Tomoko Norose

Clinicopathological comparison of the World Health Organization/Wotherspoon score to the Groupe d’Etude des Lymphomes de l’Adult grade for the post‐treatment evaluation of gastric mucosa‐associated lymphoid tissue lymphoma

Background and Aim:  The World Health Organization (WHO) has adopted criteria for the histological differential diagnosis of gastric extranodal marginal zone B‐cell lymphoma of mucosa‐associated lymphoid tissue (GML) based on the criteria proposed by Wotherspoon in 1993 (WHO/Wotherspoon score). These histological criteria are commonly used by pathologists for initial diagnoses, but have not been adopted uniformly for the post‐treatment evaluation of GML. In 2003, the Groupe d’Etude des Lymphomes de l’Adult (GELA) proposed a new histological grading system (GELA grade) in preference to use of the WHO/Wotherspoon score for post‐treatment evaluation. In the present study, we compared the WHO/Wotherspoon and GELA systems to examine which histological criterion is better for post‐treatment evaluation.

Cytology of low-grade cribriform cystadenocarcinoma in salivary glands: Cytological and immunohistochemical distinctions from other salivary gland neoplasms.

Low‐grade cribriform cystadenocarcinoma of the parotid gland is rare malignancy that is classified as a variant of cystadenocarcinoma. In routine cytologic slides from fine‐needle aspiration of a parotid gland, we found several pseudopapillary clusters comprising mucus‐producing cells. They included a few tumor cells having three‐dimensional nuclear atypia and slight hyperchromatism, although most of the tumor cells showed bland nuclei. Our initial cytological diagnosis was: “Indeterminate. Uncertain whether cystadenocarcinoma or cystadenoma.” The subsequent histological diagnosis was low‐grade cribriform cystadenocarcinoma. Immunohistochemical staining showed diffuse and strong reactivity for S‐100; tumor nests that were rimmed by p63+ cells, which suggests intraductal proliferation. Here, we report cytomorphological findings of this case, and discuss cytological and immunohistochemical distinctions between low‐grade cribriform cystadenocarcinoma and other salivary gland tumors, including a review of the literature. Diagn. Cytopathol. 2016;44:241–245.

Immunohistochemical CD73 expression status in gastrointestinal neuroendocrine neoplasms: A retrospective study of 136 patients

The WHO 2010 classification divides gastrointestinal neuroendocrine neoplasms (GI-NENs) into neuroendocrine tumor (NET) G1, NET G2, neuroendocrine carcinoma (NEC) and mixed adenoendocrine carcinoma (MANEC) groups. A total of 136 cases of GI-NENs diagnosed at our hospitals as gastrointestinal carcinoids, endocrine cell carcinomas and NENs over the last 11 years, using the WHO 2010 classification were assessed. Among the 136 cases, 88.2% (120/136) were classified into the NET group (NET G1/G2) and 11.8% (16/136) were classified into the NEC group (NEC/MANEC). The incidences of lymphatic and venous invasions were higher in the NEC group compared with in the NET group (P<0.0001 and P=0.0021, respectively). The immunohistochemical staining of cluster of differentiation 73 (CD73) was evaluated in GI-NENs. CD73 is a potentially useful molecule in tumor immunity. In general, CD73 on the tumor cell membrane converts adenosine monophosphate to adenosine, which restrains the production of interferon-γ and cytocidal activity. Although the association between stem cells of pancreatic NENs and CD73 has been reported, few studies have reported on CD73 expression in GI-NENs. Immunohistochemical CD73 expression on the cytomembrane of neuroendocrine cells was detected in 27.2% (37/136) of the GI-NENs. The positive ratio of CD73 was significantly higher in the NEC group compared with in the NET group (P=0.0015). CD73 is also considered as a potential biomarker of anti-programmed death-1 (PD-1) therapy. The expression of programmed death-ligand 1 (PD-L1) on the cytomembrane of GI-NENs was assessed. The positive ratio of PD-L1 was higher in the NEC group compared with in the NET group (P=0.0011). Furthermore, CD73 expression status was significantly correlated with PD-L1 expression (P<0.0001). These results indicate that CD73 may be an interesting candidate for a biomarker for certain prognostic factors and therapeutics concerning PD-1 therapy.

