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Abstract Melanoma is one of the most prevalent skin cancers, with high metastatic rates and poor prognosis. Understanding its molecular pathogenesis is crucial for improving its diagnosis and treatment. Integrated analysis of multi-omics data from 207 treatment-naïve melanomas (primary-cutaneous-melanomas (CM, n = 28), primary-acral-melanomas (AM, n = 81), primary-mucosal-melanomas (MM, n = 28), metastatic-melanomas (n = 27), and nevi (n = 43)) provides insights into melanoma biology. Multivariate analysis reveals that PRKDC amplification is a prognostic molecule for melanomas. Further proteogenomic analysis combined with functional experiments reveals that the cis-effect of PRKDC amplification may lead to tumor proliferation through the activation of DNA repair and folate metabolism pathways. Proteome-based stratification of primary melanomas defines three prognosis-related subtypes, namely, the ECM subtype, angiogenesis subtype (with a high metastasis rate), and cell proliferation subtype, which provides an essential framework for the utilization of specific targeted therapies for particular melanoma subtypes. The immune classification identifies three immune subtypes. Further analysis combined with an independent anti-PD-1 treatment cohort reveals that upregulation of the MAPK7-NFKB signaling pathway may facilitate T-cell recruitment and increase the sensitivity of patients to immunotherapy. In contrast, PRKDC may reduce the sensitivity of melanoma patients to immunotherapy by promoting DNA repair in melanoma cells. These results emphasize the clinical value of multi-omics data and have the potential to improve the understanding of melanoma treatment.

Abstract Soft tissue sarcoma is a broad family of mesenchymal malignancies exhibiting remarkable histological diversity. We portray the proteomic landscape of 272 soft tissue sarcomas representing 12 major subtypes. Hierarchical classification finds the similarity of proteomic features between angiosarcoma and epithelial sarcoma, and elevated expression of SHC1 in AS and ES is correlated with poor prognosis. Moreover, proteomic clustering classifies patients of soft tissue sarcoma into 3 proteomic clusters with diverse driven pathways and clinical outcomes. In the proteomic cluster featured with the high cell proliferation rate, APEX1 and NPM1 are found to promote cell proliferation and drive the progression of cancer cells. The classification based on immune signatures defines three immune subtypes with distinctive tumor microenvironments. Further analysis illustrates the potential association between immune evasion markers (PD-L1 and CD80) and tumor metastasis in soft tissue sarcoma. Overall, this analysis uncovers sarcoma-type-specific changes in proteins, providing insights about relationships of soft tissue sarcoma.

Ciliated muconodular papillary tumor (CMPT) is a rare pulmonary tumor, typically occurring in middle-aged and elderly individuals. The molecular mutation spectrum of CMPT remains insufficiently explored. Commonly known driver gene alterations include KRAS, BRAF, EGFR, and ALK rearrangement. This report details the clinicopathological features of 2 patients presenting with CMPT as pulmonary nodules during clinical examinations. Microscopic analysis revealed tumors with glandular or papillary structures, consisting of mucinous cells, ciliated columnar cells, and basal cells. Notably, both patients exhibited STRN::ALK fusion, a finding not previously associated with CMPT. STRN::ALK fusion serves as a target for therapy in various tumors, including non-small cell lung cancer, thyroid cancer, and colon cancer. Consequently, we conducted a review of relevant literature, summarizing the clinicopathological and molecular characteristics of CMPT to facilitate further research. Our insights enhance the understanding of this uncommon tumor and contribute to the expansion of its molecular alteration spectrum. [ABSTRACT FROM AUTHOR]

