A Familial Case of Multiple Endocrine Neoplasia 2A: From Morphology to Genetic Alterations Penetration in Three Generations of a Family.

This paper illustrates a rare syndrome of multiple endocrine neoplasia type 2A (MEN2A) in a family of three generations. In our case, the father, son and one daughter developed phaeochromocytoma (PHEO) and medullary thyroid carcinoma (MTC) over a period of 35 years. Because of the metachronous onset of the disease and lack of digital medical records in the past, the syndrome was not found until a recent fine needle aspiration of an MTC-metastasized lymph node from the son. All resected tumors from the family members were then reviewed and supplemented with immunohistochemical studies, previously wrong diagnoses were then corrected. Further molecular study of targeted sequencing also revealed a RET germline mutation (C634G) in the family tree including the three members with onset of the disease and one granddaughter who had no disease at the time of testing. Despite the syndrome being well-known, it may still be misdiagnosed because of its rarity and long disease onset. A few lessons can be learned from this unique case. Successful diagnosis requires high suspicion and surveillance and a tri-level methodology including a careful review of family history, pathology and genetic counselling.

Genomic profiling identifies distinct genetic subtypes in extra-nodal natural killer/T-cell lymphoma.

Extra-nodal NK/T-cell lymphoma, nasal type (ENKTCL) is a highly aggressive Epstein-Barr virus associated lymphoma, typically presenting in the nasal and paranasal areas. We assembled a large series of ENKTCL (n = 209) for comprehensive genomic analysis and correlative clinical study. The International Lymphoma Prognostic Index (IPI), site of disease, stage, lymphadenopathy, and hepatomegaly were associated with overall survival. Genetic analysis revealed frequent oncogenic activation of the JAK/STAT3 pathway and alterations in tumor suppressor genes (TSGs) and genes associated with epigenomic regulation. Integrated genomic analysis including recurrent mutations and genomic copy number alterations using consensus clustering identified seven distinct genetic clusters that were associated with different clinical outcomes, thus constituting previously unrecognized risk groups. The genetic profiles of ENTKCLs from Asian and Hispanic ethnic groups showed striking similarity, indicating shared pathogenetic mechanism and tumor evolution. Interestingly, we discovered a novel functional cooperation between activating STAT3 mutations and loss of the TSG, PRDM1, in promoting NK-cell growth and survival. This study provides a genetic roadmap for further analysis and facilitates investigation of actionable therapeutic opportunities in this aggressive lymphoma.

[Fine Needle Aspiration Cytology of Hyalinizing Trabecular Tumor of the Thyroid].

Objective To investigate the fine needle aspiration cytology and differential diagnosis of hyalinizing trabecular tumor (HTT) of the thyroid.Methods The fine needle aspiration smears of four HTT cases with histopathological controls were analyzed,which were then combined with the histopathological changes and immunophenotypes for diagnosis.The key points of cytological diagnosis and the differential diagnosis of HTT were then summarized.Results The fine needle aspiration cytology showed that the tumor cells were scattered,presenting as partially cohesive clusters or clusters with trabecular manifestations.The tumor cells were polygonal or spindle,with medium or rich cytoplasm.The nuclei were oval or short spindle,with fine granular chromatin,visible small nucleoli,common nuclear grooves and nuclear pseudoinclusions,and irregular outline,which demonstrated the nucleus characteristics of papillary thyroid carcinoma.The interstitium showed transparent basement membrane-like material deposition,loose tumor cell clusters,trabecular or syncytial structure,radially distributed tumor cells around the hyaline-like material,rich eosinophilic or dichromophile cytoplasm,elongated nuclei,no papillary structure or fibrovascular axis,and no psammoma bodies.Histopathology showed tumor cells arranged in beam and organoid,transparent basement membrane-like material deposition between trabecular beams,and polygonal or spindle cells containing fine granular eosinophilic cytoplasm and round or oval nuclei with common nuclear grooves and nuclear pseudoinclusions.Conclusion Combining the ultrasound results with the arrangement,interstitial components,and cytological characteristics of tumor cells,we suggest that Ki-67(MIB-1)staining can be employed to assist diagnosis and improve the diagnostic accuracy of HTT or intraoperative freezing can be adopted for further diagnosis.

