Protective effect of α7 nicotinic acetylcholine receptor activation on experimental colitis and its mechanism.

BACKGROUND: Inflammatory bowel disease (IBD) is a common chronic remitting disease with no satisfactory treatment. The aim of this study was to investigate the protective effect of α7 nicotinic acetylcholine receptor (α7nAChR), and to determine the underlying mechanism of its activity. METHODS: The expression and distribution of α7nAChR in the intestinal tissue of patients with ulcerative colitis and Crohn's disease were analyzed. The effects of vagal excitation on murine experimental colitis were investigated. The colitis model was induced in C57BL/6 mice by the administration of 3% dextran sulfate sodium (DSS). The therapeutic group received treatment with the α7nAChR agonist PNU-282987 by intraperitoneal injection. RESULTS: Our results showed that there was significantly increased expression of α7nAChR in colitis and Crohn's disease intestinal tissue, and its expression was mainly located in macrophages and neutrophils, which were extensively infiltrated in the disease status. Treatment with an α7nAChR agonist potently ameliorated the DSS-induced illness state, including weight loss, stool consistency, bleeding, colon shortening, and colon histological injury. α7nAChR agonist exerted anti-inflammatory effects in DSS colitis mice by suppressing the secretion of multiple types of proinflammatory factors, such as IL6, TNFα, and IL1ß, and it also inhibited the colonic infiltration of inflammatory cells by blocking the DSS-induced overactivation of the NF-κB and MAPK signaling pathways. Mechanistically, activation of α7nAChR decreased the number of infiltrated M1 macrophages in the colitis intestine and inhibited the phagocytosis ability of macrophages, which were activated in response to LPS stimulation. CONCLUSION: Thus, an α7nAChR agonist ameliorated colonic pathology and inflammation in DSS-induced colitis mice by blocking the activation of inflammatory M1 macrophages.

Pathologic evaluation of the solid variant of aneurysmal bone cysts with USP6 rearrangement with an emphasis on the frequent diagnostic pitfalls.

The solid variant of aneurysmal bone cyst (SVABC) is very uncommon and frequently misdiagnosed. We reevaluated and summarized the clinicopathologic features of 17 SVABCs and further discussed the use of this nomenclature to differ SVABCs from extragnathic giant cell reparative granuloma (GCRG) in the setting of the USP6 rearrangement era. The immunohistochemical markers included α-SMA, SATB2, AE1/AE3, Ki67, S100, CD68 and P63. USP-6 status was detected by fluorescence in situ hybridization using a break-apart probe. The 17 patients with SVABCs comprised 10 males and 7 females ranging in age from 4 to 70 years. The involved locations included the long bone (n = 11), hand (n = 4), rib (n = 1) and vertebra (n = 1). The lesions were characterized by proliferated spindle cells with scattered giant cells and hemorrhages with variable positive α-SMA, SATB2, CD68 and Ki-67 expression. All patients had USP6 rearrangements without H3F3A glycine 34 mutations. Our study reveals that SVABC shares similar clinical and histologic features with other bone lesions, which may lead to an erroneous diagnosis. The presence of an USP-6 rearrangement contributes to the diagnosis SVABC; SVABC and most of the previously documented extragnathic GCRGs may be considered within the umbrella of primary aneurysmal bone cysts.

Juxtaglomerular cell tumor: Clinicopathologic evaluation in a large series emphasizing its broad histologic spectrum.

The juxtaglomerular cell tumor (JCT) is a rare renal tumor. We re-evaluated the clinicopathologic features of 21 JCTs to summarize their variable morphologies. Immunohistochemical, fluorescent in situ hybridization and periodic acid-Schiff stains were routinely performed, and four JCT cases were detected via transmission electron microscopy. The 21 JCTs involved five males and 16 females, ranging in age from 19 years to 69 years (mean, 36.9 years; median, 34 years). The tumors were composed of large, small, or spindle cells with a round, oval or polygonal shape, arranged in various growth patterns. Both necrosis (1/21) and mitosis (2/21, with 1/50HFP, 8/50HFP) was rarely appreciated. All cases were immunoreactive for renin and CD34 (21/21), and few were positive for α-SMA (13/21;11/21, focally; 2/21, diffusely,), CD117 (9/21, focally) and synaptophysin (3/21, focally). Ultrastructurally, all four cases exhibited secretory granules in varying sizes in the cytoplasm, two of which exhibited cellular junctions. Almost all cases (20/21) had a favorable prognosis, but one succumbed due to bone and hepatic metastases, which corresponds to malignant JCT. Our study demonstrates that JCTs may have atypical clinical presentations and variable histologic appearances. A familiarity with these features may contribute to a correct diagnosis.

