Combined fine-needle aspiration and selective intraoperative frozen section to optimize prediction of malignant thyroid nodules: A retrospective cohort study of more than 3000 patients.

Background: Preoperative fine-needle aspiration (FNA) is widely used to differentiate malignant from benign thyroid nodules, while intraoperative frozen sections (FS) are suggested as a systematic supplement for intraoperative decision-making, but limitations still remain for both procedures. Methods: Medical records of 3807 patients with thyroid nodules who underwent both pathological diagnoses (FS and FNA) at our hospital were reviewed. The diagnostic accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of FNA and FS were also evaluated. We further designed an optimal integration scheme (FNA+selective FS) to predict thyroid nodule malignancy. Finally, the efficiency of the proposed integrated diagnostic model was validated using an independent external cohort. Results: For distinguishing malignant nodules, FNA had an accuracy of 90.3%, sensitivity of 90.7%, specificity of 85.2%, PPV of 98.8% and NPV of 40.4%. In contrast, the FS represented higher discriminative power (Accuracy, 94.5%; Sensitivity, 94.1%; Specificity, 100%; PPV, 100%; and NPV, 55.6%). we proposed the selective usage of FS (removed nodules with Bethesda category VI from routine FS, ~1/3 of total). The integrated new diagnostic model of FNA plus selective FS (FNA+sFS) achieved accuracy of 96.9%, sensitivity of 97.3%, specificity of 92%, PPV of 99.4%, and NPV of 71.6% (NRI=0.135, 95% CI 0.103-0.167, P <0.001) and was successfully applied to an external cohort (N=554). Conclusion: Compared with the FNA diagnostic system, FS has an increased ability to distinguish benign and malignant thyroid nodules. The newly proposed integrated diagnostic model of FNA + selective FS can optimize the accuracy of diagnosis.

Case Report: A Case of Sintilimab-Induced Cystitis/Ureteritis and Review of Sintilimab-Related Adverse Events.

Immune checkpoint inhibitors (ICIs) have been proven to be beneficial in multiple advanced malignancies. However, the widespread use of ICIs also occurred with various immune-related adverse events (irAEs). Here, we first report a case of sintilimab-related cystitis/ureteritis. A 53-year-old man with driver gene-negative pulmonary adenocarcinoma (cT1cN3M1c, Stage IVB) was being treated with sintilimab in combination of paclitaxel-albumin and bevacizumab as second-line treatment. He was hospitalized for haematuria, pollakiuria, painful micturition and low back pain after three courses. Urinalysis showed red blood cells (RBCs) and white blood cells (WBCs) were obviously increased, and serum creatinine (sCr) level was also significantly elevated. Urine culture and cytology were both negative, and cystoscopy revealed diffused redness of bladder mucosa. Urinary ultrasonography showed mild hydronephrosis and dilated ureter. The patient was diagnosed as immunotherapy-related cystitis/ureteritis after a multidisciplinary team (MDT) meeting. Once the diagnosis was made, corticosteroid therapy was given, which rapidly resolved the patient's symptoms and signs. Computer tomography angiography (CTA) and CT urography (CTU) was conducted after sCr level was back to normal and demonstrated ureter dilation and hydroureter. Once symptoms relieved, bladder biopsy was performed and confirmed the bladder inflammation. The patient was subsequently switched to maintenance dose of methylprednisolone and tapered gradually. Since sintilimab has been used in advanced malignancies, we first reported a rare case of sintilimab-induced cystitis/ureteritis and summarized sintilimab-related adverse events to improve the assessment and management of irAEs.

Disease progression and pseudoprogression following partial response with rare gingiva metastasis upon IBI308 (sintilimab) immunotherapy reflects the complexity of metastatic lung cancer: a case report.