Factors for postoperative recurrence of orbital solitary fibrous tumor: an analysis of long-term clinical follow-up results from a Chinese tertiary hospital.

BACKGROUND: This study analyzed the clinical features, imaging manifestations, histopathology, immunohistochemistry, and surgical approaches of the orbital solitary fibrous tumor (OSFT), as well as the factors for postoperative recurrence of such disease. METHODS: The clinical data of 16 patients with OSFT treated in our center from 2003 to 2020 were analyzed retrospectively, and the clinical symptoms, treatment methods, and follow-up results were recorded. RESULTS: Of the 16 patients, 8 were females (50.0 %) and 8 were males (50.0 %); the average age of treatment was 37 ± 7 years and the median follow-up time was 74 (8, 228) months. Sixteen patients with OSFT underwent a total of 29 operations, of which 12 were transorbital approach operations and 17 were transfronto-orbital approach operations. Ten patients (10/16, 62.5 %) had recurrence. The recurrence rate of transorbital approach operations was 83.3 % (10/12), and the recurrence rate of transfronto-orbital approach operations was 17.6 % (3/17). No patients had treatment-related complications. CONCLUSIONS: The main pathological feature of OSFT is a benign tumor. OSFT has a tendency to grow toward the cranio-orbital junction. The postoperative recurrence rate of OSFT is relatively high, so complete tumor resection is very important for prognosis. Inappropriate surgical approaches can lead to incomplete removal of the tumor and cause recurrence. Choosing the correct operation approach according to the position of the OSFT in the orbit and complete removal of the dura mater and bone affected by the tumor is crucial for the prognosis. Nevertheless, regular long-term follow-up after complete resection is necessary.

Prognosis Analysis and Clinical Features of Orbital Cavernous Venous Malformations With Refractory Insidious Onset.

OBJECTIVE: The present study aims to analyse the clinical presentation, treatment and prognosis of a group of patients with orbital cavernous venous malformation (OCVM) with an insidious onset. METHOD: The clinical data of 35 patients with OCVM treated at our centre between 2003 and 2020 were retrospectively analysed. The OCVMs were classified as one of six types (I-VI) according to the orbital position of the tumour. The clinical characteristics, treatment methods and follow-up results were recorded. RESULTS: A total of 35 patients with OCVM under the optic nerve sheath in the orbital apex area or the common tendon ring (Types I and II) were included in the present study. In 20 cases (57.1%), patients were misdiagnosed with optic neuritis, and in 20 cases (57.1%), the tumour was not identified based on imaging. The presentation was acute or subacute in 23 cases (65.7%). All patients underwent surgery: transnasal surgery in 22 cases (62.9%) and craniotomy in 13 cases (37.1%). A total of 9 patients (25.7%) experienced postoperative complications, and 17 patients (48.6%) experienced vision improvement. The average patient age at first diagnosis was 43.3 ± 10.3 years, and the median follow-up period was 64.5 months. Overall, 14 patients (40%) experienced postoperative complications: postoperative blindness in 6 cases, postoperative vision loss in 8 cases and orbital apex syndrome in 7 cases. CONCLUSION: Patients with Type I and Type II OCVMs are the most complex cases. They have an insidious onset and are associated with a high rate of misdiagnosis and missed diagnosis. Acute and subacute decreases in visual acuity are mainly caused by OCVM haemorrhage. The difficulty of surgical treatment and the poor prognosis of postoperative vision are characteristics of this tumour. Transnasal surgery and craniotomy can be used to remove OCVMs located in the common tendon ring or optic canal as well as those involving the intracranial area through the supraorbital fissure. Meanwhile, the orbital approach (orbitotomy) has proven to be an effective method of treating OCVMs not involving the deep orbital apex and intracranial area.

Prognostic significance of locally invaded sites and tissue types in patients with nasal extranodal natural-killer/T-cell lymphoma: a single-center retrospective analysis.