Erratum: Evaluation of the clinicopathologic features of diffuse large B cell lymphoma after CD19-targeted CAR T-cell therapy emphasizing the potential diagnostic pitfalls.

[This corrects the article on p. 6751 in vol. 12, PMID: 33194070.].

Prognostic and predictive significance of tumor infiltrating lymphocytes for ductal carcinoma in situ.

This study aims to identify the density of TILs in ductal carcinoma in situ (DCIS) in terms of prognostic significance with recurrence and the benefit of whole breast irradiation (WBI). The clinicopathological data of DCIS patients from Jan 2009 to Dec 2016 who received breast-conserving surgery (BCS) were retrospectively reviewed. Cox regression analysis was used to confirm independent prognostic factors of ipsilateral breast tumor recurrence (IBTR). Kaplan-Meier method was utilized to analyze IBTR and values of WBI. Touching-tumor-infiltrating lymphocytes (TILs) were defined by TILs touching or within one lymphocyte cell thickness from the malignant ducts' basement membrane. In total, 129 patients were enrolled in this analysis with 98 patients who received WBI. After a median follow-up of 53.0 months, there were 16 IBTR events with five invasive IBTRs. Univariate and multivariate analyses showed that touching-TILs >5 were an independent prognostic factor for higher IBTR (HR = 6.17, 95%CI 1.95-19.56, p < .01). The whole cohort was classified into two subgroups: dense group (>5 touching-TILs per duct) and sparse group (≤5 touching-TILs per duct). Dense touching-TILs were associated with unfavorable biologic characteristics. The 5-y rate of IBTR between dense and sparse group was 29.0% versus 4.5% (p < .01). For the sparse group, WBI significantly reduced the rate of 5-y-IBTR risk from 13.2% to 1.7% (p = .02), but there was no benefit of WBI in the dense group. Touching-TILs density was heterogeneous in patients with DCIS. Sparse touching-TILs were associated with better prognosis and benefit from WBI. Dense touching-TILs not only were associated with a higher risk of IBTR but also lack of benefit from WBI.

Evaluation of the clinicopathologic features of diffuse large B cell lymphoma after CD19-targeted CAR T-cell therapy emphasizing the potential diagnostic pitfalls.

Clinicopathologic data of 16 cases of DLBCL, NOS after CD19-targeted CAR T-cell therapy were retrospectively reviewed. Statistical analyses were performed to investigate the diagnostic agreement and indicate the relationship of the given types or their alterations (Group I versus Group II) to the prognosis. A total of 5 distinct histologic patterns were summarized. The CAR T cells were somewhat atypical, most of which were CD8 positive in the most cases (86.7%, 13/15), with a relatively high Ki-67 (60-90%). The rearrangement of BCR was demonstrated in all cases. The diagnostic test showed that the diagnostic accuracy in cases of types III (7%) and V (7%) was typically low; the diagnostic agreement in cases of type IV (for B, T, or nonlymphoma) and V (for T, or nonlymphoma) was consistently unsatisfactory. The rates of complete response (CR), partial response (PR), and progressive disease (PD) were 18.8% (3/16), 31.3% (5/16), 50% (8/16), respectively. In the follow-up, 25% (4/16) of cases experienced a recurrence and 31.3% (5/16) had died, of which 3 cases succumbed to the side effects. Group II had better disease-free survival (DFS, P=0.009). This study first described the pathologic features of DLBCL after CD19-targeted CAR T-cell therapy. Familiarity with these histologic features and combinations of medical history and genetic analyses facilitate avoiding misdiagnoses. Multiple biopsies are potentially helpful to estimate the treatment effects or prognosis, and stable alterations to any type of III to V, but not a single given one, may indicate a good prognosis.

Expression of TdT in Myoepithelial Cells: Investigation in Breasts, Sweat Glands, and Salivary Lesions Emphasizing the Never-Documented Immunohistochemical Findings.

Background. The expression of terminal deoxynucleotidyl transferase (TdT) in myoepithelial cells (MECs) within the breast was recently incidentally observed in our routine practice. This study aimed to elucidate the expression of TdT in MECs. Methods. TdT immunostaining was performed on 180 mammary, 89 cutaneous, and 94 salivary tissues or lesions. Other myoepithelial markers, including P63, calponin, and SMA as well as double staining for TdT and calponin, were also evaluated in some cases. Selected lesions with basal or myoid differentiation were also included in the investigation. Results. MECs were positive for TdT in mammary lesions that contained MECs (132/135) but negative when they did not contain MECs (45/45). MECs in sweat glands (24/30) and their neoplastic counterparts, including those in hidradenoma papilliferum (2/9), spiradenoma (6/6), and cutaneous mixed tumor (9/9), showed weak to moderate TdT positivity. MECs were variably immunolabeled for TdT in salivary or salivary gland-type tumors with myoepithelial differentiation (pleomorphic adenoma, 24/25; basal cell adenoma, 6/7; adenoid cystic carcinoma, 7/7; Warthin tumor, 0/6; mucoepidermoid carcinoma, 0/8; acinic cell carcinoma, 0/4), but MECs in normal salivary gland barely stained for TdT (30/32). Conclusions. Our findings indicate that TdT may be eligible as an additional auxiliary immunohistochemical marker as P63, but not a surrogate, to identify the MECs in the breast with limited cross-reactivity, particularly in lesions with a prominent proportion of MECs. Positivity for TdT, along with other relevant markers, in a subset of sweat gland lesions and salivary tumors may contribute to their diagnosis.

