The association of EGFR amplification with aberrant exon 20 insertion report using the cobas EGFR Mutation Test v2.

Determining the exact type of epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutation in lung cancer has become important. We found that not all ex20ins mutations reported by cobas EGFR test v2 could be validated by Sanger sequencing even using surgical specimens with high tumor contents. This study aimed to validate the ex20ins results reported by the cobas test and to determine whether there were clinicopathological factors associated with aberrant cobas ex20ins report. In total, 123 cobas-reported cases with ex20ins were retrospectively collected and validated by Sanger sequencing and Idylla assay. Clinicopathological features between ex20ins cobas+/Sanger+ group (n = 71) and cobas+/Sanger- group (n = 52) were compared. The Idylla assay detected ex20ins in 82.6% of cobas+/Sanger+ cases but only in 4.9% of cobas+/Sanger- cases. The cobas+/Sanger- group was significantly associated with higher tumor contents, poorly differentiated patterns, tumor necrosis, and a lower internal control cycle threshold value reported by the Idylla which suggesting the presence of increased EGFR gene copy numbers. EGFR fluorescence in situ hybridization (FISH) revealed the majority of cobas+/Sanger- group had EGFR high copy number gain (16%) or amplification (76%) according to the Colorado criteria. Among cases reported to have concomitant classic EGFR and ex20ins mutations by the cobas, the classic EGFR mutations were all detected by Sanger sequencing and Idylla, while the ex20ins mutations were undetected by Sanger sequencing (0%) or rarely reported by Idylla assay (3%). FISH revealed high EGFR copy number gain (17.9%) and amplification (79.5%) in cases reported having concomitant classic EGFR and ex20ins mutations by the cobas. This study demonstrated an unusually high frequency of EGFR amplification in cases with aberrant cobas ex20ins report which could not be validated by Sanger sequencing or Idylla assay. Ex20ins reported by the cobas test should be validated using other methods especially those reported having concomitant ex20ins and classic EGFR mutations.

The expression of nicotinic acetylcholine receptor subunits and their associations with local immune cells and prognosis in oral squamous cell carcinoma.

BACKGROUND: Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that may be responsible for cancer cell proliferation, epithelial-mesenchymal transition (EMT), and immune regulation. However, little is known about the associations of different nAChR subunits with tumor microenvironment in oral squamous cell carcinoma (OSCC). METHODS: We retrospectively reviewed pathology samples from 75 OSCC patients by immunohistochemistry. In addition, a cohort of 307 OSCC patients in The Cancer Genome Atlas was analyzed. RESULTS: Subunit α1 was specific to peri-OSCC skeletal muscle. Increased α1 was associated with increased CD44 (cancer stem cells), increased CD3 and 8 (T cells), increased CD56 and 16 (natural killer cells), a decreased T stage, and an increased N stage. Increased α3 was associated with increased CD56 and 16. Increased α5 was associated with decreased CD3, 8, and 56, a decreased T stage, an increased N stage, worse survival, and decreased epithelial features. Increased α7 was associated with increased CD3, 8, 56, and 16, decreased tumor/peritumor ratios of CD3, 8, and 56 immune cells, and increased epithelial features. Increased local immune cells were associated with a better prognosis. CONCLUSIONS: α5 is the only subunit associated with decreased local immune cells and worse survival, while α1, α3, and α7 are associated with increased local immune cells in OSCC. α5 and α7 are correlated with different EMT states to be mesenchymal-like and epithelial-like OSCC, respectively. Protein expression data of the nAChR subunits, complementary to gene expression data, could provide meaningful information regarding the EMT status of OSCC associated with immune responses and prognosis.

Intracranial Seeding Following Surgery and Chemotherapy in a Child with a Spinal Cord Endodermal Sinus Tumor: A Case Report.

We herein report a case of an extremely rare spinal cord endodermal sinus tumor (EST). A nine-year-old boy presented with progressive paraparesis, hypesthesia, and urinary retention. Gadolinium-enhanced magnetic resonance imaging (MRI) revealed multiple intradural enhancing lesions at T1 to T9 without evidence of intracranial tumors. He underwent partial resection of the lesions, and histology revealed an EST. He received chemotherapy, but 12 months after surgery, rapid tumor progression and intracranial metastases with obstructive hydrocephalus were detected. Following external ventricular drainage, the patient's condition rapidly deteriorated, and he ultimately died. EST should be considered when confronting a homogenously enhancing intradural tumor of the spine on post-contrast MRI.

