Remarkable response as a new indicator for endoscopic evaluation of local efficacy of non-surgical treatments for esophageal cancer.

In Japan, standard of care of the patients with resectable esophageal cancer is neoadjuvant chemotherapy (NAC) followed by esophagectomy. Patients unfitted for surgery or with unresectable locally advanced esophageal cancer are generally indicated with definitive chemoradiotherapy (CRT). Local disease control is undoubtful important for the management of patients with esophageal cancer, therefore endoscopic evaluation of local efficacy after non-surgical treatments must be essential. The significant shrink of primary site after NAC has been reported as a good indicator of pathological good response as well as favorable survival outcome after esophagectomy. And patients who could achieve remarkable shrink to T1 level after CRT had favorable outcomes with salvage surgery and could be good candidates for salvage endoscopic treatments. Based on these data, "Japanese Classification of Esophageal Cancer, 12th edition" defined the new endoscopic criteria "remarkable response (RR)", that means significant volume reduction after treatment, with the subjective endoscopic evaluation are proposed. In addition, the finding of local recurrence (LR) at primary site after achieving a CR was also proposed in the latest edition of Japanese Classification of Esophageal Cancer. The findings of LR are also important for detecting candidates for salvage endoscopic treatments at an early timing during surveillance after CRT. The endoscopic evaluation would encourage us to make concrete decisions for further treatment indications, therefore physicians treating patients with esophageal cancer should be well-acquainted with each finding.

Fetal Cerebellar Growth Curves Based on Biomathematics in Normally Developing Japanese Fetuses and Fetuses with Trisomy 18.

We used biomathematics to describe and compare cerebellar growth in normally developing and trisomy 18 Japanese fetuses. This retrospective study included 407 singleton pregnancies with fetuses at 14-39 weeks of gestation and 33 fetuses with trisomy 18 at 17-35 weeks. We used ultrasonography to measure fetal transverse cerebellar diameter (TCD) and anteroposterior cerebellar diameter (APCD). We hypothesized that cerebellar growth is proportional to cerebellar length at any given time point. We determined the formula L(t) ≒Keat+r, where e is Napier's number, t is time, L is cerebellar length, and a, K, and r are constants. We then obtained regression functions for each TCD and APCD in all fetuses. The regression equations for TCD and APCD values in normal fetuses, expressed as exponential functions, were TCD(t)=27.85e0.02788t-28.62 (mm) (adjusted R2=0.997), and APCD(t)=324.29e0.00286t-322.62 (mm) (adjusted R2=0.995). These functions indicated that TCD and APCD grew at constant rates of 2.788%/week and 0.286%/week, respectively, throughout gestation. TCD (0.0153%/week) and APCD (0.000430%/week) grew more slowly in trisomy 18 fetuses. This study demonstrates the potential of biomathematics in clinical research and may aid in biological understanding of fetal cerebellar growth.

Tumor-stroma ratio can predict lymph-node metastasis in cT1/2N0 oral tongue squamous cell carcinoma independent of tumor budding grade.

BACKGROUND: cT1/2 oral tongue squamous cell carcinoma (OTSCC) often metastasizes to cervical lymph nodes. However, predicting neck lymph-node metastasis (NLM) remains challenging. Pathomorphological evaluation of tumor budding grade (TBG) and tumor-stroma ratio (TSR) reportedly can predict lymph-node metastases. Hence, this study aimed to evaluate TBG and TSR in OTSCC and investigate their relationship to occult NLM and cancer relapse. METHODS: Clinicopathological data of patients with cT1/2N0 OTSCC treated at the University of Tokyo Hospital between 2007 and 2017 were collected. TBG and TSR were evaluated using hematoxylin-eosin staining and cytokeratin AE1/AE3 immunostaining. RESULTS: Out of 70 patients, 16 underwent elective neck dissection in addition to primary-tumor resection, whereas 54 did not. During follow-up, NLM was found in 35 patients. NLM correlated with the pathological depth of invasion (pDOI) (p < 0.001), TBG (p = 0.008), and TSR (p < 0.001) in univariate analysis and pDOI (p = 0.01) and TSR (p = 0.02) in multivariate analysis. The 5-year recurrence-free survival rate (RFS) was 78% for patients with a pDOI ≤ 5 mm and stroma-poor tumors and 33% for patients with a pDOI > 5 mm and stroma-rich tumors. CONCLUSION: Patients with a pDOI > 5 mm and stroma-rich tumors have a high risk for cancer relapse. TSR and pDOI may be promising NLM predictors in cT1/2N0 OTSCC.

