (P < 0.001), low (≤ 0.88) ADC (P = 0.009), high (T3-4) T stage (P = 0.030), and high (N2-3) N stage (P = 0.007) were significant in predicting poor 2-year DFS. The accuracy for predicting disease events was 81% (21/26) for SUV(max) (>12.1) and 73% (19/26) for ADC(≤ 0.88) without significant difference between them (P = 0.52). Disease event hazards ratios for significant unadjusted SUV(max) (P = 0.015) and ADC (P = 0.039) remained significant when adjusted for other dichotomized clinical covariates (SUV(max); P = 0.009-0.039, ADC; P = 0.017-0.037) except SUV(max) for ADC and ADC for SUV(max) and T stage. CONCLUSION: These results suggest that pretreatment primary tumor SUV(max) and ADC correlate significantly and negatively and both may have similar potential to predict DFS or disease events of HNSCC.

MUC1 expression is regulated by DNA methylation and histone H3 lysine 9 modification in cancer cells.

MUC1 is a transmembrane mucin that is highly expressed in various cancers and correlates with malignant potential. Important cancer-related genes such as p16 and E-cadherin are controlled epigenetically; however, MUC1 has been overlooked in epigenetics. Herein, we provide the first report that MUC1 gene expression is regulated by DNA methylation and histone H3 lysine 9 (H3-K9) modification of the MUC1 promoter. The recently developed MassARRAY assay was performed to investigate the DNA methylation status of 184 CpG sites from -2,753 to +263. Near the transcriptional start site, the DNA methylation level of MUC1-negative cancer cell lines (e.g., MDA-MB-453) was high, whereas that of MUC1-positive cell lines (e.g., MCF-7) was low. Histone H3-K9 modification status was also closely related to MUC1 gene expression. Furthermore, MUC1 mRNA expression in MUC1-negative cells was restored by treatment with the DNA methylation inhibitor 5-aza-2'-deoxycytidine. Our results indicate that DNA methylation and histone H3-K9 modification in the 5' flanking region play a critical role in MUC1 gene expression, and this study defines MUC1 as a new member of the class of epigenetically controlled genes. An understanding of the epigenetic changes of MUC1 may be of importance for diagnosis of carcinogenic risk and prediction of outcome for cancer patients.

Mucin expression profile in pancreatic cancer and the precursor lesions.

In this review article, we demonstrate the mucin expression profile in normal tissue, invasive ductal carcinoma (IDC), two subtypes of intraductal papillary-mucinous neoplasm (IPMN dark cell type and IPMN clear cell type), pancreatic intraepithelial neoplasia (PanIN), and mucinous cystic neoplasm (MCN) of the pancreas. In MUC1, there are various glycoforms, such as poorly glycosylated MUC1, sialylated MUC1, and fully glycosylated MUC1. IDCs showed high expression of all the glycoforms of MUC1. IPMNs dark cell type showed no expression or low expression of all the glycoforms of MUC1. IPMNs clear cell type showed low expression of poorly glycosylated MUC1, but expression of sialylated MUC1 and fully glycosylated MUC1. Expression of MUC2 was negative in IDCs, high in IPMNs dark cell type and low in IPMNs clear cell type. MUC5AC was highly expressed in IDCs, IPMNs dark cell type, and IPMNs clear cell type. MUC6 expression was higher in IPMNs clear cell type than in IDCs and IPMNs dark cell type. Our recent study demonstrated that high expression of MUC4 in IDCs is correlated with a poor outcome for patients. In PanINs, expression of both MUC5AC and MUC6 are an early event, whereas up-regulation of MUC1 is a late event. MCNs do not look as if they will show a specific mucin expression profile according to the literature review.

A micropapillary pattern is predictive of a poor prognosis in lung adenocarcinoma, and reduced surfactant apoprotein A expression in the micropapillary pattern is an excellent indicator of a poor prognosis.

A micropapillary pattern is defined as papillary tufts without a fibrovascular core and is known to be a factor that indicates a poor prognosis in numerous cancers. However, their role in lung adenocarcinoma has not been investigated widely. In 185 cases of small-size lung adenocarcinoma (< or =3 cm), cases with a micropapillary pattern ratio of more than 1% (analyzed by NIH image) were defined as micropapillary pattern positive. Correlations between the micropapillary pattern and clinicopathological factors were investigated and immunohistochemical expression of mucin and various antigens was examined in regions with and without micropapillary patterns. Micropapillary pattern-positive tumors (micropapillary pattern ratio > or =1%) were observed in 11.4% of cases (21/185) and the micropapillary pattern ratio correlated with TNM stage (P=0.0002), lymphatic invasion (P=0.0002) and lymph node metastasis (P=0.03). Disease-free interval (P<0.0002) and survival (P=0.027) were significantly shorter for micropapillary pattern-positive patients, and micropapillary pattern-positive stage IA cases also had a significantly shorter disease-free interval (P<0.0001). MUC1 was expressed strongly across the surface of the micropapillary structure, whereas MUC4 tended to show lower expression in the micropapillary pattern. It was noteworthy that the disease-free interval in patients with high surfactant apoprotein A expression was significantly better than in patients with low surfactant apoprotein A expression (P=0.03), and no recurrence or death occurred in patients with high surfactant apoprotein A expression. Our results show that the micropapillary pattern ratio correlates with lymphatic invasion and lymph node metastasis, and that a high micropapillary pattern ratio leads to a poor prognosis. High MUC1 expression on the surface is an important characteristic of a micropapillary pattern, and reduced surfactant apoprotein A expression in the micropapillary pattern may be an excellent indicator for poor prognosis in small-size lung adenocarcinoma.