The differential diagnosis of progression and pseudoprogression is one difficulty in current immunotherapy. Since the time point and criteria for pseudoprogression diagnosis are not yet unified, current diagnosis and treatment rely on imaging and pathology. Here we report a 57-year-old Chinese male presented solitary left lower lung nodule with enlarged left hilar and mediastinal lymph nodes. Bilateral adrenal nodules and bilateral parietal lobe nodules were identified. The nodules were considered malignant by CT or MRI examinations. The patient was diagnosed left lower peripheral lung cancer with left hilar and mediastinal lymph node metastasis, bilateral adrenal metastasis, and bilateral parietal lobe metastasis. Progression was observed after the first-line pemetrexed + cisplatin (PP) standard chemotherapy. Due to the identification of strong positive PD-L1 expression (90%) in primary tissue immunohistochemistry, second-line IBI308 (sintilimab) immunotherapy was implemented. After the third cycle of immunotherapy, partial response was observed with the left lung lesion and the lung hilus and adrenal metastases, while pseudoprogression was found at the left lung and right hepatic lobe, and rare gingival progression was also identified. Palliative surgery was performed to remove the gingival metastatic lesion. The lesions of the lung, hilar and mediastinal lymph nodes and adrenal gland responded well, but the patient died due to uncontrollable progression of metastatic lesions in the brain. Whole-exome sequencing on gingival metastasis revealed pathogenic mutations in several important driver genes, including TP53, ErbB2, MET and PTEN. This study reported the coexistence of primary lesion response, pseudoprogression and progression in immunotherapy in lung cancer patient with rare gingival metastasis, and provided experience for handling mixed responses in immunotherapy.

Cytology cell blocks from malignant pleural effusion are good candidates for PD-L1 detection in advanced NSCLC compared with matched histology samples.

BACKGROUND: Detection of programmed cell death ligand-1 (PD-L1) by immunohistochemistry (IHC) has been commonly used to predict the efficacy of treatment with PD-1/PD-L1 inhibitors. However, there is limited literature regarding the reliability of PD-L1 testing using malignant pleural effusion (MPE) cell blocks. Here, we assess PD-L1 expression in sections from MPE cell blocks and evaluate the value of IHC double staining in the interpretation of PD-L1 expression. METHODS: In all, 124 paired formalin-fixed tissues from advanced NSCLC patients, including MPE cell blocks and matched histology samples, were included. PD-L1 expression was assessed using the SP263 assay, and the tumor proportion score (TPS) and the staining intensity were evaluated. PD-L1 staining results were also compared between IHC double and single staining techniques. RESULTS: PD-L1 expression was concordant in most paired cases (86/101, 85.1%) among three TPS cut-offs (<1%, 1-49% and ≥ 50%), with a kappa value of 0.774. Moreover, a significant difference in PD-L1 expression between MPE cell blocks and biopsy samples was observed (p = 0.005). For the 15 discordant pairs, 13 MPE cell block samples showed increased expression of PD-L1. Compared with the standard IHC single PD-L1 assay, double staining with anti-TTF-1 and anti-PD-L1 revealed a negative effect on PD-L1 expression testing and resulted in weaker staining intensity and a lower TPS (p = 0.000). CONCLUSIONS: MPE cell block samples are good candidates for PD-L1 expression detection in advanced NSCLC patients. The mechanism and clinical significance of the higher PD-L1 expression rate in MPE cell blocks compared with small biopsy samples remain to be evaluated prospectively.

Prognostic Significance of Serum Complement Component 3 in Chronic Rhinosinusitis with Nasal Polyps.

OBJECTIVE: The aim of this study was to assess the relationship between serum complement component 3 (C3) levels and disease recurrences in patients with chronic rhinosinusitis with nasal polyps (NPs). METHODS: Ninety-seven patients with NPs and 30 controls were recruited. Clinical features were collected. Serum concentrations of C3 and C4 were measured before and after endoscopic sinus surgery. RESULTS: Compared to the controls, increased C3 levels were found in patients with NPs. Patients with polyp recurrences had higher pre- and postoperative serum C3 levels than patients without polyp recurrences. Serum C3 levels dropped after surgery. After polyp regrowth, the mean C3 level in the recurrent group elevated again to the degree similar to that before surgery. When patients were stratified by tissue eosinophilia, no significant difference was seen in pre-/postoperative, absolute change after surgery, and post-recurrent C3 levels between patients without and with eosinophilic NPs in the group with disease recurrences. CONCLUSION: Serum C3 may be involved in the pathogenesis of NPs. Higher serum C3 levels may pinpoint patients at high risk of recurrence as an independent factor. Furthermore, the change in C3 levels after surgery may have the potential to serve as a predictor for polyp progression. Adding serum C3 measurement to the routine walk-up in the clinical management of NPs is worth further investigation and may help physicians make a more rational diagnostic and/or therapeutic decision regarding this disease.