BACKGROUND: Extranodal natural killer/T-cell lymphoma (ENKTL), nasal type, is an aggressive entity within the World Health Organization classification of lymphoid tumors. The International Prognostic Index is reported to be prognostically meaningful for ENKTL, but lacks discriminatory power for stage I/II ENKTL with extensive local invasion. This study aimed to evaluate the prognostic effects of local invasion by site and tissue type in patients with ENKTL. METHODS: We retrospectively analyzed data of 86 patients who were diagnosed with ENKTL by the Department of Pathology of Beijing Tongren Hospital from June 2002 to April 2016, and ascertained tumor infiltration of adjacent structures (AS), bone, and soft tissue for each patient, using physical findings and imaging scans. We used univariate and multivariate analysis to assess the association of each involved tissue or site with patients' overall survival (OS). RESULTS: Of the 86 patients, 71 (82.6%) experienced invasion of AS, 22 (25.6%) of soft tissue, and 26 (30.2%) had bone involvement. Overall, patients with AS involvement did not show significantly shorter survival than those without AS involvement (Log rank χ = 1.177, P = 0.278); however, patients who had involved eyeballs or brains showed significantly lower 2-year OS rates than those without eyeball involvement (Log rank χ = 4.105, P = 0.043) or brain involvement (Log rank χ = 7.126, P = 0.008). Patients with involved local soft tissue or bones, respectively, showed lower 2-year OS rates than those without involved local soft tissue (Log rank χ = 10.390, P = 0.001) or bones (Log rank χ = 8.993, P = 0.003). Multivariate analysis showed that involvement of the cheek or facial muscles (hazard ratio, HR = 5.471, 95% confidence interval [CI]: 1.466-20.416, P = 0.011) and the maxilla bone (HR = 6.120, 95% CI: 1.517-24.694, P = 0.011) were significantly independent predictors of lower 2-year OS rates. CONCLUSIONS: Imaging can accurately detect ENKTL invasion of AS, soft tissue, and bone. Involvement of local soft tissue or bone was significantly associated with lower 2-year OS rates. Involvements of the cheek or facial muscle, as well as maxilla bone, are independent predictors of lower 2-year OS rates in ENKTL patients.

Inflammatory myofibroblastic tumors of the nasal cavity and paranasal sinus: a clinicopathologic study of 25 cases and review of the literature.

Inflammatory myofibroblastic tumor (IMT) is rare in nasal cavity and paranasal sinus. The aim of this study was to describe the clinicopathological features of sinonasal IMT and analyze the relationship between the clinicopathological features and the prognosis. A retrospective study of 25 IMT patients between 2001 and 2012 was performed. Data on clinical features, treatment, and follow-up were recorded. The histological characters were observed. Overall survival (OS) and event-free survival (EFS) were estimated using the Kaplan-Meier method. Clinically, the most common symptoms were nasal obstruction, facial pain, and toothache. Twenty patients received follow-ups 6-120 months after initial diagnosis. Fifteen (75 %) developed recurrence 1 or more times. One patient had left cervical lymph node metastasis (5 %). Five patients died of the tumor (25 %). Histologically, the IMTs composed of bland spindle cells admixed with a prominent infiltrate of plasma cells and lymphocytes and showed obvious atypia in recurrent cases. Histology with necrosis, mitosis (≥1/10 HPF), ganglion-like cells, histological pattern I or II and relapse (≥4 times) was significantly associated with poor OS and EFS. IMT of the nasal cavity and paranasal sinuses exhibits relatively bland histologic appearances, but can shows strongly aggressive behavior and relatively poor outcomes. Multiple relapse, necrosis, frequent mitosis, the presence of ganglion-like cells, and histological pattern might be associated with poor clinical outcomes.

Recurrent laryngeal inflammatory myofibroblastic tumor with positive anaplastic lymphoma kinase mimicking recurrent respiratory papillomatosis: a case report.

Inflammatory myofibroblastic tumor (IMT) of the larynx is an unusual lesion, particularly in the pediatric age group. Laryngeal IMTs in children follow a benign clinical course with reports of only rare recurrences and no metastases. Although anaplastic lymphoma kinase (ALK) has been associated with IMTs, there is only one pediatric laryngeal IMT reported to be ALK-positive with immunohistochemical staining. Here, we present a case of a 10-year-old boy with a laryngeal IMT that recurred four times and was misdiagnosed as recurrent respiratory papillomatosis after the initial three operations. ALK positivity was demonstrated by both immunohistochemical staining and fluorescence in situ hybridization. To the best of our knowledge, this case report is the first to describe a laryngeal IMT that recurred multiple times and was confirmed to be ALK-positive at the molecular level.