An autopsy case of COVID-19-like acute respiratory distress syndrome after mRNA-1273 SARS-CoV-2 vaccination.

We report the first case with COVID-19-like acute respiratory distress syndrome after mRNA-1273 SARS-CoV-2 vaccination. An 88-year-old woman developed dyspnea several hours after vaccination with the second dose of mRNA-1273. She was hospitalized on day nine due to worsening dyspnea. Chest computed tomography showed bilateral ground-glass opacities and consolidations, mainly in the peripheral lung areas. Repeat polymerase chain reaction tests for SARS-CoV-2 were negative, although the serum level of antibodies against spike protein was extremely elevated. Her condition did not improve with high-dose corticosteroids and high-flow nasal cannula oxygen therapy; she died on day 18. Autopsy findings revealed very early-phase diffuse alveolar damage in the whole lung without other lung diseases. The clinical and pathological findings suggested vaccine-induced acute respiratory distress syndrome. Serological and pathological tests might be useful to differentiate the disease from COVID-19.

The first case of gastric leiomyosarcoma developed through malignant transformation of leiomyoma.

Malignant transformation of gastric leiomyoma has not been reported, and therefore it is considered to have virtually no malignant potential. We report a case of gastric leiomyosarcoma arising from leiomyoma. The patient is a 72-year-old man with a submucosal mass measuring 20 mm in diameter, which was incidentally identified by an endoscopic surveillance. A biopsy suggested a diagnosis of leiomyosarcoma, and local excision was performed. Pathological examination revealed that the tumor was composed of two distinct components: typical leiomyoma-like area in the periphery and leiomyosarcoma component exhibiting higher cellularity, prominent nuclear atypia, necrosis, and increased mitosis. Immunohistochemically, in the latter, p53 overexpression, increased Ki-67 labeling index, and attenuated expression of smooth muscle markers were noted. This is the first report to demonstrate the presence of leiomyoma-leiomyosarcoma sequence in the stomach that is well recognized in the uterus. Our observation highlights the potential occurrence of malignant transformation of gastrointestinal leiomyoma.

Potential roles of gastroesophageal reflux in patients with superficial esophageal squamous cell carcinoma without major causative risk factors.

BACKGROUND: Cigarette smoking, alcohol consumption, and Lugol-voiding lesions (LVLs) are the major causative risk factors of esophageal squamous cell carcinoma (ESCC); however, reports on ESCC cases unrelated to these risk factors are very limited. Here, we investigated the clinicopathological features and etiology of such cases. METHODS: We retrospectively analyzed 704 consecutive superficial ESCC tumors of 512 patients who were treated with endoscopic submucosal dissection. The enrolled patients were divided into two groups-the very low-risk (VLR)-group and risk (R)-group-based on the presence of the abovementioned risks. Clinical, endoscopic, and pathological characteristics and genetic findings were assessed in both groups. RESULTS: The VLR-group consisted of 21 (4.1%) patients, who were characteristically female. Patients in the VLR-group presented gastroesophageal reflux disease (GERD), hiatal hernia, and non-open-type atrophic gastritis, and were negative for Helicobacter pylori. We found unique endoscopic features-frequently observed in the posterior wall of the middle thoracic esophagus-with a linear shape that closely resembled the erosion-like form of GERD. Additionally, histopathological examination showed that these tumors presented atypical nuclei limited to the basal and parabasal layer, sequential to the surrounding changes that presented pathological chronic inflammation of esophagitis. Evaluation of somatic mutations in cancer-related genes using next-generation sequencing revealed that the positive carcinogenic potential (TP53 mutation) of the tumors was relatively frequent in the VLR-group. CONCLUSIONS: Our study suggests that ESCC without major causative factors is related to GERD, with no remarkable oncogenic difference.

Colitis-associated colorectal adenocarcinomas frequently express claudin 18 isoform 2: implications for claudin 18.2 monoclonal antibody therapy.

