[Clinicopathological and genetic characteristics of congenital cystic adenomatoid malformation of lung and its associated lung cancer in adults].

Objective: To investigate the clinicopathological features and genetic characteristics of congenital cystic adenomatoid malformation (CCAM) of lung and CCAM associated lung cancer in adults. Methods: A total of 13 cases of CCAM of lung in adults, diagnosed from June 2015 to May 2023, were collected from the Department of Pathology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, China. Their histopathological features were correlated with probable development into lung cancer. Next-generation sequencing was performed on the benign and malignant areas of all cases. Results: The pathological classification of all cases were of CCAM of lung type 1. There were 4 male and 9 female cases, age ranged from 18 to 65 years, with a mean age of 41 years. Six cases were accompanied by lung cancer, all of them were mucinous adenocarcinoma. Next-generation sequencing showed no gene mutation in 2 of the 13 cases; KRAS mutations in exon 2 were detected in 7 cases, in which there were 6 cases complicated with lung mucinous adenocarcinoma and no matter in the malignant or benign regions, the same case exhibited the same mutation sites in KRAS gene. Conclusions: CCAM of the lung is a congenital disease, and in adults, type 1 is most commonly found in the pathological classification, and it is often accompanied by cancer. Gene mutations are frequently detected in CCAM of the lung, KRAS being the most recurrent mutation which may play an important role in the carcinogenesis.

[The distribution of blood pressure and associated factors of the elderly with type 2 diabetes in Jiangsu Province].

Objective: To investigate the distribution of blood pressure and analyze the associated factors of blood pressure of the elderly with type 2 diabetes in Jiangsu Province. Methods: The elderly over 60 years old participants with type 2 diabetes in the communities of Huai'an City and Changshu City, Jiangsu Province were selected in this study. They were divided into two groups: taking antihypertensive drugs and not taking antihypertensive drugs. The demographic characteristics, such as age and sex, and relevant factors were collected by questionnaire. The systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured by physical examination. The percentile of SBP and DBP in each age group of men and women were described. The kernel density estimation curve was used to show the blood pressure distribution. The trend of blood pressure with age was fitted by locally weighted regression. The logistic regression model was used to analyze relevant factors of blood pressure. Results: A total of 12 949 participants were included in this study, including 7 775 patients in the antihypertensive drug group and 5 174 patients in the group without antihypertensive drugs. The SBP of participants was concentrated at 140-160 mmHg, and their DBP was concentrated at 75-85 mmHg. There were significant differences in the distribution of blood pressure among the subgroups of body mass index (BMI) and rural areas whether taking antihypertensive drugs and not. For participants aged under 80 years old, the SBP showed an increasing trend with age and the DBP showed a decreasing trend with age. Age, BMI ≥24 kg/m2, fasting blood glucose ≥7.0 mmol/L, living in rural areas and no smoking were influencing factors of the elevated SBP; BMI ≥24 kg/m2, male, living in rural areas, no smoking, drinking alcohol and not receiving drug hypoglycemic treatment were influencing factors of the elevated DBP. Conclusion: The SBP of older diabetic adults in Jiangsu Province is at a high level, and the distribution of blood pressure is significantly different between men and women in taking antihypertensive drugs group. The SBP presents a rising trend and the DBP is decreasing at the age of 60-80 years. The blood pressure level of this population are mainly affected by age, BMI, urban and rural areas, smoking.

[Application of the WHO Classification of Thoracic Tumors (2021) grading system in invasive pulmonary adenocarcinoma and its correlation with the targeted genes' variations].

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.

[Pulmonary granular cell tumors: a clinicopathological analysis of five cases].

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.

[Clinicopathological and genetic characteristics of bronchial sialadenoma papilliferum: report of four cases].

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.

[Primary lung salivary gland-type duct carcinoma: a clinicopathological analysis of two cases and review of literature].

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 characterization of primary pulmonary and tracheal glomus tumors].

