EGFR overexpression and macrophage infiltration correlate with poorer prognosis in HPV-negative oropharyngeal cancer via STAT6 signaling.

BACKGROUND: The prevalence of HPV-negative oropharyngeal cancer (OPC) is higher in Asian countries. Patients with HPV-negative OPC suffer poor outcomes. Multi-omics analysis could provide researchers and clinicians with more treatment targets for this high-risk group. We aimed to explore the prognostic significance of EGFR overexpression and macrophage infiltration in OPC, especially HPV-negative OPC in this study. METHODS: EGFR alternation was evaluated with TCGA, PanCancer Atlas through cBioProtal. EGFR mRNA expression in HPV-negative head and neck squamous cell carcinoma was analyzed using the Tumor Immune Estimation Resource (TIMER 2.0). We also examined EGFR/STAT6/MRC1 expression in paraffin-embedded tissues from a p16-negative OPC cohort. The correlation between EGFR expression and macrophage activation was explored using Person's correlation coefficient. The impact of biomarkers or macrophage infiltration on 5-year overall survival and recurrence-free survival were analyzed using Kaplan-Meier survival curves. RESULTS: EGFR alteration rate was 15%, 13%, and 0% for HPV-negative HNSCC (excluding OPC), HPV-negative OPC, and HPV-positive OPC. High EGFR expression was associated with increased tumor infiltration of immune cells, such as macrophages. We observed positive correlations between EGFR, STAT6, and MRC1 expression in p16-negative OPC. Higher MRC1 expression was associated with poorer survival rates. CONCLUSIONS: There is strong correlation between EGFR overexpression and M2 polarization in patients with p16-negative OPC. Immunotherapy with or without EGFR inhibitor could be considered in these high-risk patients.

Prognostic stratification of oropharyngeal cancer patients in a betel nut chewing and low HPV area.

BACKGROUND: This study aimed to establish a simple predictive model for oropharyngeal cancer (OPC) in an area with a relatively low prevalence of human papillomavirus (HPV) and frequent betel nut chewing. METHODS: A total of 116 patients with OPC were recruited from the clinical research database of a referral cancer center between 2013 and 2018. Patient characteristics-including age, gender, tumor stage, differentiation, and treatment modality-were extracted from the database. Patients diagnosed after 2018 were staged using the 7th AJCC staging system to explore the impact of extra-nodal tumor extension (ENE) on survival. Immunohistochemical analysis was performed for p16, epidermal growth factor receptor (EGFR), p53, and programmed cell death ligand 1 (PD-L1). ENE status was evaluated by pathological analysis or radiological features. Primary outcome was disease-specific overall survival (OS). Univariate and multivariate Cox regression were used to establish a predictive model. RESULTS: Mean age was 57.3 ± 9.9 years; 103 patients (88.8%) were male. P16 positive OPC was positively associated with higher PD-L1 and a tonsillar sub-site and negatively associated with betel nut chewing and cigarette smoking. In Cox regression, age, p16 status, EGFR, cT4, ENE, and cigarette smoking were significantly associated with OS. In survival tree analysis, cT stage was the most important risk stratification parameter, followed by EGFR expression and p16 status. Patients with cT4 stage or high EGFR were classified as the high-risk group and had poorest OS. CONCLUSIONS: Due to the low prevalence of HPV and popularity of betel nut chewing in Asia, the relative importance of prognostic predictors for OPC are not identical to Western countries. Identification of significant prognostic biomarkers may improve treatment. Trial registration This study was registered and approved by the Institutional Review Board (IRB) of Kaohsiung Veterans General Hospital (VGHKS19-CT9-07; date of approval: Aug 9, 2019).

Sunitinib-related high-grade proteinuria and allograft dysfunction in a kidney recipient: a rare case report.