AIMS: Claudin 18 (CLDN18) is a member of the claudin family of cell surface proteins, which are widely expressed in epithelial cells and play a role in cell-cell adhesion. CLDN18 isoform 2 (CLDN18.2) is specifically expressed in gastric epithelial cells, and is frequently expressed at high levels in gastric adenocarcinoma. On the basis of this, zolbetuximab, a targeted monoclonal antibody, has been developed for patients with CLDN18.2-positive gastro-oesophageal adenocarcinoma. Colitis-associated colorectal adenocarcinomas (CACs) tend to lose intestinal markers and show aberrant gastric mucin expression. Furthermore, clinical trials of human epidermal growth factor receptor 2 (HER2) inhibitor therapy for colorectal carcinoma are ongoing. However, the expression profile of CLDN18.2 and HER2 has not been described in a series of human CACs. METHODS AND RESULTS: We performed immunohistochemistry for CLDN18 and HER2 on 56 consecutive CACs from 55 inflammatory bowel disease patients, and compared the expression profile with that of a control group of 56 sporadic colorectal adenocarcinomas (CRCs). CLDN18.1 expression and CLDN18.2 expression were validated by reverse transcription polymerase chain reaction (PCR) in paraffin-embedded CRC tissues. CLDN18 was positive in 27% (15/56) of CACs and in 5% (3/56) of sporadic CRCs (P = 0.004), and CLDN18-positive CACs were more likely to have lymph node metastasis than CLDN18-negative CACs (67% versus 36%; P = 0.017). CLDN18 expression was significantly associated with MUC5AC expression (P < 0.001) and loss of special AT-rich sequence-binding protein 2 expression (P = 0.005) in CACs. CLDN18.2 was expressed in CRCs that were immunoreactive for CLDN18. Only 4% of CACs were immunoreactive for HER2, and no differences were identified in sporadic CRCs. CONCLUSIONS: These findings suggest that certain CAC cases may be candidates for targeted zolbetuximab therapy.

Frequent DYRK2 gene amplification in micropapillary element of lung adenocarcinoma - an implication in progression in EGFR-mutated lung adenocarcinoma.

The present study aimed to discern the molecular alterations involved in the progression of EGFR-mutated lung adenocarcinoma (LADC). We previously demonstrated that the micropapillary (mPAP) element is the most important histological factor for assessing malignant grades in LADCs. Therefore, mPAP and other elements were separately collected from three cases of EGFR-mutated LADC using laser capture microdissection and subjected to a comprehensive mRNA expression analysis. We focused on DYRK2 in this study because its level showed a substantial increase in EGFR-mutated LADCs with mPAP. We also immunohistochemically examined 130 tumors for the expression of DYRK2. The results confirmed a strong expression of DYRK2 in EGFR-mutated LADC with mPAP. Fluorescent in situ hybridization (FISH) analyses targeting the DYRK2 locus revealed frequent gene amplification in EGFR-mutated LADC, specifically occurring in the high-grade components, like mPAP. In summary, the results of this study suggest that DYRK2 overexpression through gene amplification is one of the molecular mechanisms responsible for promoting the progression of EGFR-mutated LADC.

Histopathological validation of magnifying endoscopy for diagnosis of mixed-histological-type early gastric cancer.

BACKGROUND: The undifferentiated-type (UDT) component profoundly affects the clinical course of early gastric cancers (EGCs). However, an accurate preoperative diagnosis of the histological types is unsatisfactory. To date, few studies have investigated whether the UDT component within mixed-histological-type (MT) EGCs can be recognized preoperatively. AIM: To clarify the histopathological characteristics of the endoscopically-resected MT EGCs for investigating whether the UDT component could be recognized preoperatively. METHODS: This was a single-center retrospective study. First, we attempted to clarify the histopathological characteristics of the endoscopically-resected MT EGCs with emphasis on the UDT component. Histopathological examination investigated each lesion's UDT component: (1) Whole mucosal layer occupation of the UDT component; (2) UDT component exposure to the surface of the mucosa; and (3) existence of a clear border between the differentiated-type and UDT components. Then, preoperative endoscopic images with magnifying endoscopy with narrow-band imaging (ME-NBI) were examined to identify whether the endoscopic UDT component finding was recognizable within the area where it was present in the histopathological examination. The preoperative biopsy results and comparative relationships between endoscopic and histopathological findings were also examined. RESULTS: In the histopathological examination, the whole mucosal layer occupation of the UDT component and exposure of the UDT component to the mucosal surface were observed in 67.3% (33/49) and 79.6% (39/49) of samples, respectively. A clear distinction of the border between the differentiated-type and UDT components could not be drawn in 65.3% (32/49) of MT lesions. In the endoscopic examination, the preoperative endoscopic images showed that only 24.5% (12/49) of MT EGCs revealed the UDT component within the area where it was present histopathologically. Histopathological UDT predominance was the single significant factor associated with the presence of the endoscopic UDT component finding (61.5% vs 11.1%, P = 0.0009). Only 26.5% (13/49) of the lesions were diagnosed from the pretreatment biopsy as having a UDT component. Combined results of the pretreatment biopsy and ME-NBI showed the preoperative presence of the UDT component in 40.8% (20/49) of MT EGCs. CONCLUSION: Recognition of a UDT component within MT EGCs is difficult even when pretreatment biopsy and ME-NBI are combined. Endoscopic resection plays a significant role in both treatment and diagnosis.