This study is to examine EGFR and c-Met variation in precancerous lesion, early esophageal squamous cell carcinoma (ESCC), and advanced ESCC and to explore their prognostic significance. EGFR and c-Met were detected by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Of 158 endoscopy resection (ER) specimens, c-Met high expression and FISH positive were 44.9 and 12.6 %, respectively. EGFR high expression and FISH positive were 2.5 and 19.6 %, respectively. Of 84 surgical specimens, c-Met high expression and FISH positive were 50 and 8.3 %, respectively. EGFR high expression and FISH positive were 7.1 and 28.5 %, respectively. A significant correlation was observed between c-Met and EGFR FISH positive both in ER ( P < 0.001) and surgical specimens ( P = 0.029). Patients with EGFR high expression had poorer disease-free survival (DFS) and overall survival (OS) ( P = 0.031 and P = 0.013) in c-Met high-expression group but not in c-Met low-expression group ( P = 0.301 and P = 0.439). C-Met FISH positive did not represent a statistically significant adverse prognosis until 24 months later ( P = 0.027 and 0.048). EGFR and c-Met might be involved in the tumorigenesis and development of ESCC. EGFR high expression has different prognostic significance in patients with differing c-Met expression status. C-Met FISH positive represent delayed prognostic factor. [ABSTRACT FROM AUTHOR]

We undertook a study of tumour infiltrating lymphocytes (TILs) in a large and relatively homogeneous group of patients with completely resected esophageal squamous cell carcinoma (ESCC). Hematoxylin and eosin-stained sections of 235 ESCC tumours were evaluated for density of TILs in intratumoural (iTIL) and stromal compartments (sTIL). Foxp3+, CD4+, and CD8+ T cells in tumoural and stromal areas were evaluated by immunohistochemistry. Of the 235 tumours, high sTIL (>10%), and iTIL (>10%) were observed in 101 (43.0%) and 98 (41.7%), respectively. The median follow-up period was 36.0 months (95% CI 29.929-42.071). Univariate analysis revealed that sTIL (>10%), iTIL (>20%), vessels involvement, lymph node metastasis, and clinical stage were significantly associated with postoperative outcome. In multivariate analysis, high sTIL (HR: 0.664, P = 0.019 for Disease free survival; HR: 0.608, P = 0.005 for Overall survival) was identified as independent better prognostic factor. Further analysis, sTIL was identified as independently prognostic factor in Stage III-IVa disease, which was not found in Stage I-II disease. Our study demonstrated that sTIL was associated with better ESCC patients' survival, especially in Stage III-IVa disease. Assessment of sTIL could be useful to discriminate biological behavior for ESCC patients. [ABSTRACT FROM AUTHOR]

Objective: To compare the histologic features of immune-mediated hepatitis (IMH) due to immune checkpoint inhibitors (ICIs) monotherapy and combined ICIs anti-angiogenesis tyrosine kinases (TKIs) targeted therapy. Methods: Twenty-one IMH patients who had liver biopsy during ICIs treatment in Zhongshan Hospital of Fudan University from 2015 to 2019 were included. Among them, ten were treated with ICIs monotherapy, and 11 were treated with combined ICIs and anti-angiogenesis targeted therapy. The histologic features of IMH were assessed by HE staining and PD-L1/2 was evaluated by immunohistochemical staining. Results: Patients treated with monotherapy ICIs presented with different levels of lobular hepatitis and portal inflammation. Besides, there were also cholangitis, endothelialitis, Kupffer cells activation and peliosisi hepatitis. Eight cases (8/10) showed mild and two cases (2/10) showed moderate hepatic injury. As for patients receiving combined ICIs and TKIs therapy, the extent of IMH was more severe, with four cases (4/11) showing moderate-severe liver injury, with confluent or bridging necrosis, portal inflammation, cholangitis, interface hepatitis. Among these, one patient developed acute severe hepatitis with massive hepatocyte necrosis and died of multisystem dysfunction. In those cases with severe liver injury, many CD8 positive lymphocytes aggregated in the portal area and hepatic sinusoid, and PD-L1 was expressed in many endothelial cells. There were both 2 cases of death in ICIs monotherapy and combination therapy group. Among the latter group, 1 patient developed acute severe hepatitis with massive hepatocyte necrosis and died of multisystem dysfunction. Conclusion: Compared with ICIs monotherapy, combined ICIs and anti-angiogenesis targeted TKIs therapy may cause overlapping hepatic injury, leading to severe IMH.