BACKGROUND: Sunitinib-induced high-grade proteinuria and irreversible renal allograft dysfunction are rare conditions. Here, we present a patient who had received renal allograft and later developed metastatic clear cell renal cell carcinoma(cc-mRCC), for which he was prescribed sunitinib. High-grade proteinuria, hypoalbuminemia, peripheral edema and renal allograft dysfunction (manifesting as an increase in the serum creatinine concentration) occurred 5 months after sunitinib prescription. CASE PRESENTATION: The patient was a 58-year-old male who had end-stage renal disease with regular hemodialysis through arteriovenous fistula for 17 years since 1998 and received a renal allograft from a deceased kidney donor in 2015. Unfortunately, in 2019, the patient developed cc-mRCC originating from the left native kidney. We suggested a needle biopsy on left native kidney or radical left nephrectomy, but the patient refused. Sunitinib was prescribed. Follow-up urine analysis showed proteinuria (500 mg/dL) 2 weeks after sunitinib prescription. He was hospitalized 5 months later because of body weight gain, decreased urine output, pitting edema of both lower extremities, and shortness of breath. The image studies showed progression in his cc-mRCC. His serum creatinine level and spot urine protein at admission increased to 4.26 mg/dL and 300 mg/dL, respectively. He agreed on a biopsy for the renal allograft and the pathology studies showed focal segmental glomerulosclerosis, acute interstitial nephritis, and acute tubular injury. Based on the time sequence of clinical presentations with the laboratory and pathological findings, sunitinib-induced renal allograft dysfunction secondary to high-grade proteinuria was most likely. Despite of discontinuation of sunitinib and increased dose of everolimus, renal impairment progressed. Thus, he had to receive hemodialysis starting 2 week after hospitalization. Unfortunately, the patient died of advanced metastasis despite of aggressive medical treatments 3 weeks after admission. CONCLUSION: This case report is a reminder that renal allograft dysfunction can happen secondary to proteinuria after taking sunitinib. Hence, clinicians must regularly check renal function and urine protein for renal allograft recipients. Monitoring and modifying drug prescription, especially sunitinib, is necessary if persistent proteinuria accompanied by deteriorating serum creatinine level occurs. Renal biopsy may be considered if more evidence is required to make a differential diagnosis.

Spinal gouty tophus presenting as an epidural mass lesion - A case report.

INTRODUCTION: Gout is a metabolic disease secondary to an increased body pool of urate with hyperuricemia. Gout typically affects the peripheral joints and rarely involves the intra-spinal area. CASE PRESENTATION: A 43-year-old man, who had metabolic syndrome s/p bariatric surgery and gout suffered from severe left low back pain with radiation to the lateral side of his left thigh and anterior side of his left leg for more than 7 days. His L-spine MRI showed an abnormal posterior epidural space occupying lesion at L4-L5 level. For tissue diagnosis and neural structures decompression, he underwent surgical removal of the epidural mass lesion. The surgical specimen showed a picture of gout and he got a good recovery after operation. DISCUSSION: The differential diagnoses of an epidural mass includes synovial cysts, ligament cyst, cystic neuromas, tumors, hematomas and abscesses. Gout in the spinal canal is difficult to diagnosis before surgery because it is rare and its clinical presentation and radiologic findings mimic tumor, abscess, tuberculosis, and degenerative spinal diseases. Patients with spinal gout may present with axial pain and a variety of neurological symptoms. CONCLUSION: Spinal gouty tophus should be considered in the different diagnoses of spinal epidural masses especially in patients with systemic gout. Surgery is needed for final diagnosis. If spinal gouty tophus is highly suspected during the surgery, the specimen should not be preserved with Formalin because birefringent crystals under polarized light is a unique feature for gouty tophus but they dissolve in Formalin.

Prognostic Influence of Cytoplasmic/Nuclear Hepatoma-derived Growth Factor in Head and Neck Cancer.

BACKGROUND/AIM: We investigated the prognostic influence of both hepatoma-derived growth factor (HDGF) and p53 expression in head and neck cancer. MATERIALS AND METHODS: HDGF and p53 immunostaining was scored based on staining intensities and percentage of tumor cells stained using tissue microarray composed of total 102 head and neck cancer samples. RESULTS: Over-expression of HDGF and p53 was observed in cancer compared with adjacent normal tissues (p<0.001). In multivariate analyses, tumors with higher nuclear and cytoplasmic HDGF staining scores (p=0.019), and tumors with cN1-cN2 (compared with cN0) (p=0.014), were associated with worse overall survival. CONCLUSION: The increased expression of HDGF and p53 in the tumor compared with adjacent normal tissues could be a risk factor for tumorigenesis. Increased nuclear and cytoplasmic expression of HDGF, and cN staging correlated with overall survival and negatively influenced prognosis in head and neck cancer.