Clinicopathological features of early gastric cancers arising in Helicobacter pylori uninfected patients.

BACKGROUND: Persistent Helicobacter pylori (H. pylori) infection causes chronic inflammation, atrophy of the gastric mucosa, and a high risk of developing gastric cancer. In recent years, awareness of eradication therapy has increased in Japan. As H. pylori infections decrease, the proportion of gastric cancers arising from H. pylori uninfected gastric mucosa will increase. The emergence of gastric cancer arising in H. pylori uninfected patients though rarely reported, is a concern to be addressed and needs elucidation of its clinicopathological features. AIM: To evaluate the clinicopathological features of early gastric cancer in H. pylori-uninfected patients. METHODS: A total of 2462 patients with 3375 instances of early gastric cancers that were treated by endoscopic submucosal dissection were enrolled in our study between May 2000 and September 2019. Of these, 30 lesions in 30 patients were diagnosed as H. pylori-uninfected gastric cancer (HpUIGC). We defined a patient as H. pylori-uninfected using the following three criteria: (1) The patient did not receive treatment for H. pylori, which was determined by investigating medical records and conducting patient interviews; (2) Lack of endoscopic atrophy; and (3) The patient was negative for H. pylori after being tested at least twice using various diagnostic methods, including serum anti-H. pylori-IgG antibody, urease breath test, rapid urease test, and microscopic examination. RESULTS: The frequency of HpUIGC was 1.2% (30/2462) for the patients in our study. The study included 19 males and 11 females with a mean age of 59 years. The location of the stomach lesions was divided into three sections; upper third (U), middle third (M), lower third (L). Of the 30 lesions, 15 were U, 1 was M, and 14 were L. Morphologically, 17 lesions were protruded and flat elevated type (0-I, 0-IIa, 0-IIa + IIc), and 13 lesions were flat and depressed type (0-IIb, 0-IIc). The median tumor diameter was 8 mm (range 2-98 mm). Histological analysis revealed that 22 lesions (73.3%) were differentiated type.The HpUIGC lesions were classified into fundic gland type adenocarcinoma (7 cases), foveolar type well-differentiated adenocarcinoma (8 cases), intestinal phenotype adenocarcinoma (7 cases), and pure signet-ring cell carcinoma (8 cases). Among 30 HpUIGCs, 24 lesions (80%) were limited to the mucosa; wherein, the remaining 6 lesions showed submucosal invasion. One of the submucosal invasive lesions showed more than 500 µm invasion. The mucin phenotype analysis identified 7 HpUIGC with intestinal phenotype and 23 with gastric phenotype. CONCLUSION: We elucidated the clinicopathological characteristics of HpUIGC, revealing recognition not only undifferentiated-type but also differentiated-type. In addition, intestinal phenotype tumors were also observed and could be an important tip.

The protective effect of Bifidobacterium bifidum G9-1 against mucus degradation by Akkermansia muciniphila following small intestine injury caused by a proton pump inhibitor and aspirin.