Amplification of the fibroblast growth factor receptor 1 ( FGFR1 ) is believed to predict response to FGFR inhibitors. The aim of this study was to investigate the frequency and the prognostic impact of FGFR1 amplification in patients with resected esophageal squamous cell carcinoma (ESCC) by using fluorescent in situ hybridization. Microarrayed paraffin embedded blocks were constructed, and the cohort of tissues came from 506 patients with ESCC. FGFR1 high amplification ( FGFR1 high ) was defined by an FGFR1 /centromere 8 ratio of ≥ 2.0, or average number of FGFR1 signals/tumor cell nucleus ≥ 6.0, or percentage of tumor cells containing ≥ 15 FGFR1 signals, or large cluster in ≥ 10% of cancer cells. FGFR1 low amplification was defined by ≥ 5 FGFR1 signals in ≥ 50% of cancer cells. Kaplan-Meier curves with log-rank tests and Cox proportional hazards model were used to analyze patients' survival. Among 506 patients, high amplification, low amplification, and disomy were detected in 8.7%, 3.6% and 87.7%, respectively. In general, the FGFR1 high group trended towards worse disease-free survival (DFS) and overall survival (OS) compared to the FGFR1 low amplification/disomy ( FGFR1 low/disomy ) group (DFS, P =0.108; OS, P =0.112), but this trend was amplified for patients with DFS ≥ 30 months (DFS, P =0.009; OS, P =0.007). Furthermore, when patients were stratified into stage I-II and stage III-IV, the FGFR1 high group directly presented with adverse DFS and OS than the FGFR1 low/disomy group in stage I-II patients (DFS, P =0.019; OS, P =0.034), especially with DFS ≥ 30 months (DFS, P =0.002; OS, P =0.001). However, for patients in stage III-IV, FGFR1 high had no effect on prognosis regardless of DFS time. FGFR1 high occurs in a minority of ESCC, and it predicts delayed poor prognosis in stage I and II ESCC patients., Competing Interests: CONFLICTS OF INTEREST The authors have no conflicts of interest to declare.

Accumulating evidence has shown that PD-L1 expression is associated with clinicopathological features in various human malignancies. We searched for correlations between PD-L1 expression and clinicopathological data in esophageal squamous cell carcinoma (ESCC) patients. PD-L1 expression in primary tumors from 278 patients was evaluated using immunohistochemistry (IHC) in ESCC tissue microarray. Survival curves were constructed by using the Kaplan-Meier method. Univariate and multivariate Cox proportional hazard regression models were performed to identify associations with outcome variables. Overall, tumoral PD-L1 expression (≥10%, 20% or 30% as cut-off value) was associated with favorable DFS and OS upon multivariate analysis. When the patients stratified into stage I-II (168, 60.4%) and stage III-IV (110, 39.6%), or with lymph node metastasis (133, 47.8%), the prognostic role was not consistent. In patients with stage I-II disease, tumoral PD-L1 expression (≥5%, 10%, 20% or 30%) was associated with better DFS and OS upon multivariate analysis. In patients without lymph node metastasis, tumoral PD-L1 expression (≥1%, 5%, 10%, 20%, or 30%) was associated with improved DFS and OS in univariate or multivariate analysis. However, PD-L1 expression was not correlated with prognosis in patients with stage III-IV disease or with lymph node metastasis. Our results for the first time showed the prognostic role of tumoral PD-L1 expression was variable in different stages and lymph node status of ESCC. Tumoral PD-L1 expression was independent favorable predictor in ESCC patients with Stage I-II disease or without lymph node metastasis, not in stage III-IV or lymph node metastasis.