Using the Fat-Clearing Technique to Improve Lymph Node Retrieval in Colorectal Cancer.

College of American Pathologists recommended that at least 12 lymph nodes should be harvested for adequate staging of colorectal carcinoma. Lymph node harvesting is routinely performed by a manual technique of inspection and palpation, which is laborious and time-consuming. The study assessed the influence of the improved fat-clearing technique on the number of lymph nodes retrieved from colorectal cancer specimens and the clinical efficacy. Seventy colorectal cancer resection specimens were examined and assessed by 4 pathology residents. Thirty-five specimens were handled with the conventional manual technique by inspection and palpation, and the other 35 specimens with the improved fat-clearing technique to retrieve lymph nodes. As a result, compared with the conventional manual technique, the numbers of lymph nodes retrieved with the improved fat-clearing technique were significantly increased from 14.7 ± 6.2 lymph nodes to 20.8 ± 9.0 lymph nodes per specimen (P < .05). Besides, the percentage of cases with at least 12 lymph nodes retrieved increased from 80% to 91%. The result of this study pointed out that using the improved fat-clearing technique to process colorectal specimens could increase the lymph node yield effectively, and was effective, practical, and suitable for routine gross examination.

Association of ATG4B and Phosphorylated ATG4B Proteins with Tumorigenesis and Prognosis in Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) is one of the major leading causes of cancer death worldwide due to the limited availability of biomarkers and therapeutic targets. Autophagy related protease 4B (ATG4B) is an essential protease for the autophagy machinery, and ATG4B phosphorylation at Ser383/392 increases its proteolytic activity. ATG4B expression and activation are crucial for cancer cell proliferation and invasion. However, the clinical relevance of ATG4B and phospho-Ser383/392-ATG4B for OSCC remains unknown, particularly in buccal mucosal SCC (BMSCC) and tongue SCC (TSCC). With a tissue microarray comprising specimens from 498 OSCC patients, including 179 BMSCC and 249 TSCC patients, we found that the protein levels of ATG4B and phospho-Ser383/392-ATG4B were elevated in the tumor tissues of BMSCC and TSCC compared with those in adjacent normal tissues. High protein levels of ATG4B were significantly associated with worse disease-specific survival (DSS) in OSCC patients, particularly in patients with tumors at advanced stages. In contrast, phospho-Ser383/392-ATG4B expression was correlated with poor disease-free survival (DFS) in TSCC patients. Moreover, ATG4B protein expression was positively correlated with phospho-Ser383/392-ATG4B expression in both BMSCC and TSCC. However, high coexpression levels of ATG4B and phospho-Ser383/392-ATG4B were associated with poor DFS only in TSCC patients, whereas they had no significant association with DSS in BMSCC and TSCC patients. In addition, silencing ATG4B with an antisense oligonucleotide (ASO) or small interfering RNA (siRNA) diminished cell proliferation of TW2.6 and SAS oral cancer cells. Further, knockdown of ATG4B reduced cell migration and invasion of oral cancer cells. Taken together, these findings suggest that ATG4B might be a biomarker for diagnosis/prognosis of OSCC and a potential therapeutic target for OSCC patients.

Pituitary spindle cell oncocytoma presented as pituitary apoplexy.

