Pulmonary granular cell tumors: a clinicopathological analysis of five cases / 中华病理学杂志

Objective: To investigate the clinicopathological features of pulmonary granular cell tumors (pGCTs) and to improve the diagnostic accuracy of the tumor. Methods: A total of 5 pGCTs were diagnosed from February 2016 to January 2022 at Shanghai Pulmonary Hospital, Tongji University School of Medicine and Fudan University Shanghai Cancer Center, China. Immunohistochemical staining, and analysis of the clinicopathological characteristics were performed. Results: The average age of the pGCTs patients was 46 years (ranging from 24 to 54 years), with 3 females and 2 males. One case occurred in the bronchus with multiple nodules in the lung, 2 cases occurred in the bronchial opening, and 2 cases were solitary nodules in the lung. The maximum diameter of the tumors ranged from 12 to 15 mm (mean size 14 mm). Microscopically, the tumor showed infiltrative growth and consisted of round, oval or polygonal cells. Abundant eosinophilic cytoplasm was noted, and the nucleoli were prominent. None of the 5 cases showed any mitosis or necrosis. Immunohistochemical and histochemical study showed positive staining for S-100 (5/5), SOX10 (5/5), Vimentin (5/5), TFE3 (4/5), PAS (3/5), and amylase-digested-PAS (3/5), while 4 cases were negative for CD68. TFE3 FISH analyses on 2 cases showed that no signal abnormality was detected in these 2 cases. The average proliferation index of Ki-67 was 2.2% (range 0-5%). There was no recurrence in 4 cases of pGCTs with a follow-up time ranging from 2 months to 60 months. Conclusions: pGCTs are very rare tumors, most likely originating from Schwann cells. Immunohistochemical staining is the conventional diagnostic tool for pGCTs diagnosis. Recognition of this entity is essential for pathologists to avoid misdiagnosis and unnecessary treatments.

Application of the WHO Classification of Thoracic Tumors (2021) grading system in invasive pulmonary adenocarcinoma and its correlation with the targeted genes' variations / 中华病理学杂志

Objective: To investigate the applicability of the 2021 WHO classification of thoracic tumors' new grading system for invasive pulmonary adenocarcinoma (IPA) with different clinical stages and its correlation with the characteristics of targeted genes' variation. Methods: A total of 2 467 patients with surgically resected primary IPA in Shanghai Pulmonary Hospital, Shanghai, China from September to December 2020 were retrospectively analyzed. Eligible cases were graded using the new grading system of IPA of the 2021 WHO classification of thoracic tumors. The clinicopathological data and targeted-gene abnormality were collected. The utility of new grading system of IPA in different clinical stages was investigated. The correlation of clinicopathological features and targeted-gene abnormality in different grades of IPA were compared. Results: All 2 311 cases of IPA were included. There were 2 046 cases of stage Ⅰ IPA (88.5%), 169 cases of stage Ⅱ (7.3%), and 96 cases of stage Ⅲ (4.2%). According to the new classification system of IPA, 186 cases (9.1%), 1 413 cases (69.1%) and 447 cases (21.8%) of stage-Ⅰ adenocarcinoma were classified as Grade 1, Grade 2 and Grade 3, respectively. However, there were no Grade 1 adenocarcinomas in stages Ⅱ and Ⅲ cases. Among stage-Ⅱ and Ⅲ IPA cases, there were 38 Grade 2 cases (22.5%) and 131 Grade 3 cases (77.5%), and 3 Grade 2 cases (3.1%) and 93 Grade 3 cases (96.9%), respectively. In stage-Ⅰ cases, no tumor cells spreading through airspace (STAS), vascular invasion or pleural invasion was found in Grade 1 of IPA, while the positive rates of STAS in Grade 2 and 3 IPA cases were 11.3% (159/1 413) and 73.2% (327/447), respectively. There was a significant difference among the three grades (P<0.01). Similarly, the rates of vascular and pleural invasion in Grade 3 IPA cases were 21.3% (95/447) and 75.8% (339/447), respectively, which were significantly higher than those of 1.3% (19/1 413) and 3.0% (42/1 413) in Grade 2 (P<0.01). EGFR mutational rates in Grades 1, 2 and 3 IPA were 65.7% (94/143), 76.4% (984/1 288) and 51.3% (216/421), respectively. The differences among the three grades were statistically significant (P<0.01). No fusion genes were detected in Grade 1 IPA, while the positive rates of ROS1 and ALK fusion genes in Grade 3 were 2.4% (10/421) and 8.3% (35/421), respectively, which were significantly higher than that of 0.5% (7/1 288) and 1.6% (20/1 288) in Grade 2 (P<0.01). In stage-Ⅱ cases, only EGFR mutation rate in Grade 2 adenocarcinoma (31/37, 83.8%) was higher than that in Grade 3 adenocarcinoma (71/123, 57.7%; P<0.01). However, the correlation between the new grade system of IPA and the distribution characteristics of targeted-gene variation cannot be evaluated in stage Ⅲ cases. Conclusions: The new grading system for IPA is mainly applicable to clinical stage-Ⅰ patients. Tumor grades of IPA are strongly correlated with the high-risk factors of prognosis and the distribution features of therapeutic targets. It is of great significance and clinical value to manage postoperative patients with early-stage IPA.