This study is to examine EGFR and c-Met variation in precancerous lesion, early esophageal squamous cell carcinoma (ESCC), and advanced ESCC and to explore their prognostic significance. EGFR and c-Met were detected by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Of 158 endoscopy resection (ER) specimens, c-Met high expression and FISH positive were 44.9 and 12.6 %, respectively. EGFR high expression and FISH positive were 2.5 and 19.6 %, respectively. Of 84 surgical specimens, c-Met high expression and FISH positive were 50 and 8.3 %, respectively. EGFR high expression and FISH positive were 7.1 and 28.5 %, respectively. A significant correlation was observed between c-Met and EGFR FISH positive both in ER (P < 0.001) and surgical specimens (P = 0.029). Patients with EGFR high expression had poorer disease-free survival (DFS) and overall survival (OS) (P = 0.031 and P = 0.013) in c-Met high-expression group but not in c-Met low-expression group (P = 0.301 and P = 0.439). C-Met FISH positive did not represent a statistically significant adverse prognosis until 24 months later (P = 0.027 and 0.048). EGFR and c-Met might be involved in the tumorigenesis and development of ESCC. EGFR high expression has different prognostic significance in patients with differing c-Met expression status. C-Met FISH positive represent delayed prognostic factor.

Objective: To study the clinicopathological characteristics of hepatic angiomyolipoma (HAML) and to evaluate the correlation between clinicopathological parameters and tumor subtypes., Methods: Retrospective analysis of clinicopathological features was conducted in 182 cases of HAML., Results: HAML patients were predominantly female (M:F=1:4) and most commonly presented with non-specific symptoms. The median age at diagnosis was 46 years, ranged from 17 to 77 years. Tumor diameter was ranged from 0.3 to 32.0 cm with an average of 5.0 cm. Majority of the tumor was epithelioid type (112/165, 67.9%). Extramedullary hematopoiesis, multinucleated giant cells, intranuclear inclusions, nucleolus, cellular atypia, invasive growth pattern, multiple masses, hyperpigmentation and purpura-like changes mostly occurred in the epithelioid type (P<0.05). Extramedullary hematopoiesis was commonly seen in HAML, the significance of which was still uncertain., Conclusions: Most of HAML are epithelioid type, characterized by a proliferation of predominantly epithelioid cells, in which extramedullary hematopoiesis is commonly seen. Some morphologic features that may predict malignant such as necrosis, mitotic figures, and tumor emboli are only found in the epithelioid HAML. Mitotic activity, tumor necrosis, tumor thrombus, giant cells, periportal invasion, multiple lesions and tumors size over 10 cm are closely related with tumor recurrence and metastasis.

Objective: To study the clinicopathologic features of focal nodular hyperplasia (FNH) of liver., Methods: The clinical, radiologic, pathologic findings and follow-up data of 238 cases of FNH were retrospectively analyzed., Results: The patients included 93 females and 145 males. The age of the patients ranged from 11 to 77 years (median = 39.1 years). Amongst the 233 patients who had clinical information available, 188 were asymptomatic, 216 had no history of hepatitis B and/or C infection and 232 had negative serum alpha-fetoprotein level. Amongst the 185 patients who had undergone radiologic examination, 123 (66.5%) were accurately diagnosed as such. Macroscopically, of the 284 lesions from 238 patients, the average diameter was 3.7 cm. Two hundred and fifteen cases (90.3%) were solitary, 172 cases were located in the right lobe and 115(40.5%) had central stellate fibrotic scars or lobulated cut surface. Histologically, 229 lesions belonged to classic type and 9 lesions were of non-classic type. The latter was further classified as the telangiectatic form (6 lesions) and the mixed hyperplastic and adenomatous form (3 lesions). There was no evidence of significant cytologic atypia. Follow-up data were available in 173 patients (72.7%). None of them died of the disease and 2 patients suffered from relapses after 2 and 4 years, respectively., Conclusions: FNH is a hyperplastic response of normal liver cells to local blood flow anomalies. It has no obvious sex predilection and more than 66% can be diagnosed accurately with radiologic examination. The lesions in the current study show no cytologic atypia.