Spindle cell oncocytoma is a rare nonfunctioning neoplasm of the adenohypophysis, and was first described in 2002 by Roncaroli et al. In 2007, spindle cell oncocytoma has been categorized as a separate entity by the World Health Organization (WHO) and is classified as a Grade 1 tumor of the central nervous system. Spindle cell oncocytoma of pituitary gland usually occurs in adults and accounts for 0.1-0.4% of all sellar region tumors. Clinically and radiologically, they are indistinguishable from nonfunctioning pituitary adenomas. From 2002 to 2018, approximately 46 cases of spindle cell oncocytoma of pituitary gland had been reported in the English literature and we would like to report a case of 28-year-old woman presented with pituitary apoplexy proved to be a case of spindle cell oncocytoma of pituitary gland which probably will be the 47th reported case.

Coexistence of intracranial solitary fibrous tumor/hemangiopericytoma and right middle cerebral artery aneurysm.

Intracranial solitary fibrous tumors are rare mesenchymal neoplasms originating in the meninges and constitute a heterogeneous group of rare spindle cell tumors that include benign and malignant neoplasms of which hemangiopericytoma is nowadays considered a cellular phenotypic variant. From literatures, the incidence of coexistence of brain tumors and intracranial aneurysms is ~0.7-5.4%. Meningioma is the most frequent tumor coexisted with intracranial aneurysms, followed by pituitary adenoma, neuroepithelial tumor, and metastatic tumor. We would like to report a case of 74-year-old man harboring a rare intracranial solitary fibrous tumor/hemangiopericytoma and an unruptured aneurysm of the right middle cerebral artery which probably the first report of these combinations in the English literature. Both lesions were treated surgically in one session with favorable outcome. Magnetic resonance angiography should be performed in patients with brain tumor preoperatively not only to visualize neoplastic vascularization but also to pick up incidental aneurysm.

Log margin-to-thickness ratio improves disease-specific survival prediction in oral cancer: A single cancer centre database.

OBJECTIVE: We examined whether dynamic margin criteria margin-to-thickness (MTR) ratio has superior predictive value compared with the resection margin or tumour thickness alone in the survival outcome in oral squamous cell carcinoma (OSCC). DESIGN: This is a retrospective cohort study. SETTING: Oral squamous cell carcinoma patients treated in Kaohsiung Veterans General Hospital Cancer Center between January 2006 and December 2013. PARTICIPANTS: A cohort of 302 patients with OSCC who had undergone surgical management. MAIN OUTCOMES MEASURES: Log MTR was calculated for each patient, and survival data were analysed using a multivariable Cox regression model. Discriminative analysis was performed using chi-square, Akaike information criterion (AIC) and Harrell's C tests. RESULTS: After assessing for discriminative ability, the linear trend of log MTR surpassed those of resection margin and tumour thickness in chi-square, AIC and Harrell's C tests for the advanced pathologic T (pT) category. A multivariate Cox proportional hazard regression model revealed that log MTR <33% was associated with less favourable 5-year disease-specific survival (DSS) (P = 0.006) in the entire oral cancer study cohort. Other significant factors included perineural invasion (P = 0.021), pT category, (P = 0.005), pathologic N category (P < 0.001) and differentiation category (P = 0.022). CONCLUSIONS: Log MTR < 33% may be a predictor of less favourable outcome in the DSS of OSCC. Log MTR outperformed both resection margin and tumour thickness alone in terms of discriminative analysis. Our study could help in presurgical planning for high-risk patients and in aiding the decision-making process for adjuvant treatment.