[Effect of the near infrared spectrum resolution on the nitrogen content model in green tea].

The effect of different resolutions(2, 4, 6, 8, 16 cm(-1)) on the near infrared spectrogram and nitrogen content model for green tea was studied. Test results showed that instrument resolution could influence the spectra quality. The higher the resolution was, the richer the information would be, but the noise would increase. With lower resolution, spectrogram would be much more smooth, but get seriously distorted, and prediction accuracy would decrease at the same time. The partial least squares model was built after spectral pretreatment. When resolution was 4 cm(-1), the RMSEP value of external validation set was 0.054 6, which was obviously lower than others. The Corr. Coeff. was 0.998 2. Its prediction performance was the best and the prediction accuracy better. STDEV and RSD were 0.020 and 0.334 respectively. Resolution 4 cm(-1) for near infrared spectrometer collecting green tea samples was the optimal resolution. This research can provide a reference for parameters selection when collecting green tea spectra with near infrared spectrometer, improve the stability and prediction performance of the model and promote the application and promotion of the near infrared spectroscopy for tea.

[Expression and significance of IgG4 in inflammatory disease of nasal cavity and paranasal sinuses].

OBJECTIVE: To study the prevalence of IgG4-positive plasma cells in inflammatory disease of nasal cavity and paranasal sinuses and its association with IgG4-related sclerosing disease (IgG4-SD). METHODS: The expression of IgG4 and IgG in plasma cells of 103 cases diagnosed as inflammatory disease of nasal cavity and paranasal sinuses with dense lymphoplasmacytic infiltrate was studied by immunohistochemistry (EnVision) and quantitatively analyzed by medical image analysis system. RESULTS: Immunohistochemical study showed marked infiltration by IgG4-positive plasma cells (>50 per high-power field) in 28 cases, moderate infiltration (30 to 50 per high-power field) in 23 cases, mild (10 to 29 per high-power field) in 30 cases and negative (<10 per high-power field) in 22 cases (P < 0.05). Twenty-two cases studied fulfilled the diagnostic criteria of IgG4-SD (>50 IgG4-positive plasma cells per high-power field and IgG4-to-IgG ratio > 40%), including 3 cases of chronic sinusitis (3/20), 3 cases of nasal polyps (3/18), 3 cases of inflammatory pseudotumor (3/17), 4 cases of fungal sinusitis (4/20), 1 case of rhinoscleroma (1/12), 7 cases of Wegener's granulomatosis (7/11) and 1 case of Rosai-Dorfman disease (1/2). CONCLUSION: Inflammatory disease of nasal cavity and paranasal sinuses fulfilling the diagnostic criteria IgG4-SD is not uncommon. Definitive diagnosis of IgG4-SD requires correlation with other clinical and laboratory findings. Some cases of unexplained inflammatory disease of nasal cavity and paranasal sinus may represent a member of the IgG4-SD spectrum. IgG4 carries diagnostic value in differential diagnosis of inflammatory disease occurring in nasal cavity and paranasal sinuses.

[Expression and significance of respiratory chain enzyme of cells in urine sediment in MELAS syndrome].

OBJECTIVE: To explore the expression and significance of respiratory chain enzyme of cells in urine sediment in mitochondrial encephalopathy myopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome. METHODS: Through enzyme histochemistry, the authors analyzed the changes of respiratory chain enzyme in urine sediment in 20 MELAS patients due to mitochondrial A3243G mutation (MELAS group) and 20 health peoples (control group). And the impact on the expression of protein encoded by nuclear DNA (A21347) and mitochondrial DNA (A6404) was detected by immunochemistry. Image pro Plus 6.0 software was used for analysis of absorbance (A) of staining images as staining intensity. The data were expressed as M (Q1, Q3) and analyzed through statistical software. RESULTS: The staining intensity of complexes Iin the MELAS group was lower than that in the control group (0.06(0.01, 0.12) vs 0.12(0.01, 0.62), P = 0.010). The intergroup staining intensity of complex II showed no marked difference. Increased density of blue particle and cytoplasmic gathering was found in 13 cased (65%) of the MELAS group under light microscope. The staining intensity of complexes IV was expressed at a low level in the MELAS group (0.14(0.03, 0.32) vs 0.23(0.06, 0.43), P = 0.038). The expression of protein encoded by nuclear DNA (A21347) was lower than that in the control group (0.05(0.02, 0.45) vs 0.17(0.03, 0.70), P = 0.000). The expression of protein encoded by mitochondrial DNA (A6404) was also lower than that in the control group (0.03(0.01, 0.07) vs 0.15 (0.09, 0.23), P = 0.000). CONCLUSION: Abnormal change of respiratory chain enzyme in urine sediment in MELAS due to mitochondrial A3243G mutation and a low expression of proteins encoded by two kinds of DNA in complexes IV can help to confirm the genetic diagnosis of mitochondrial encephalomyopathies so that different subtypes may be classified and its pathogenesis elucidated.