Atypical appearance of hepatic hemangiomas with contrast-enhanced ultrasound.

To describe the atypical enhancement pattern of hepatic hemangiomas on contrast-enhanced sonography. 22 patients with hepatic hemangiomas that were atypical on contrast-enhanced ultrasound were included in the study, all of them were confirmd by biopsy or surgery pathology. Atypical appearance of hepatic hemangiomas on contrast-enhanced ultrasound were divided into seven subtypes: (i) peripheral nodular enhancement in the arterial phase with centripedal filling, hypoechoic change in the delayed phase; (ii) peripheral circular enhancement; (iii) peripheral nodular enhancement; (iv) none enhancement; (v) septal enhancement; (vi) a central enhancing focus in the arterial phase, followed by a centrifugal enhancement in the portal venous phase, hypoechoic change in the delayed phase; (vii) slowly spoke wheel enhancement. Atypical appearance of hepatic hemangiomas were various. Radiologists should be aware. Establishing knowledge of the entire spectrum of atypical hepatic hemangiomas may benefit the rational approach to future cases.

Breast adenoid cystic carcinoma: report of a case with emphasis on routine sonographic findings and shear wave elastography.

Adenoid cystic carcinoma (ACC) of the breast is a rare malignant tumor. Its sonographic characteristics have been described in some reports, but there are few such reports available that describe the sonoelastographic findings of this tumor and provide additional information about the nature of the lesion. In this case report, we describe the routine sonographic findings and shear wave elastography findings of a breast adenoid cystic carcinoma in a 53-year-old woman.

Hand-assisted laparoscopic surgery compared with open resection for mid and low rectal cancer: a case-matched study with long-term follow-up.

BACKGROUND: This study was designed to compare the long-term surgical outcomes of patients with mid and low rectal cancer after open or hand-assisted laparoscopic surgery (HALS). METHODS: A case-matched controlled prospective analysis of 116 patients who underwent hand-assisted laparoscopic surgery (HALS) for stage I to III mid and low rectal cancer from 2005 to 2010 was performed. Contemporary patients who underwent open rectal surgery were matched to the HALS group at the ratio of 1:1. The perioperative clinical outcomes, postoperative pathology, and survival outcomes were compared between the groups. RESULTS: The patient characteristics between the two groups were comparable. Ninety patients in the open group and 85 in the HALS group received sphincter-preserving surgery. HALS resulted in less blood loss and wound infection, faster return to oral diet, shorter postoperative hospital stay, and longer operating time. The two groups had similar complication rates. Lymph node retrieval and involvement of circumferential and distal margins were similar for both procedures. Cumulative incidences of locoregional recurrence, disease-free, or overall survival rates were statistically similar. CONCLUSIONS: This study suggests that HALS for mid and low rectal cancer is acceptable in terms of short-term clinical outcomes and long-term survival results.

Cell block samples from malignant pleural effusion might be valid alternative samples for anaplastic lymphoma kinase detection in patients with advanced non-small-cell lung cancer.