Map1lc3b and Sqstm1 Modulated Autophagy for Tumorigenesis and Prognosis in Certain Subsites of Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) is one of the most common cancer types worldwide and can be divided into three major subsites: buccal mucosal SCC (BMSCC), tongue SCC (TSCC), and lip SCC (LSCC). The autophagy marker microtubule-associated protein light chain 3B (MAP1LC3B) and adaptor sequestosome 1(SQSTM1) are widely used proteins to evaluate autophagy in tumor tissues. However, the role of MAP1LC3B and SQSTM1 in OSCC is not fully understood, particularly in certain subsites. With a tissue microarray comprised of 498 OSCC patients, including 181 BMSCC, 244 TSCC, and 73 LSCC patients, we found that the expression levels of MAP1LC3B and cytoplasmic SQSTM1 were elevated in the tumor tissues of three subsites compared with those in adjacent normal tissues. MAP1LC3B was associated with a poor prognosis only in TSCC. SQSTM1 was associated with poor differentiation in three subsites, while the association with lymph node invasion was only observed in BMSCC. Interestingly, MAP1LC3B was positively correlated with SQSTM1 in the tumor tissues of BMSCC, whereas it showed no correlation with SQSTM1 in adjacent normal tissue. The coexpression of higher MAP1LC3B and SQSTM1 demonstrated a significantly worse disease-specific survival (DSS) and disease-free survival (DFS) in patients with BMSCC and LSCC, but not TSCC. The knockdown of MAP1LC3B and SQSTM1 reduced autophagy, cell proliferation, invasion and tumorspheres of BMSCC cells. Additionally, silencing both MAP1LC3B and SQSTM1 enhanced the cytotoxic effects of paclitaxel in the tumorspheres of BMSCC cells. Taken together, MAP1LC3B and SQSTM1 might modulate autophagy to facilitate tumorigenesis and chemoresistance in OSCC, particularly in BMSCC.

Glioblastoma with Both Oligodendroglioma and Primitive Neuroectodermal Tumor-Like Components in a Case with 9-Year Survival.

INTRODUCTION: Glioblastoma multiforme (GBM), the most common primary malignant brain tumor in adults, is characterized by extensive heterogeneity in its clinicopathological presentation. A primary brain tumor with both astrocytic differentiation and neuronal immunophenotype features is rare. Here, we report a long-term survival patient who presented this rare form of GBM in the disease course. PRESENTATION OF CASE: A 23-year-old woman, presenting with rapidly progressive headache and right-side weakness, was diagnosed with brain tumor over the left basal ganglion. She underwent the first craniectomy for tumor removal, and histopathology revealed classic GBM. Tumor recurrence occurred 8 years later. Another gross total resection was performed and pathology revealed GBM with the oligodendroglioma component (GBM-O). Due to disease progression, she received debulking surgery the following year. The third pathology revealed glioblastoma with primitive neuroectodermal tumor-like component (GBM-PNET). DISCUSSION: GBM-PNETs are collision tumors with both neuronal and glial components. They are rare, and a few case reports have suggested that these tumors are associated with favorable outcomes but a higher risk of cerebrospinal fluid dissemination. CONCLUSION: We report a patient who developed the distinct pathologic variants of classic GBM, GBM-O, and GBM-PNET, throughout the disease course. Young age, aggressive surgical resection, and pathologic and genetic features may have contributed to the long-term survival of the patient.

Left orbital roof giant cell tumor of bone: A case report.

BACKGROUND: Giant cell tumor of bone originating from the connective tissue within the bone marrow is benign but locally aggressive lesion. In all, 90% of the cases involve the epiphysis of long bones and less than 2% involve the skull. Giant cell tumors of the skull occur most frequently in the sphenoid and temporal bones, and very rarely in the ethmoid, frontal, parietal, and occipital bones. We would like to share a case of giant cell tumor of bone arising from the left orbital roof with involving ethmoid sinus, which was diagnosed to be a meningioma before surgery. CASE DESCRIPTION: A 32-year-old lady presented to us with the chief complain of left proptosis, diplopia, and left eye soreness without decline of visual acuity for about 2 months. Her orbital magnetic resonance imaging (MRI) disclosed a mass lesion located in the left frontal base, orbital roof, and upper medial orbital region with adjacent dural-tail sign favoring meningioma. She underwent a left supraorbital pterional craniotomy with the gross total removal of tumor and dura reconstruction. Histology examination of the tumor showed a picture of giant cell tumor of bone. Considering giant cell tumor of bone is locally aggressive, postoperative adjuvant therapy with Denosumab was introduced after full explanation. CONCLUSION: Standard treatments of skull-base giant cell tumors have yet to be established due to small number of cases reported in the literature. The standard treatment of giant cell tumor of bone is complete resection of the tumor.

Assessment of EGFR and ERBB2 (HER2) in Gastric and Gastroesophageal Carcinomas: EGFR Amplification is Associated With a Worse Prognosis in Early Stage and Well to Moderately Differentiated Carcinoma.