Objective: To investigate the clinical pathological features of primary pulmonary and tracheal glomus tumors. Methods: The clinical and pathological features of 11 cases (4 cases from Shanghai Pulmonary Hospital, Tongji University School of Medicine, China and 7 cases from Fudan University Shanghai Cancer Center, China) of respiratory glomus tumor diagnosed from 2010 to 2019 were analyzed, and reviewed in light of the relevant literature. Results: In the 11 cases, there were 5 males and 6 females, with the onset ages of 29‒66 years (median age of 43). Six tumors were located in the lung, and 5 in the trachea. The tumor diameters ranged 1.0‒7.5 cm, with the average diameter of 2.6 cm. At low magnification, the tumors were diffuse or lobulated in shape. The tumor cells composed of sheets of oval to short spindle cells, with sharply defined cell border and prominent branching thin-walled vessels. Among the 4 benign glomus tumors, one was classified as benign symplastic glomus tumor owing to the hyperchromatic or degeneration nuclei. Two cases were classified as glomus tumors of uncertain malignant potential, on the account of cellular atypia and rare atypical mitotic figures. Five cases were classified as malignant glomus tumors, owing to the tumor necrosis, vascular invasion, marked nuclear atypia, prominent nucleoli and brisk mitoses (2-20/10HPF) including pathological mitotic figures. The tumor cells showed strong immunostaining for SMA, vimentin, type Ⅳ collagen and caldesmon to different extents, while CD34, cytokeratin and S-100 stains were negative. One of the cases was positive for desmin, and one case positive for synaptophysin. Follow-up information was available in 8 patients with the duration ranging from 6 to 95 months. At the end of the follow-up, 6 patients were alive without recurrence or metastasis, and two of the patients with malignant glomus tumors died. Conclusions: Primary pulmonary and tracheal glomus tumors is rare. Among the reported cases, malignant glomus tumor is the most frequent, followed by benign glomus tumors and uncertain malignant potential glomus tumors. Glomus tumors show sheet-like growth pattern and clusters of round epithelioid cells with numerous vascular spaces. They can be easily misdiagnosed as carcinoid tumor. The final diagnosis should be combined with immunohistochemical staining, such as SMA, caldesmon and vimentin.

[Study on the establishment of HMLD model and the expression of KL-6/TGF-beta in rat].

Objective: To establish an animal model of hard metal lung disease (HMLD) in rats, and to screen the indications for diagnosis of HMLD. Methods: The rats were randomly divided into 5 groups, each group included 8 rats: saline group, pure cobalt group, pure tungsten carbide group, silica group and hard metal (HM) group. 10 mg subjects were administered in each group by using the pulmonary endotracheal tube. After 8 week, the lung CT scan and lung tissue pathology were observed, the serum and bronchoalveolar lavage fluid (BALF) were collected for KL-6, TGF-beta1 and TGF-beta2. Results: The lung tissue structure of HM group was destroyed, a large number of nuclear giant cells and epithelial like cells appeared in the stroma, and uncommon CT scan images appeared in the lung. KL-6, TGF-beta1, TGF-beta2 expression in each group was not the same, the difference was statistically significant (P<0.05) . The expression of KL-6 and TGF-beta1 in serum was not identical in all the groups, the difference was statistically significant (P<0.05) . The expression of TGF-beta2 had no significant difference between the groups (P>0.05) . Conclusion: Rats can be successfully established HMLD model, rats in vivo lung CT scan images appear abnormal, which are provided with assistant diagnostic value for HMLD. The expression of KL-6 and TGF-beta2 in serum and BALF on HMLD rats are not highly specific, and TGF-beta1 has reference value in the rat HMLD auxiliary diagnosis.

[Prognostic significance of the changes of elastic fibers in acinar predominant or papillary-predominant pulmonary adenocarcinomas].

OBJECTIVE: To evaluate the role of elastic fiber changes in predicting survival outcomes in intermediate-grade lung adenocarcinoma. METHODS: All pulmonary adenocarcinoma resections conducted between January 2009 and December 2009 were reviewed. Pathologically confirmed adenocarcinomas smaller than 3 cm were included in the present study. All cases were categorized into three elastic fiber patterns (EFP): complete loss as pattern Ⅰ (EFP Ⅰ), partial loss as pattern Ⅱ (EFP Ⅱ), normal and diffusely increase as pattern Ⅲ (EFP Ⅲ). Patients with different EFP were compared. RESULTS: One hundred and ninety four patients were included in this study, with 67(34.5%), 70(36.1%)and 57(29.4%) cases presenting as EFP Ⅰ, EFP Ⅱ, and EFP Ⅲ, respectively. Lymph nodal metastases occurred in 35.8% (24/67), 40.0% (28/70), and 10.5% (6/57) of EFP Ⅰ, EFP Ⅱ and EFP Ⅲ patterns, respectively. The percentage of EFP Ⅰ and Ⅱ increased with increasing tumor size, these patterns occurring in 55.1% (38/69) of tumors ≤2.0 cm, and 79.2% (99/125) of tumors 2.1-3.0 cm in sizes, respectively. The overall 5-year overall survival rate was 75.8%, and 67.2% for EFP I, 68.6% for EFP II, and 94.7% for EFP Ⅲ. CONCLUSION: In patients with intermediate-grade lung adenocarcinoma, EFP should be formally recognized as a feature of tumor invasion, and its evaluation can help to recognize tumor invasive and access clinical prognosis.