The role of microvessel density, lymph node metastasis, and tumor size as prognostic factors of distant metastasis in colorectal cancer

Angiogenesis is essential for tumor growth and metastasis. CD105 is reportedly a specific marker for tumor angiogenesis. It has been demonstrated that monoclonal antibodies to CD105 have high affinity for activated endothelial cells. A relationship between metastasis and microvessel density (MVD), as an indicator of neovascularization, has been identified in patients with colorectal cancer as shown by the presence of monoclonal antibodies to CD105. However, data on potentially confounding factors such as lymphatic and vascular infiltration and tumor size are lacking. We further investigated the relationship between MVD and distant metastasis, along with potentially confounding clinicopathological factors, to more precisely characterize this relationship. In this retrospective study, we analyzed colorectal cancer specimens surgically or endoscopically resected from January to September 2009. We defined MVD as the number of microvessels stained by monoclonal antibodies to CD105 per ×400 field. Selected clinicopathological factors were analyzed and stepwise multivariate logistic regression was performed to identify independent risk factors for distant metastasis. We analyzed 129 lesions. The median follow-up time was 34 months (range, 6-85 months) in patients with distant metastasis and 61 months (range, 60-86 months) in those without distant metastasis. At the time of resection or during subsequent follow-up, 32 patients had distant metastases. The MVD was significantly greater in patients with than without distant metastases (mean ± standard deviation: 10.4±4.9 vs. 7.6±3.3, P=0.008; Welchs t-test). Stepwise multivariate logistic regression indicated that MVD, regional lymph node metastasis, and tumor size were independent risk factors for distant metastases. Combining assessment of monoclonal antibodies to CD105-positive MVD with assessment of regional lymph node metastasis and tumor size may help to identify patients who need more intensive surveillance after surgery for colorectal cancer.

A case of Degos disease: demonstration of C5b-9-mediated vascular injury

Abstract A 68-year-old Japanese male presented with atrophic erythematous white lesions with peripheral dark reddish rims on his back. Multiple ulcers were detected from his stomach to his large intestine using endoscopy. Although the patient was given high doses of a steroid, aspirin, dipyridamole, and intravenous immunoglobulin therapy, he died of gastrointestinal hemorrhage, perforation and septic shock. An autopsy examination revealed pauci-inflammatory thrombotic microangiopathy with endothelial cell injury, fibrous occlusive arteriopathy, and vascular C5b-9 deposition in the wall of the gastrointestinal tract from the esophagus to the large intestine as well as in the dermis of the skin.

[Retracted] Analysis of YAP1 and TAZ expression by immunohistochemical staining in malignant mesothelioma and reactive mesothelial cells

[This retracts the article DOI: 10.3892/ol.2018.8225.].

Expression of matrix metalloproteinase-7 correlates with the invasion of T1 colorectal carcinoma

T1 colorectal carcinomas (CRCs) are an initial site of metastatic spread. Various risk factors for lymph node metastasis have been investigated in T1 CRCs. However, the major step in the entire process of metastasis remains unclear. In terms of carcinoma invasion and metastasis, matrix metalloproteinases (MMPs) have recently gained increasing attention. Notably, MMP-7 is frequently overexpressed in CRCs, but its implication has not been determined in T1 CRCs yet. The present study aimed to clarify the associations between the pathological risk factors of T1 CRCs and MMP-7. In the current study, 211 lesions of T1 CRC that were resected endoscopically or surgically at Showa University Northern Yokohama Hospital (Yokohama, Japan) between April 2008 and December 2009 were retrospectively analyzed. MMP-7 was immunostained and evaluated by its frequency of expression. Pathological factors of T1 CRCs were analyzed in association with MMP-7 expression. Furthermore, the ultrastructural alterations of carcinoma invasion were examined using low vacuum-scanning electron microscopy (LV-SEM). MMP-7 expression was associated with venous invasion (P=0.005), and LV-SEM revealed the disappearance of the normal structure of collagen and elastic fibers of veins invaded by tumor cells expressing MMP-7. At the invasive front, MMP-7 has a vital role in carcinoma invasion, correlating with venous invasion of T1 CRCs.