BACKGROUND: Proton pump inhibitors (PPIs) can alleviate upper gastrointestinal injury but paradoxically exacerbate aspirin (ASA)-induced small intestine injury. In this study, our goal was to simulate this exacerbation by developing an appropriate animal model, which may help in establishing treatments. Methods: Male mice were fed a 60% fructose diet for 9 weeks, then administered 200 mg/kg ASA 3 h before sacrifice. The PPI omeprazole was administered intraperitoneally once daily for 9 weeks. Bifidobacterium bifidum G9-1 was administered orally for the last week. In addition, Akkermansia muciniphila was administered orally for 9 weeks instead of omeprazole. Results: ASA-induced small-intestine injury was observed in high-fructose fed mice. Omeprazole exacerbated ASA-induced intestinal damage, significantly decreased Bifidobacteria levels, and significantly increased A. muciniphila counts in the jejunum. The direct administration of A. muciniphila caused thinning of the jejunum mucus layer, which was also observed in mice that received ASA and omeprazole. On the other hand, the administration of Bifidobacterium bifidum G9-1 inhibited A. muciniphila growth and reduced thinning of the mucus layer. The number of goblet cells in the jejunum was reduced by the administration of ASA and omeprazole, while Bifidobacterium bifidum G9-1 prevented the reduction. Conclusions: These results suggest that omeprazole-induced gut dysbiosis promotes Akkermansia growth and inhibits Bifidobacterium growth, leading to a thinning of the mucus layer through a reduction in goblet cells in the small intestine. Probiotics are, therefore, a promising approach for the treatment of small intestine injury.

Distribution of PAPP-A and total hCG between 11 and 13 weeks of gestation in Japanese pregnant women.

Objectives: To establish the reference values for PAPP-A and total hCG between 11 and 13 weeks of gestation for the use of risk assessment of fetal aneuploidy in Japanese pregnant women.Methods: A multicenter prospective study was conducted. The subjects included only Japanese pregnant women with viable singleton who requested the first trimester combined (nuchal translucency and maternal serum marker) screening for fetal aneuploidy. Reference values of PAPP-A and total hCG in Japanese population were made and compared with them in Caucasian.Results: Overall 1,751 Japanese pregnant women were analyzed. Median vales of maternal serum concentration in Japanese pregnant women from 11 + 0-13 + 6 weeks' gestation were ranged from 3.01 to 9.51 mIU/mL for PAPP-A and from 70.2 to 58.3 IU/mL for total-hCG, respectively. Regression curve of median maternal serum PAPP-A and total-hCG concentration against gestational days are significantly higher in Japanese comparing with Caucasian. At most distant values, Japanese serum concentration indicated 1.45 MoM for total-hCG and 1.70 MoM for PAPP-A based on Caucasian regression curves.Conclusion: A modification of the equations by specific reference values is necessary for Japanese pregnant women at the risk assessment of chromosomal abnormalities using the first trimester maternal serum marker.

Impact of Referral Center Pathology Review on Diagnosis and Management of Patients With Appendiceal Neoplasms.

CONTEXT.­: Data regarding the clinical impact of subspecialist pathology review of appendiceal neoplasms are limited. OBJECTIVE.­: To determine whether pathology review by gastrointestinal pathologists at a tertiary-care referral center resulted in significant changes in the diagnosis and clinical management of appendiceal neoplastic lesions. DESIGN.­: We conducted a retrospective review of all patients with an initial diagnosis of appendiceal neoplasm referred to a tertiary-care referral center in Ontario, Canada, from 2010-2016. The discordance rate between original and review pathology reports, the nature of discordances, and the impact of any discordance on patient management were recorded. RESULTS.­: A total of 145 patients with appendiceal lesions were identified (low-grade mucinous appendiceal neoplasm [n = 79], invasive mucinous adenocarcinoma [n = 12], "colorectal type" adenocarcinoma [n = 12], goblet cell carcinoid and adenocarcinomas ex goblet cell carcinoid [n = 24], and other lesions/neoplasms [n = 20]). One or more changes in diagnoses were found in 36 of 145 cases (24.8%), with changes within the same category of interpretation (n = 10), stage (n = 7), grade (n = 6), and categoric interpretation (n = 5) being the most common. In 10 of 36 patients (28%), the diagnostic change led to a significant change in management, including recommendation for additional surveillance, systemic chemotherapy, additional surgery, or discontinuation of surveillance. CONCLUSIONS.­: Subspecialist pathology review of appendiceal neoplastic lesions led to a change in diagnosis in 36 of 145 cases (24.8%), of which nearly 30% (10 of 36 cases) led to a change in clinical management. The overall rate of clinically significant discordances was 7% (10 of 145). Our findings suggest that subspecialist pathology review of appendiceal neoplasms referred to specialized centers is justified.