Measurement of viscoelastic properties in multiple anatomical regions of acute rat brain tissue slices.

Mechanical property data for brain tissue are needed to understand the biomechanics of neurological disorders and response of the brain to different mechanical and surgical forces. Most studies have characterized mechanical behavior of brain tissues over large regions or classified tissue properties for either gray or white matter regions only. In this study, spatially heterogeneous viscoelastic properties of ex vivo rat brain tissue slices were measured in different anatomical regions including the cerebral cortex, caudate/putamen, and hippocampus using an optical coherence tomography (OCT) indentation system. Cell viability was also tested to observe neuronal degeneration and morphological changes in tissue slices and provide a proper timeline for mechanical tests. Shear modulus was estimated by fitting normalized deformation data (D/ti), which was defined as the ratio of deformation depth (D) to initial thickness of the tissue slice (ti), to a viscoelastic finite element model. The estimated shear modulus decayed nonlinearly over 10min in each anatomical region, and the range of instantaneous to equilibrium shear modulus was 3.8-0.54kPa in the cerebral cortex, 1.4-0.27kPa in the hippocampus and 1.0-0.17kPa in the caudate/putamen. Although these regions are all gray matter structures, their measured mechanical properties were significantly different. Accurate measurement of inter-regional variations in mechanical properties will contribute to improved understanding organ-level structural parameters and regional differential susceptibility to deformation injury within CNS tissues.

Optically based-indentation technique for acute rat brain tissue slices and thin biomaterials.

Currently, micro-indentation testing of soft biological materials is limited in its capability to test over long time scales due to accumulated instrumental drift errors. As a result, there is a paucity of measures for mechanical properties such as the equilibrium modulus. In this study, indentation combined with optical coherence tomography (OCT) was used for mechanical testing of thin tissue slices. OCT was used to measure the surface deformation profiles after placing spherical beads onto submerged test samples. Agarose-based hydrogels at low-concentrations (w/v, 0.3-0.6%) and acute rat brain tissue slices were tested using this technique over a 30-min time window. To establish that tissue slices maintained cell viability, allowable testing times were determined by measuring neuronal death or degeneration as a function of incubation time with Fluor-Jade C (FJC) staining. Since large deformations at equilibrium were measured, displacements of surface beads were compared with finite element elastic contact simulations to predict the equilibrium modulus, µ(∞) . Values of µ(∞) for the low-concentration hydrogels ranged from 0.07 to 1.8 kPa, and µ(∞) for acute rat brain tissue slices was 0.13 ± 0.04 kPa for the cortex and 0.09 ± 0.015 kPa for the hippocampus (for Poisson ratio = 0.35). This indentation technique offers a localized, real-time, and high resolution method for long-time scale mechanical testing of very soft materials. This test method may also be adapted for viscoelasticity, for testing of different tissues and biomaterials, and for analyzing changes in internal structures with loading.

Optical coherence tomography for noninvasive diagnosis of epithelial cancers.

We summarize our recent progress in the development of the optical coherence tomography (OCT) systems suitable for clinical diagnosis and the preliminary results for in vivo diagnosis of epithelial cancers (e.g., bladder cancers). The endoscopic spectral-domain OCT system allows simultaneous, real-time, cross-sectional OCT images of tissue structure and functions (i.e., local Doppler blood flow) of biological tissue for enhanced diagnosis. A new approach to use spectral demodulation of elastic scattering is discussed for potential cancer grading. The transverse and axial resolutions of the OCT scopes are 12 microm and 10 microm, respectively. Results of the preliminary clinical studies show that unlike animal carcinogenesis models, bladder cancers in humans are more complicated in terms of epithelial backscattering changes: some lesions exhibit enhanced backscattering; some show reduced scattering owing to complex surface condition changes such as asperities or invaginations induced by tumorigenesis (e.g., papillary transitional cell cancers). Nevertheless, promising results can be provided by incorporating other diagnostic parameters such as changes in local vasculature and urothelial heterogeneity.