Objective: To study the pathologic features and immunophenotype of 3 cases of melanotic epithelioid clear cell tumor of kidney., Methods: More than 2000 cases of renal tumors were retrospectively reviewed. Three cases of melanotic epithelioid clear cell tumor were identified. Immunohistochemical study was carried out using the paraffin-embedded tissue samples. Electron microscopy was also performed in 1 case., Results: Amongst the 3 cases studied, the male-to-female ratio is 1:2. Histologically, 2 cases showed a clear cell carcinoma-like pattern. Papillary structures covered by clear cells and eosinophilic cells were observed in 1 case. Immunohistochemical study showed that the tumor cells in all cases expressed HMB 45. Two of them were also positive for Melan A. The staining for epithelial markers and S-100 protein was negative. Melanosomes were not identified by ultrastructural examination., Conclusions: Melanotic epithelioid clear cell tumor is a rarely seen neoplasm of kidney. There are some histologic overlaps with renal cell carcinoma, epithelioid angiomyolipoma and melanoma. Immunohistochemical study is useful in confirming the diagnosis. The tumor represents a morphologic variant of epithelioid angiomyolipoma.

Objective: To improve the understanding and diagnosis of pulmonary lymphangioleiomyomatosis (LAM)., Methods: Fifteen cases of LAM of our hospital were presented and 73 cases reported in domestic literature from 1993 to 2008 were reviewed. By means of histological and immunohistochemical(IHC)studies, the clinical and pathological features of LAM were analyzed., Results: All the 88 cases were female, with an average age of onset at (37 +/- 9) years. The main clinical manifestations included dyspnea (83/88, 94%), hemoptysis (48/88, 54%), pneumothorax (41/88, 47%), and chylothorax (28/88, 32%). High resolution computerized tomography (HRCT) showed thin-walled air-filled cysts throughout both lungs. Pathological features showed cystic changes in the lung, and abnormal smooth muscle cells (LAM cells) lined the airways, bronchioles, lymphatics and blood vessels leading to airflow obstruction and replacement of the lung parenchyma by cysts. In the autopsy case, extrapulmonary organs (eg, kidney, lymph nodes and soft tissues) were also involved. Abnormal manifestations in abdomen, including renal mass, retroperitoneal mass and retroperitoneal lymphadenopathy, were detected in 23 cases., Conclusions: LAM is a multisystem disease. Chest HRCT had confirmative value for diagnosis of LAM. In practice, chest HRCT, as well as other routine abdominal and pelvic imaging examinations, should be performed for child-bearing-age women with progressive dyspnea, hemoptysis, or spontaneous pneumothorax.

Aim: To recognize cystic neoplasia of the pancreas and thus to identify a panel of curable diseases., Methods: Sixty-four cases of cystic neoplasia of the pancreas, including 28 cases of intraductal papillary mucinous neoplasia (IPMN), 12 cases of serous cystic neoplasia (SCN), 11 cases of mucinous cystic neoplasia (MCN), 11 cases of solid pseudo-papillary neoplasia (SPN), and 2 cases of solid tumor with cystic degeneration were examined immunohistochemically for their expression of MUC1, MUC2, MUC4, MUC5AC, and MUC6, as well as other related antigens., Results: Adenoma type of IPMN and borderline lesions exhibited high expressions of MUC2, and MUC5AC. In contrast, IPMN with invasive carcinoma component showed MUC1 immunoreactivity. SCN was mainly positive for MUC1 and MUC6, while negative for MUC2, MUC4 and MUC5AC. Noninvasive MCN, regardless of its cellular atypia degree, was positive for MUC5AC and negative for MUC1. MUC1 expression was only observed in patients with an invasive component. No mucin expression was found in SPN., Conclusion: Mucin profile may, in conjunction with histologic study, provide important information on tumor types and patient treatment of cystic neoplasia of the pancreas.

Objective: To explore the therapeutic effect of STI571(imatinib mesylate) on advanced gastrointestinal stromal tumors (GISTs)., Methods: Clinical data of 5 cases with advanced GISTs were analyzed retrospectively., Results: The expression of c- kit (CD117) was detected by immunohistochemical method in five patients with advanced GISTs . All patients failed to systematic chemotherapy or radiofrequency and operation because of extensive and multiple metastases (4 cases underwent 1 to 3 times of exploratory surgery). Tumor size was markedly decreased one to six months after STI571 given without serious drug- related side effects., Conclusions: STI571 is an effective chemotherapy for advanced unresectable or metastatic GISTs. Inhibitor of the Kit signal- transduction pathway is a promising regimen that is different from conventional chemotherapy for advanced GISTs.