Correlation between the macroscopic severity of Crohn's disease in resected intestine and bowel wall thickness evaluated by water-immersion ultrasonography.

Objectives: Transabdominal ultrasonography is a common and accurate tool for managing Crohn's disease (CD); however, the significance of the resulting data is poorly understood. This study was performed to determine the association between bowel wall thickness evaluated by water-immersion ultrasonography and macroscopic severity, namely, refractory inflammation and subsequent fibrosis in CD surgical specimens.Materials and methods: We retrospectively evaluated 100 segments of colon and small intestine from 27 patients with CD. The resected specimens were placed in saline postoperatively, and bowel wall thickness was measured by water-immersion ultrasonography and compared with macroscopic findings. Correlations between bowel wall thickness and macroscopic findings were assessed using analysis of variance and receiver operating characteristic curves.Results: According to the progression of macroscopic severity, the mean bowel wall thickness was increased as follows: macroscopically intact: 4.1 mm, longitudinal ulcer scars: 5.4 mm, longitudinal open ulcers: 6.0 mm, large ulcers: 6.4 mm, cobblestone-like lesions: 7.1 mm, and fibrotic strictures: 7.4 mm. For all lesions except longitudinal ulcer scars, the bowel wall thickness was significantly thicker than that of macroscopically-intact areas (p < .001). According to receiver operating characteristic curves, bowel wall thickness >4.5 mm was associated with CD lesions, and thickness >5.5 mm was associated with more severe lesions.Conclusions: The bowel wall thickness of CD lesions was evaluated by water-immersion ultrasonography correlated with macroscopic disease severity.

Pulmonary melanocytic nevus - A case report with a mutation analysis of common driver oncogenes.

Nevi are benign melanocytic tumors, and some nevi are considered to develop into malignant melanomas. Most nevi arise in the skin, but nevi occasionally occur in the conjunctiva, esophageal mucosa, or at other sites. Pulmonary melanocytic nevi are extremely rare, and only one case has been reported in the literature. Here, we present a case of pulmonary melanocytic nevus, involving a BRAF gene mutation (V600E), and we discuss the potential significance of this condition as a precursor to pulmonary malignant melanoma.

Unique expression profiles of mucin proteins in interstitial pneumonia-associated lung adenocarcinomas.

In order to clarify idiopathic interstitial pneumonia (IIP)-associated lung adenocarcinoma (LADC), we herein focused on the expression profiles of mucin proteins, the most common cellular differentiation markers. The expression of the mucin (MUC) 1, MUC2, MUC3B, MUC4, MUC5AC, MUC5B, MUC6, MUC7, MUC9, and MUC21 proteins was examined immunohistochemically and their levels were semi-quantified in 80 IIP-associated LADCs and 106 non-IIP LADCs. LADCs were divided into low and high expressers based on thresholds obtained from the receiver operating characteristic (ROC) curves of each mucin protein. Low expressers of MUC1, MUC7, and MUC21 and high expressers of MUC4, MUC5AC, MUC5B, and MUC9 were dominant in the IIP group. Multivariate analyses confirmed that the correlations between mucin expression profiles and IIP-associated LADCs were independent of putative confounding factors, such as smoking, gender, histological types, and cytological types. Thus, the expression profiles of these mucin proteins significantly differed between the IIP and non-IIP groups. IIP-associated LADCs appear to have unique cellular differentiation features and they may develop through a distinct histogenetic pathway. This is the first study to demonstrate that IIP-associated LADCs have unique mucin expression profiles.

Specific expression of MUC21 in micropapillary elements of lung adenocarcinomas - Implications for the progression of EGFR-mutated lung adenocarcinomas.