Analysis of YAP1 and TAZ expression by immunohistochemical staining in malignant mesothelioma and reactive mesothelial cells Retraction in /10.3892/ol.2018.9405

Gene mutations are involved in the development of malignant mesothelioma. Important mutations have been identified in the genes for cyclin-dependent kinase inhibitor 2A (p16) alternative reading frame, breast cancer-associated protein 1 (BAP1) and neurofibromatosis type 2 (NF2). Previously, the utility of detecting the loss of BAP1 by immunohistochemistry (IHC) and p16-deletion by fluorescence in situ hybridization has been identified in several studies. However, NF2-associated examinations have not been performed. The present study aimed to evaluate the expression of yes-associated protein 1 (YAP1) and tafazzin (TAZ) protein, which are associated with NF2 gene mutations, in malignant mesothelioma (MM) and reactive mesothelial cells (RMCs). Formalin-fixed paraffin-embedded tissues from 31 MM and 33 RMC samples were analyzed. The expression of YAP1 and TAZ protein were examined by IHC. Positivity for YAP1 was identified 27/31 MM and 15/33 RMC samples. Positivity for TAZ was identified in 28/31 MM and 18/33 RMC samples. Using the optimal cutoff points determined by the receiver operating characteristic curve, a positive IHC result for YAP1 and TAZ was 74% sensitive and 94% specific for detecting MM. The results indicate that increased expression of YAP1 and TAZ may be associated with mesothelial tumorization, and aid in the diagnosis of MM.

A case of rectal neuroendocrine carcinoma in a patient with long-standing ulcerative colitis involving alterations of the p16-Rb pathway

The patient was a 54‐year‐old male who had been suffering from extensive ulcerative colitis (UC) for 17 years. Colonoscopy revealed an elevated lesion in the affected rectum, and its biopsy demonstrated neuroendocrine carcinoma (NEC). The surgical specimen obtained on laparoscopic high anterior resection showed extensive active inflammatory and dysplastic lesions and three grossly visible multifocal malignant lesions: a polypoid fungating tumor of NEC (type 1, 20 mm in diameter, pT3) that had been preoperatively noticed, a polypoid fungating tumor of adenocarcinoma (type 1, 22 mm, pT2) and a protruded sessile polypoid tumor (0–Is, 5 mm, pTis) of adenocarcinoma. The NEC was adjacently accompanied by dysplasia‐carcinoma sequential lesions and showed a diffuse immunohistochemical overexpression of p53 and p16 proteins and the loss of Rb with no abnormal immunohistochemical staining of microsatellite instability markers and no KRAS mutations. Fifteen months later, the patient showed liver metastasis from the NEC component, followed by bone and spinal metastasis; he died 22 months after the initial diagnosis. A rare case of lethal NEC arising from long‐standing extensive UC was reported. The NEC appeared to be UC‐related, not incidental, and complicated by progression from dysplasia to carcinoma involving alterations of the p16‐Rb pathway.

Oral tolerance is inducible during active dextran sulfate sodium-induced colitis

AIM To investigate whether oral tolerance is inducible during the active phase of dextran sulfate sodium (DSS)-induced colitis. METHODS Colitis was induced in 6- to 8-wk-old female BALB/c mice by the administration of 2% DSS. To induce oral tolerance, mice that received water with DSS [DSS (+)] and mice that received autoclaved water [DSS (-)] were intragastrically (i.g.) administered ovalbumin (OVA) as a tolerogen before systemic challenge with OVA. Following this, serum levels of OVA-specific IgE antibodies were measured. In mice with active colitis, CD4(+)CD25(+)Foxp3(+) cell and B10 cell frequencies were evaluated using flow cytometry. Cytokine mRNA expression profiles were evaluated by reverse transcription real-time polymerase chain reaction. RESULTS Regardless of the presence of DSS colitis, OVA-specific immunoglobulin E concentrations were significantly reduced in mice that were i.g. administered OVA compared to mice that were i.g. administered PBS [DSS (+): 4.4 (4.2-9.5) ng/mL vs 83.9 (66.1-123.2) ng/mL, P < 0.01; DSS (-): 27.7 (0.1-54.5) ng/mL vs 116.5 (80.6-213.6) ng/mL, P < 0.01]. These results demonstrated that oral tolerance was induced in both the presence and absence of colitis. In the spleen and mesenteric lymph nodes (MLN), the frequencies of CD4(+)CD25(+)Foxp3(+) cells and B10 cells, both of which are associated with oral tolerance, did not significantly change. In the spleen, interferon-γ mRNA expression significantly decreased in mice with colitis [DSS (+): 0.42 (0.31-0.53) vs DSS (-): 1.00 (0.84-1.39), P < 0.01]. The expression levels of other cytokines did not significantly change. CONCLUSION Oral tolerance is inducible during active DSS colitis. The stability of regulatory cell populations in the spleen and MLN in colitis might correlate with these results.