[High-grade transformation in adenoid cystic carcinoma: a clinicopathologic study].

OBJECTIVE: To study the clinicopathologic features and possible molecular mechanisms of adenoid cystic carcinoma with high-grade transformation. METHODS: Four cases of adenoid cystic carcinoma with high-grade transformation were enrolled into the study. Immunohistochemical study for smooth muscle actin, p63, p53 and Ki-67 was carried out. C-myc gene status was analyzed by fluorescence in-situ hybridization. RESULTS: There were altogether 3 males and 1 female. The mean age of the patients was 55.5 years. Two patients died 17 months and 29 months after operation, respectively. One patient had distant metastasis 23 months after operation and was still alive at 26-month follow up. The remaining patient remained tumor free at 3-month follow up. High-grade transformation in adenoid cystic carcinoma presented either as poorly differentiated adenocarcinoma or undifferentiated carcinoma. Histologic examination showed sheets of pleomorphic tumor cells occupying more than one low-power field. The high-grade carcinoma cells showed increased nuclear-cytoplasmic ratio, prominent eosinophilic nucleoli and active mitosis (ranging from 8 to 25 per high-power field). Comedo necrosis was observed in 2 cases and multiple foci of calcifications in 3 cases. Immunohistochemical study demonstrated loss of myoepithelial differentiation, overexpression of p53 and high proliferative index by Ki-67. No c-myc translocation or copy-number changes were observed. CONCLUSIONS: High-grade transformation in adenoid cystic carcinoma is rare. The histopathologic features are rather distinctive and the biologic behavior is aggressive. C-myc gene mutation does not seem to play a key role in the pathogenesis.

A semi-quantitative method for correlating brain disease groups with normal controls using SPECT: Alzheimer's disease versus vascular dementia.

PURPOSE: To demonstrate the utility of semi-quantitative circumferential-profile analysis of regional cerebral blood flow (rCBF) SPECT in Alzheimer's disease (AD) versus white matter vascular dementia (WM-VaD). METHODS: Subjects underwent dementia evaluation, MRI and Tc-99m HMPAO SPECT. rCBF patterns from 11 AD and 20 WM-VaD patients were compared to 17 controls using semi-quantitative circumferential-profile analysis. RESULTS: AD patients showed more significant semi-quantitative circumferential-profile reductions in the posterior temporo-parietal regions, whereas WM-VaD patients demonstrated greater reductions involving the frontal regions of the brain. CONCLUSION: Semi-quantitative circumferential-profile analysis provides a practical semi-quantitative method to evaluate brain SPECT scans in AD versus WM-VaD patients.

Detection of C-MYC oncogene translocation and copy number change in the normal-dysplasia-carcinoma sequence of the larynx by fluorescence in situ hybridization.

The aim of this study was to determine the translocation and copy number change of the C-MYC gene in patients with laryngeal dysplasia and laryngeal squamous cell carcinoma (LSCC), and to evaluate the prevalence of such expression in relation to the normal-dysplasia-carcinoma sequence. Fluorescent in situ hybridization (FISH) was applied on formalin-fixed paraffin-embedded blocks of 93 laryngeal lesion specimens (14 normal epithelium, 15 mild dysplasia, 18 moderate dysplasia, 16 severe dysplasia, 9 carcinoma in situ, and 21 invasive carcinoma). C-MYC translocation was not observed in all laryngeal tissue. The high frequency for C-MYC copy-number increased (100%) in invasive carcinoma: 57.14% amplifications and 42.86% gains, and the positive rate of C-MYC amplification and copy-number change increased with the increasing severity of laryngeal lesions (P < 0.0001). The results suggest that C-MYC may be activated by gain/amplification in LSCC and precancerous lesions. Thus, C-MYC may play an important role in promoting LSCC progression, and early FISH detection of C-MYC may be exploited to set a screening test for laryngeal dysplasia.