We investigated the significance of MUC21 in EGFR-mutated lung adenocarcinoma (LADC). Two-hundred forty-one surgically resected LADCs (116 EGFR-mutated and 125 wild-type tumors) were examined for immunohistochemical expression of MUC21 protein. A polyclonal antibody and two monoclonal antibodies (heM21C and heM21D) that bind differentially glycosylated MUC21 epitopes were used, and MUC21 proteins detected by these antibodies were named MUC21P, MUC21C, and MUC21D, respectively. MUC21 mRNA levels were semi-quantified and classified into "high" and "low". Among the immunohistochemical expression detected by three different antibodies, high expressors tended to be related to EGFR mutations. The three varieties of the immunohistochemical expressions were related to different histological elements in the EGFR-mutated LADCs. Either MUC21P or MUC21C high expressors had a higher proportion of lepidic elements with low papillary structure and micropapillary elements. MUC21D high expressors had a significantly higher proportion of micropapillary elements (Mann-Whitney test P ≤0.0001). Furthermore, MUC21D high expressors showed high incidence of lymphatic canal invasion and lymph node metastasis (Pearson x2 test, P = 0.0021, P = 0.0125), and a significantly higher recurrence rate (5-year recurrence-free survival 50.7% vs. 73.8%, log-rank test P = 0.0495). MUC21 proteins with a specific glycosylation status may be involved in the progression of EGFR-mutated LADCs, particularly at the stage where tumors are transforming from pure lepidic to micropapillary through low papillary lepidic lesions.

Colitis-associated colorectal adenocarcinomas are frequently associated with non-intestinal mucin profiles and loss of SATB2 expression.

The special AT-rich sequence binding protein 2 (SATB2) is a sensitive and specific diagnostic marker for colorectal adenocarcinoma and reduced expression of SATB2 is associated with a poor prognosis. Colitis-associated colorectal adenocarcinoma often shows distinct morphologic and molecular phenotypes compared to sporadic cases. However, the SATB2 expression profile in colitis-associated carcinoma has not been defined. We performed immunohistochemistry for SATB2 as well as CDX2, MUC5AC, MUC6 and mismatch repair proteins on 60 consecutive colitis-associated carcinomas from 58 inflammatory bowel disease patients and compared the expression profile to a control group of 32 sporadic colorectal carcinomas. Only 26 (43%) colitis-associated carcinomas expressed SATB2, compared to 29 (91%) sporadic colorectal carcinomas (p < 0.0001). MUC5AC expression was more frequently observed in colitis-associated carcinomas than sporadic colorectal caracinomas (52% and 25% respectively; p = 0.013). Eight (13%) cases of colitis-associated carcinoma showed loss of CDX2 expression, which was retained in all of the sporadic controls (p = 0.047). In colitis-associated carcinoma, 50% of SATB2 negative cases had lymph node metastasis compared to only 15% of SATB2 positive cases (p = 0.007). Loss of SATB2 was particularly frequent in mucinous-type tumors, occurring in 83% of these cases. There was no significant association between SATB2 expression and mismatch repair protein status. These data show that the immunoprofile of colitis-associated carcinoma is different than that seen in sporadic cases. In particular, SATB2 is significantly less sensitive in colitis-associated carcinoma and it should be interpreted cautiously as a marker of colorectal origin in colitis patients. The association between loss of SATB2 and lymph node metastasis suggests that it may have similar prognostic value in the setting of inflammatory bowel disease as in sporadic cases.

A molecular pathological study of four cases of ciliated muconodular papillary tumors of the lung.

Ciliated muconodular papillary tumors (CMPTs) are a recently categorized benign or low-grade malignant neoplasm that develops in the peripheral lung. Only about 40 cases have been reported to date, and the clinicopathological characteristics have yet to be defined in detail. Here, we present four cases of CMPTs with a focus on their immunohistochemical profiles and driver gene mutations. These tumors were a papillary proliferation of a mixture of ciliated, mucous, and basal cells located in the peripheral lung. Ciliated, mucous and basal cells were positive for TTF-1 when using the clone SPT24, but negative for HNF-4α. Basal cells were positive for p40. Mucous cells in some tumors were positive for MUC5AC and MUC6. The Ki-67 index was less than 5%, and strong expression of p53 was not detected. Three of the four tumors had a BRAF (V600E) driver mutation, an EGFR (del E746-T751/S752V) driver mutation, or driver mutations in both EGFR (E709G) and KRAS (G12V). These mutation types are rare for any histological type of lung cancer. The present results confirmed that CMPT is a neoplasm with immunohistochemical features and driver gene mutations that are distinct from those of common lung tumors.