AIM: To evaluate the clinical value of cell block samples from malignant pleural effusion (MPE) as alternative samples to tumour tissue for anaplastic lymphoma kinase (ALK) detection in patients with advanced non-small-cell lung cancer (NSCLC). METHODS AND RESULTS: Fifty-two matched samples were eligible for analysis. ALK status was detected by Ventana immunohistochemistry (IHC) (with the D5F3 clone), reverse transcription polymerase chain reaction (RT-PCR) and fluorescence in-situ hybridization (FISH) in MPE cell block samples, and by FISH in tumour tissue block samples. In total, ALK FISH results were obtained for 52 tumour tissue samples and 41 MPE cell block samples. Eight cases (15.4%) were ALK-positive in tumour tissue samples by FISH, and among matched MPE cell block samples, five were ALK-positive by FISH, seven were ALK-positive by RT-PCR, and eight were ALK-positive by Ventana IHC. The ALK status concordance rates between tumour tissue and MPE cell block samples were 78.9% by FISH, 98.1% by RT-PCR, and 100% by Ventana IHC. In MPE cell block samples, the sensitivity and specificity of Ventana IHC (100% and 100%) and RT-PCR (87.5% and 100%) were higher than those of FISH (62.5% and 100%). CONCLUSIONS: Malignant pleural effusion cell block samples had a diagnostic performance for ALK detection in advanced NSCLC that was comparable to that of tumour tissue samples. MPE cell block samples might be valid alternative samples for ALK detection when tissue is not available. Ventana IHC could be the most suitable method for ALK detection in MPE cell block samples.

Short hairpin RNA-mediated down-regulation of CENP-A attenuates the aggressive phenotype of lung adenocarcinoma cells.

BACKGROUND: Deregulation of centromere protein (CENP)-A, a centromere-specific histone variant, has in the past been linked to cancer initiation and progression. Additionally, our previous work has shown that CENP-A upregulation predicts a poor overall survival in patients with lung adenocarcinoma. The aim of this study was to uncover the biological role of CENP-A in lung adenocarcinoma growth and invasion, including its underlying molecular mechanisms. METHODS: CENP-A expression was knocked down in human lung adenocarcinoma A549 and PC-9 cells using a short hairpin RNA (shRNA) technology. Subsequently, the effects of this knock down on the proliferation, apoptosis, cell cycle progression, colony formation, migration, invasion and tumorigenicity were assessed. Additionally, Western blot analyses were performed to examine concomitant expression changes in key proteins involved in cell cycle regulation and apoptosis. RESULTS: We found that shRNA-mediated knock down of CENP-A significantly inhibited the in vitro proliferation and colony formation of A549 and PC-9 cells as compared to control shRNA-transfected cells. In addition, CENP-A down-regulation was found to induce G0/G1 cell cycle arrest and apoptosis, and to inhibit the in vitro migration and invasion of A549 and PC-9 cells. Down-regulation of CENP-A was also found to significantly suppress the in vivo growth of xenografted A549 cells. At the protein level, we found that the expression of p21, p27, CHK2 and Bax was markedly increased and that the expression of CCNG1, Skp2, Cks1 and Bcl-2 was markedly decreased in CENP-A down-regulated cells. CONCLUSION: Based on our results we conclude that down-regulation of CENP-A may attenuate the aggressive phenotype of lung adenocarcinoma cells. As such, CENP-A may serve as a promising therapeutic target for lung adenocarcinoma.

Clinical features and hypoxic marker expression of primary sinonasal and laryngeal small-cell neuroendocrine carcinoma: a small case series.

BACKGROUND: Small-cell neuroendocrine carcinoma (SCNEC) of the head and neck is rare. The prognosis of SCNEC in the nasal cavity and larynx is poor. The aim of this study was to investigate the clinicopathological features of nasal and laryngeal SCNEC and to determine the expression of HIF-1α, GLUT-1, PI3K, and p-Akt in SCNEC. METHODS: Between 2003 and 2012, 10 consecutive patients with histologically demonstrated nasal and laryngeal SCNEC were enrolled. Clinicopathological materials and follow-up data were analyzed retrospectively. Immunohistochemistry was used to detect GLUT-1, HIF-1α, PI3K, and p-Akt expression in paraffin wax-embedded tumor specimens. RESULTS: The subjects were eight males and two females with a mean age of 60.8 (range: 53 to 71) years. Tumors were located in the maxillary sinus (n = 3) and larynx (n = 7). At last follow-up, four patients (40.0%) had local recurrence and five patients (50.0%) had developed distant metastases. Six patients died. The mean overall survival was 19.3 ± 2.1 months. Expression of GLUT-1, HIF-1α, PI3K, and p-Akt was seen in sinonasal and laryngeal SCNEC in 80 (8 out of 10), 50 (5 out of 10), 40 (4 out of 10), and 40% (4 out of 10) of cases, respectively. Expression of GLUT-1, HIF-1α, PI3K, and p-Akt was higher in sinonasal and laryngeal SCNEC than in precancerous lesions. CONCLUSIONS: Primary sinonasal and laryngeal SCNEC is rare. This paper presents 10 cases of sinonasal and laryngeal SCNEC with more common local recurrence and distant metastasis. HIF-1α, GLUT-1, PI3K, and p-Akt expression was higher in sinonasal and laryngeal SCNEC than in precancerous lesions.