Clinicopathological features and prognosis of SMARCA4-deficient non-small cell lung carcinoma: an analysis of 127 cases / 中华病理学杂志

Objective: To investigate and elucidate the clinicopathological and prognostic characteristics of SMARCA4-deficient non-small cell lung cancer. Methods: The clinicopathological and prognostic data were collected in 127 patients with SMARCA4-deficient non-small cell lung cancer diagnosed in Shanghai Pulmonary Hospital, Shanghai, China from January 2020 to March 2022. The variation and expression of biomarkers related to treatment were retrospectively reviewed. Results: One hundred and twenty-seven patients were eligible for enrollment. Among them 120 patients (94.5%) were male and 7 cases (5.5%) were female, while the average age was 63 years (range 42-80 years). There were 41 cases (32.3%) of stage Ⅰ cancer, 23 cases (18.1%) of stage Ⅱ, 31 cases (24.4%) of stage Ⅲ and 32 cases (25.2%) of stage Ⅳ. SMARCA4 expression detected by immunohistochemistry was completely absent in 117 cases (92.1%) and partially absent in 10 cases (7.9%). PD-L1 immunohistochemical analyses were performed on 107 cases. PD-L1 was negative, weakly positive and strongly positive in 49.5% (53/107), 26.2% (28/107) and 24.3% (26/107) of the cases, respectively. Twenty-one cases showed gene alterations (21/104, 20.2%). The KRAS gene alternation (n=10) was most common. Mutant-type SMARCA4-deficient non-small cell lung cancer was more commonly detected in females, and was associated with positive lymph nodes and advanced clinical stage (P<0.01). Univariate survival analysis showed that advanced clinical stage was a poor prognosis factor, and vascular invasion was a poor predictor of progression-free survival in patients with surgical resection. Conclusions: SMARCA4-deficient non-small cell lung cancer is a rare tumor with poor prognosis, and often occurs in elderly male patients. However, SMARCA4-deficient non-small cell lung cancers with gene mutations are often seen in female patients. Vascular invasion is a prognostic factor for disease progression or recurrence in patients with resectable tumor. Early detection and access to treatment are important for improving patient survivals.

Primary lung salivary gland-type duct carcinoma: a clinicopathological analysis of two cases and review of literature / 中华病理学杂志

Objective: To investigate the clinicopathological features, diagnostic criteria and differential diagnosis of primary salivary gland-type duct carcinoma of lung(LSDC). Methods: Two patients with LSDC after surgical resection in Shanghai Pulmonary Hospital from 2020 to 2021 were included; their clinical parameters as well as pathological, immunohistochemical and molecular characteristics of the tumors were analyzed. The relevant literature was also reviewed. Results: Both patients were male, aged 49(case 1) and 64(case 2) years, respectively, and with a history of smoking. The chest computed tomography scan showed both lesions to be centrally located. Gross examination showed the maximum diameters were 16 mm and 35 mm, respectively. The histomorphology of LSDC resembled ductal carcinoma of breast, with intraductal islands of neoplastic cells, which also formed solid nests, papillary, micropapillary and cribriform structures. There was frequent accompanying comedo-like necrosis. The neoplasm cells were markedly heteromorphic, possessing large irregular nuclei with prominent nucleoli, abundant eosinophilic or clear cytoplasm, and mitotic figures were common. Both cases of LSDC were immunoreactive for CKpan, CK7, AR, HER2 staining was (2+) and were negative for TTF1, Napsin A, p40, GATA3, mammaglobin, GCDFP15, SOX10, PSA, P504S, ER, PR, vimentin, S-100, SMA, CK5/6 and p63. The tumor showed double-layer cell structure of the duct, and some basal cells/myoepithelial cells expressed p40 and CK5/6. Case 1 had no gene mutation while case 2 harbored TP53 and KMT2A gene mutation detected by next generation sequencing. Conclusions: LSDC is a very rare and highly aggressive salivary-type malignant tumor. The postoperative diagnosis mainly depends on histopathology and immunohistochemistry, attention should be paid to differential diagnosis to prevent missed diagnosis.