Primary adrenal schwannoma: a series of 31 cases emphasizing their clinicopathologic features and favorable prognosis.

PURPOSE: Primary adrenal schwannoma (PAS) is a very rare benign tumor, and most of them have been described in case reports. This study aimed to analyze their distinct clinicopathologic features and follow-up data through the largest series yet. METHODS: Clinicopathologic features of 31 primary adrenal schwannomas were retrospectively studied. Imaging and histologic features were re-evaluated and summarized. Immunohistochemical markers were measured, including S100, SOX10, AE1/AE3, EMA, SMA, Desmin, HMB45, GLUT1, and Ki67. Follow-up of all cases was performed. RESULTS: All the tumors were clinically misdiagnosed as nonfunctioning adrenal adenoma (NAA; 23/31), aldosterone-producing adenoma/aldosteronoma (APA; 3/31), cortisol-producing adenoma (CPA; 3/31), or pheochromocytoma (PCC; 2/31). Some 87% (27/31) presented with adrenal incidentaloma, and 13% (4/31) had a clinical symptom or unregulated hormone levels. They comprised conventional (19/31), cellular (7/31), plexiform (2/31), ancient (1/31), epithelioid (1/31) and microcystic/reticular variants (1/31) and had various histologic features. Immunohistochemically, all tumors (31/31) were positive for S100 and Sox10, with a low Ki-67 proliferative index. In the long-term follow-up (mean, 53 mo.; median, 56 mo.), none had evidence of recurrence and metastasis. Univariate analysis showed that OS and DFS were not associated with age; sex; tumor side, size, or number; adrenal-related symptoms; gross feature (solid vs. cystic); or any histologic feature (P > 0.9999). CONCLUSION: PAS is an extremely rare tumor and mostly appears as an incidentaloma. Clinically, it tends to be misdiagnosed as other common adrenal tumors. This tumor has a benign biologic behavior and prognosis, without correlations with clinical or histologic parameters.

Clinicopathologic Study of Calcifying Fibrous Tumor Emphasizing Different Anatomical Distribution and Favorable Prognosis.

AIMS: Calcifying fibrous tumor (CFT) is a very rare begin fibroblastic tumor featuring a widely anatomical distribution and may mimic various spindle cell tumors. Misdiagnosis and hence mistreatment are likely caused due to unfamiliarity to clinicians or junior pathologists. We collected a relatively large series of CFTs in our institution aiming at further summarizing their clinicopathologic features in Chinese patients and discussing the diagnosis and differential diagnosis in clinical practice. METHODS: Clinicopathologic data of 22 CFTs were retrospectively reviewed. Histologic features were reevaluated and summarized. Immunostaining markers include CD34, SMA, Desmin, keratin, S100, ALK1, CD117, IgG, IgG4, and Ki-67. Follow-up of all cases was performed. RESULTS: 22 CFTs include gastric (n=8), pulmonary (n=2), hepatic (n=2), cervical (n=1), appendiceal (n=1), esophageal (n=1), retroperitoneal (n=1), intra-abdominal (n=1), diaphragmatic (n=1), spermatic cord and scrotum (n=1), anconeal (n=1), mesenteric (n=1), and omental (n=1) lesions. Coexisting hepatocellular carcinoma, pancreatic carcinoma, pheochromocytoma, Castleman disease, and leiomyoma of the uterus and other metabolic or functional disorders were also appreciated. CFT histologically features spindle cells embedded dense hyalinized stroma with scattered psammomatous calcifications and lymphoplasmacytic infiltration and immunohistochemically for CD34. None of any individuals die of CFT per se. CONCLUSION: Our study discloses that CFT is a bona fide benign fibroblastic lesion, regardless of its developing location. Involvement of digestive tract seems much more common in the Chinese population. Awareness of the clinicopathologic characteristics of this rare entity and its mimickers contribute to avoiding misdiagnosis and mistreatment in clinical practice.