Epithelioid malignant mesothelioma presenting with features of gastric tumor in a child.

Localized malignant mesothelioma is very uncommon and mainly arises in pleura and peritoneum, and preferentially occurs in older adults. In this article, we report a case of a Localized malignant mesothelioma that was developed in the stomach of a 6-year-old boy. This boy was admitted to hospital for anemia. An epigastric mass was palpated through systemic physical examination and MR scanning demonstrated an 8×6 cm-sized, well-defined elliptic mass at gastric corpus. Partial resection of the stomach was performed for this boy and no nodules were found on the liver, peritoneum, and other abdominal sites in surgery. In view of the morphological and immunohistochemical findings, a diagnosis of localized malignant mesothelioma, epithelial type was made. This is the first case report of localized malignant mesothelioma arising in the stomach of a child. Accumulation of more cases of malignant mesothelioma involving gastrointestinal tract and longer follow-up of the patients are necessary to further characterize the features of this rare disease.

Prognostic value of perineural invasion in gastric cancer: a systematic review and meta-analysis.

BACKGROUND: The prognostic role of perineural invasion in gastric cancer is controversial. Here, we present a systemic review and meta-analysis of the association between perineural invasion and survival in resectable gastric cancer patients. METHODS: A comprehensive literature search for relevant reports published up to April 2013 was performed using PubMed, Embase, Web of Science and Wanfang Data. Studies that investigated the role of perineural invasion with a sample size greater than 100 were included and analyzed. RESULTS: A total of 30,590 gastric cancer patients who had undergone curative gastrectomy from twenty-four studies were included. The median rate of perineural invasion positive was 40.9% (6.8%-75.6%). Fourteen studies investigated overall survival unadjusted for other variables in 23,233 gastric cancer patients. The relative hazard estimates ranged from 0.568-7.901 with a combined random effects estimate of 2.261 (95% CI = 1.841-2.777, P = 0.000). The effect of perineural invasion on overall survival adjusted for other prognostic factors was reported in 17 studies incorporating 8,551 cases. The hazard estimates ranged from 0.420-8.110 with a pooled random effects estimates of 1.484 (95% CI = 1.237-1.781, P = 0.000). There was heterogeneity between the studies (Q = 49.22, I-squared = 67.5%, P = 0.000). Disease-free survival was investigated adjusted in four studies incorporating 9,083 cases and the pooled fixed hazard ratio estimate was 1.371(95% CI = 1.230-1.527, P = 0.000). CONCLUSION: Perineural invasion is an independent prognostic factor affecting overall survival and disease-free survival of gastric cancer patients who had undergone the curative resection. This effect is independent of lymph node status, tumor size and the depth of invasion as well as a range of other biological variables on multivariate analysis. Large prospective studies are now needed to establish perineural invasion as an independent prognostic marker for gastric cancer.

Accurate and economical detection of ALK positive lung adenocarcinoma with semiquantitative immunohistochemical screening.