Epidermal growth factor receptor 1 (EGFR) and erb-b2 receptor tyrosine kinase 2 (ERBB2/HER2) are frequently dysregulated in human cancers. We analyzed EGFR and ERBB2 status in 105 gastric and gastroesophageal junction carcinoma and their clinicopathologic features. For EGFR, 92 (88%) tumors were scored as 0, 2 (2%) as 1+, 7 (7%) as 2+, and 4 (3%) as 3+ by immunohistochemistry (IHC) and 4 (4%) tumors showed EGFR amplification by fluorescence in situ hybridization (FISH). For ERBB2, 90 (86%) tumors were scored as 0, 4 (4%) as 1+, 6 (6%) as 2+, and 5 (5%) as 3+ by IHC and 12 (12%) showed ERBB2 amplification by FISH. The concordance rate between IHC and FISH of EGFR was 98.1% (P<0.001) and of ERBB2 was 93.3% (P<0.001). Most tumors with ERBB2 amplification were tubular adenocarcinoma (N=11, P=0.02) and Lauren intestinal type (N=12, P=0.016). There was no statistically significant difference between EGFR amplification and tumor classification. EGFR amplification had significant impact on overall survival in certain subgroups: early stages (stages I and II) (P<0.001), well to moderately differentiated tumors (P=0.001), and fewer regional lymph node metastasis (pN1) (P=0.001). ERBB2 status had little predictive value on overall survival. In conclusion, this study showed ERBB2 amplification was significantly observed in tubular adenocarcinoma and Lauren intestinal-type carcinoma. The IHC scoring criteria for ERBB2 can be applied to EGFR. EGFR amplification had associated with poor prognosis in early, well to moderately differentiated carcinoma.

Sustained renal inflammation following 2 weeks of inhalation of occupationally relevant levels of zinc oxide nanoparticles in Sprague Dawley rats.

Exposure to zinc oxide (ZnO) has been linked to adverse health effects, but the renal effects of ZnO nanoparticles (ZnONPs) remain unclear. The objective of this study was to determine the renal toxicity of inhaled ZnONPs. Sprague Dawley (SD) rats were exposed to occupationally relevant levels of 1.1 (low dose) and 4.9 mg/m3 (high dose) ZnONPs or high-efficiency particulate arresting-filtered air (HEPA-FA) via inhalation for 2 weeks. Histopathological examinations of rat kidneys were performed at 24 hours, 7 days, and 1 month after exposure. A significant increase in microscopic inflammatory foci with pronounced periglomerular inflammation and interstitial lymphocytic infiltration was found in rats exposed to low and high doses of ZnONPs compared with rats exposed to HEPA-FA at the three time points following 2 weeks of exposure. Tubulitis featuring lymphocytic infiltrate within the tubular epithelium was found after 24 hours but had disappeared at 7 and 30 days in both the low- and high-dose exposure groups. Our findings demonstrate that inhaled ZnONPs cause sustained renal periglomerular and interstitial inflammation through lymphocytic infiltration. These findings provide histopathological evidence regarding sustained renal inflammation of nanoparticle exposure in rats and may provide some insight into the occupational health effects of ZnONPs on exposed workers.

Uterine lipoleiomyosarcoma: report of 2 cases and review of the literature.

Uterine lipoleiomyosarcoma is a rare entity with only 6 case reports in the Pubmed database at the time of writing this article. We report 2 additional cases of uterine lipoleiomyosarcoma, characterized on microscopy by coexistence of leiomyosarcomatous and liposarcomatous components, with focal intermingling, without an intervening lipoleiomyomatous area. The liposarcomatous component in both of our cases had the morphology of myxoid liposarcoma. Both cases underwent postoperative chemotherapy. One of our cases had recurrence in the pelvis with microscopic features of myxoid liposarcoma. This patient died with multiple metastases 4.5 yr after hysterectomy, with the metastatic lesions being liposarcomas, without an evident leiomyosarcomatous component. Although lacking a treatment protocol because of the rarity of such cases, postoperative adjuvant therapy is mandatory.