[Utility of NUT gene expression and rearrangement in diagnosis of NUT midline carcinoma in upper respiratory tract].

OBJECTIVE: To investigate the importance of expression of the NUT gene and its rearrangement in diagnosing NUT midline carcinoma (NMC) of the upper respiratory tract; and to evaluate the prevalence, histological features and differential diagnosis of NMC of the upper respiratory tract. METHODS: One-hundred and sixty-three small cell malignant tumors of the upper respiratory tract were reviewed at the Beijing Tongren Hospital, Capital Medical University over a 20-year period. These cases included poorly-differentiated squamous cell carcinomas (n = 31), undifferentiated carcinoma (n = 1), non-keratizing undifferentiated nasopharyneal carcinomas (n = 60), small cell neuroendocrine carcinomas (n = 6) and non-epithelial small round cell malignant tumors (n = 65). The clinical and pathologic features were investigated. All cases were subjected to Epstein-Barr virus encoded RNA (EBER) in situ hybridization and NUT monoclonal antibody immunohistochemical staining. Cases positive for NUT immunohistochemistry and negative for EBER in situ hybridization were submitted for fluorescent in situ hybridization (FISH) for rearrangements in both BRD4 and NUT genes, and immunohistochemical staining for a set of cytokeratins (AE1/AE3, CK7, CK8), p63,and neuroendocrine markers (NSE, Syn, CgA, S-100 protein, CD56). RESULTS: Three cases of poorly-differentiated squamous cell carcinomas and one case of undifferentiated carcinoma showed diffuse nuclear immunohistochemical staining with antibody against NUT. These positive cases approximately accounted for 12.5% (4/32) of this group, 4.1% (4/98) of the malignant epithelial carcinomas and 2.5% (4/163) of all small round cell malignant tumors in the study. The age of these patients were 42 - 59 years. Other groups were all negative for NUT immunohistochemistry. These four cases also stained for antibodies against cytokeratins and p63, but were negative for neuroendocrine markers and not associated with EBV infection. Only two of these four cases showed rearrangements of the NUT and BRD4 genes by FISH. These two patients died within one year. The other two patients that did not demonstrate NUT rearrangement by FISH were alive and did not have an aggressive clinical course, surviving 40 and 12 months respectively. CONCLUSIONS: NMC is a rare small round cell malignant tumor in the upper respiratory tract. Only in the groups of primary poorly differentiated squamous cell carcinoma and undifferentiated carcinoma were positive for NUT immunohistochemical staining and NUT rearrangement by FISH. NMC typically occurs in midline organs, and affects the sinonasal tract. It is not associated with EBV infection. There is difference in the clinical course and prognosis among NMC patients. NUT immunohistochemical staining and NUT gene rearrangement analysis can differentiate NMC from other small cell tumors in the upper respiratory tract.

Research on the optical spectra, g factors and defect structures for two tetragonal Y²+ centers in the irradiated CaF2: Y crystal.

Based on the defect models that the tetragonal Y(2+) (1) center in the irradiated CaF(2): Y crystal is due to Y(2+) at Ca(2+) site associated with a nearest interstitial F(-) ion along C(4) axis and the tetragonal Y(2+) (2) center is Y(2+) at Ca(2+) site where the tetragonal distortion is caused by the static Jahn-Teller effect, the two optical spectral bands and anisotropic g factors for both tetragonal Y(2+) centers are calculated. The calculations are made by using two methods based on the cluster approach, one is the complete diagonalization (of energy matrix) method (CDM) and another is the perturbation theory method (PTM). The calculated results for each Y(2+) center from CDM and PTM coincide and show reasonable agreement with the experimental values. The calculated isotropic g factor for Y(2+) (2) center at higher temperature owing to the dynamical Jahn-Teller effect is also consistent with the observed value. The defect structures (i.e., tetragonal distortion) of the two Y(2+) centers are obtained from the calculation. It appears that both theoretical methods can be applied to explain the optical and EPR data, to study the defect model and to determine the defect structures for d(1) ions in crystals.