Right detection of anaplastic lymphoma kinase (ALK) gene rearrangement is pivotal to selection of patients with lung adenocarcinoma for ALK-targeted therapy. We explored the potential of combination of immunohistochemistry (IHC) screening and fluorescence in situ hybridization (FISH) as an affordable practice. We analyzed 410 unselected lung adenocarcinomas by ALK IHC (D5F3 clone) and FISH. Some equivocal cases were further analyzed by RT-PCR. The EGFR mutation was detected by pyrosequencing assay. In total 368 cases which got all IHC, FISH, EGFR mutation results were eligible for analysis. Cases were evaluated as IHC score 3+ (n = 26), score 2+ (n = 9), score 1+ (n = 51), and score 0 (n = 282), respectively. 23 of 26 IHC 3+ and 5 of 9 IHC 2+ cases were FISH positive, whereas 3 of 26 IHC 3+, 4 of 9 IHC 2+ and all 333 IHC 1+/0 cases were FISH negative. If considering FISH as the standard, the sensitivity and specificity of ALK IHC 3+/2+ as ALK positive were 100% and 97.9%, respectively. Three IHC 3+ cases reported as FISH "negative" were actually ALK positive confirmed by ALK RT-PCR or re-detected. Based on the final classify, ALK IHC 3+/2+ was 100% sensitive and 98.8% specific. However, FISH was 90.3% sensitive and 100% specific. IHC 2+ was regarded as equivocal and need to be confirmed by FISH or RT-PCR. In the 368 cases, 8.4% cases had ALK positive, 52.2% cases had EGFR mutation, and only one case had a coexisting. Manually semiquantitative ALK IHC (primary antibody D5F3 coupled with secondary DAKO Envision system) used as the initial screening combined with auxiliary FISH confirmation is a reliable, economical approach to identify ALK positive lung adenocarcinoma. The IHC can find some ALK positive cases which would be missed by FISH only.

[Evaluation of the inadequate diagnostic rate of ultrasound guided fine needle aspiration cytology inthyroid calcified nodules].

OBJECTIVE: To evaluate the inadequate diagnostic rate of ultrasound guided fine needle aspiration cytology (USFNAC) in thyroid calcified nodules. METHODS: 208 thyroid calcified nodules in 202 patients were retrospective analyzed, and all of the nodules were acquired cytological diagnosis. RESULTS: There was no significant complication in the all 208 thyroid calcified nodules. The inadequate diagnostic rate was 25.5% in thyroid calcified nodules. The inadequate diagnostic rates in micro calcifications , macro calcifications and circumjacent arc calcifications were 16.0%, 26.4% and 76.5%. The inadequate diagnostic rate in circumjacent arc calcifications were higher than those in micro calcifications and macro calcifications (P < 0.01) , and the rates were no significance in micro calcifications and macro calcifications. There was no statistical significance in different size of thyroid calcified nodules. CONCLUSIONS: The inadequate diagnostic rate in circumjacent arc calcifications was higher, and should to avoid USFNAC in these nodules.

Concurrent primary carcinoid tumor arising within mature teratoma and clear cell renal cell carcinoma in the horseshoe kidney: report of a rare case and review of the literature.

Primary carcinoid tumor arising in a mature teratoma of the horseshoe kidney is exceptionally rare and only 4 such cases have been reported in the world literature to date. The simultaneous occurrence of different subtypes of renal cell carcinoma (RCC) or RCC coexistence with non-RCC neoplasms from the same kidney is unusual and infrequently reported. Herein we report a case of primary carcinoid tumor arising within mature teratoma, concurrent with a clear cell RCC in the horseshoe kidney of a 37-year-old man. Histologically, both the carcinoid tumor and clear cell RCC demonstrated the characteristic morphology in their classic forms. In addition to the carcinoid tumor, the mature teratoma consisted of variably sized, large cystic spaces lined by cytologically bland mucinous columnar epithelium, pseudostratified columnar epithelium, ciliated epithelium and mature smooth muscle fibers were also identified within the cystic wall. Furthermore, foci of round, small nodules composed of mature prostatic acinus were noted in the teratoma which was confirmed by exhibiting strong immunoreactivity for prostate specific antigen. The present case serves to expand the histologic component that may be encountered in the mature terotoma of the kidney and further broadens the spectrum of primary tumors occurring in the horseshoe kidney.

One-stage complete removal of intracardiac leiomyomatosis without cardiac arrest.

We present here a woman with an intracardiac leiomyoma originating from uterine leiomyomatosis. The tumor was completely removed in a one-stage procedure using cardiopulmonary bypass without cardiac arrest. Most one-stage operations were performed with total circulation arrest; however, using of on-pump beating-heart technique when removing the intracardiac mass has seldom been reported in detail. The patient was asymptomatic with no evidence of recurrence on 13-month follow-up.