Clinicopathological and genetic characteristics of bronchial sialadenoma papilliferum: report of four cases / 中华病理学杂志

Objective: To investigate the clinicopathological, immunophenotypic, and molecular genetic features of bronchial sialadenoma papilliferum (BSP). Methods: Four cases of BSP collected at the Shanghai Pulmonary Hospital from May 2018 to June 2021 were retrieved and analyzed. These cases were evaluated for their clinical, histological, immunohistochemical (IHC) and genomic features. The patients were followed up and relevant literature was reviewed. Results: All four patients were male, aged from 55 to 75 years (mean 62 years), with tumor diameter of 6 to 21 mm (mean 13.5 mm), and lesions were located in the left lower lobe (n=2), right lower lobe (n=1), and trachea (n=1). They were characterized by a combination of surface exophytic endobronchial papillary proliferation and an endophytic two-cell layered ductal structure. IHC staining showed that CK7 and EMA were strongly positive in ductal epithelium; p63, p40, CK5/6 were positive in ductal and papillary basal cells; SOX10 was positive in ductal epithelium and basal cells; S-100 was positive in basal cells and ductal epithelium in two cases. Next generation sequencing showed that two cases harbored BRAF V600E mutation. Conclusions: BSP is an extremely rare primary lung tumor arising from the salivary gland under bronchial mucosa. The primary treatment choice of this tumor is complete surgical resection. The diagnosis and differential diagnosis of this tumor depend on classic histomorphologic and IHC features, and BRAF V600E gene mutation can be detected.

Identify Candidate Genes in the Interaction between Abdominal Aortic Aneurysm and Type 2 Diabetes Mellitus by Using Biomedical Discovery Support System / 中国医学科学杂志(英文版)

Objective To explore the candidate genes that play significant roles in the interconnection between abdominal aortic aneurysm (AAA) and type 2 diabetes mellitus (DM). Methods We used the Biomedical Discovery Support System (BITOLA) to screen out the candidate intermediate molecular (CIM) "Gene or Gene Product" that are related to AAA and DM. The dataset of GSE13760, GSE7084, GSE57691, GSE47472 were used to analyze the differentially expressed genes (DEGs) of AAA and DM compared to the healthy status. We used the online tool of Venny 2.1 assisted by manual checking to identify the overlapped DEGs with the CIMs. The Human eFP Browser was applied to examine the tissue specific expression levels of the detected genes in order to recognize strong expressed genes in both human artery and pancreatic tissue. Results There were 86 CIMs suggested by the closed BITOLA system. Among all the DEGs of AAA and DM, 8 genes in GSE7084 (ISG20, ITGAX, DSTN, CCL5, CCR5, AGTR1, CD19, CD44) and 2 genes in GSE13760 (PSMD12, FAS) were found to be overlapped with the 86 CIMs. By manual checking and comparing with tissue-specific gene data through Human eFP Browser, the gene PSMD12 (proteasome 26S subunit, non-ATPase 12) was recognized to be strongly expressed in both the aorta and pancreatic tissue. Conclusion We proposed a hypothesis through text mining that PSMD12 might be involved or potentially involved in the interconnection between AAA and DM, which may provide a new clue for studies on novel therapeutic strategies for the two diseases.

Roles of cyclooxygenase-2 in microvascular endothelial cell proliferation induced by basic fibroblast growth factor / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>The level of basic fibroblast growth factor (bFGF) increases rapidly after cerebral ischemia. However, the molecular mechanisms for the effects of bFGF on cerebral microvascular endothelial cells (cMVECs) have not yet been fully elucidated. In this study, a murine cMVEC line, bEnd.3, was employed to study the effects of bFGF on cyclooxygenase (COX) expression and its downstream effects in cMVECs.</p><p><b>METHODS</b>After treatment with bFGF, RT-PCR and Western blotting analyses were carried out to evaluate the changes in COX-2 mRNA and protein expression, respectively. MTT assays were performed to measure cell proliferation. The prostaglandin E2 (PGE2) and vascular endothelial growth factor (VEGF) concentrations in the culture medium were measured by enzyme-linked immunosorbent assay (ELISA).</p><p><b>RESULTS</b>COX-2 mRNA and protein expressions in bEnd.3 cells were induced by bFGF in time- and dose-dependent manners. The bFGF-induced COX-2 upregulation led to enhanced PGE2 production by bEnd.3 cells, and this effect was abolished by the selective COX-2 inhibitor NS-398. bFGF also increased VEGF production by bEnd.3 cells, and this effect was blocked by NS-398 and the EP1/2 (PGE2 receptors) antagonist AH6809. Furthermore, exogenous PGE2 increased VEGF production in bEnd.3 cells, and AH6809 blocked this effect.</p><p><b>CONCLUSION</b>bFGF increases VEGF production in an autocrine manner by increasing COX-2-generated PGE2 in cMVECs and subsequently stimulates MVEC proliferation and angiogenesis.</p>