Expression of astrocyte-elevated gene-1 indicates prognostic value of fluoropyrimidine-based adjuvant chemotherapy in resectable stage III colorectal cancer.

It is unclear which prognostic factor such as pathological features and gene mutation are majorly relevant for stage III disease and whether they aid in determining patients who will be benefit from postoperative adjuvant chemotherapy. The expression of astrocyte-elevated gene-1 (AEG-1), thymidylate synthase (TS), excision repair cross-complementation group 1 (ERCC1), epidermal growth factor receptor (EGFR), and vascular endothelial growth factor (VEGF) was examined to investigate their role in adjuvant chemotherapy for patients with resectable stage III colorectal cancer (CRC). A significant positive correlation was observed between AEG-1, TS, ERCC1, EGFR, and VEGF gene expression levels in CRC cell lines, and low AEG-1 and TS expression were highly sensitive to 5-fluorouracil treatment. Our results showed that AEG-1 expression was high in T4 and caused CRC recurrence or metastasis. Patients with T4, high AEG-1, TS and VEGF expression had a significantly short disease-free survival and overall survival. In multivariate Cox regression analysis, high AEG-1 expression could be an independent prognostic factor indicating poor survival in patients with resectable stage III CRC treated with adjuvant chemotherapy. In conclusion, AEG-1 expression and tumor grade are potential prognostic factors for recurrence and survival in patients with stage III CRC receiving adjuvant fluoropyrimidine-based chemotherapy.

Distinguishing lupus lymphadenitis from Kikuchi disease based on clinicopathological features and C4d immunohistochemistry.

OBJECTIVES: Distinguishing Kikuchi disease (KD) from lupus lymphadenitis (LL) histologically is nearly impossible. We applied C4d immunohistochemical (IHC) stain to develop diagnostic tools. METHODS: We retrospectively investigated clinicopathological features and C4d IHC staining in an LL-enriched development cohort (19 LL and 81 KD specimens), proposed risk stratification criteria and trained machine learning models, and validated them in an external cohort (2 LL and 55 KD specimens). RESULTS: Clinically, we observed that LL was associated with an older average age (33 vs 25 years; P=0.005), higher proportion of biopsy sites other than the neck [4/19 (21%) vs 1/81 (1%); P=0.004], and higher proportion of generalized lymphadenopathy compared with KD [9/16 (56%) vs 7/31 (23%); P=0.028]. Histologically, LL involved a larger tissue area than KD did (P=0.006). LL specimens exhibited more frequent interfollicular pattern [5/19 (26%) vs 3/81 (4%); P=0.001] and plasma cell infiltrates (P=0.002), and less frequent histiocytic infiltrates in the necrotic area (P=0.030). Xanthomatous infiltrates were noted in 6/19 (32%) LL specimens. Immunohistochemically, C4d endothelial staining in the necrotic area [11/17 (65%) vs 2/62 (3%); P<10-7], and capillaries/venules [5/19 (26%) vs 7/81 (9%); P=0.048] and trabecular/hilar vessels [11/18 (61%) vs 8/81 (10%); P<10-4] in the viable area was more common in LL. During validation, both the risk stratification criteria and machine learning models were superior to conventional histological criteria. CONCLUSIONS: Integrating clinicopathological and C4d findings could distinguish LL from KD.

The expression and prognostic impact of proinflammatory cytokines and their associations with carcinogens in oropharyngeal squamous cell carcinoma.

In oropharyngeal squamous cell carcinoma (OPSCC), the relationships between immune responses, carcinogens, and prognoses are not clarified yet. Here, we retrospectively reviewed the pathology samples of 46 OPSCC patients, and used p16 to determine their human papillomavirus (HPV) status. The Cancer Genome Atlas (TCGA) database was also analyzed for further comparison. The immunofluorescence staining of proinflammatory cytokines showed that high interferon gamma (IFNγ; T helper 1; Th1), low interleukin 4 (IL4; T helper 2; Th2), low thymic stromal lymphopoietin (TSLP; Th2), and low transforming growth factor beta (TGFß; T regulatory; Treg) expressions were good prognostic factors for OPSCC. p16-positive OPSCC showed higher Th1, lower Th2/Treg proinflammatory cytokine expressions, and a better prognosis than p16-negative OPSCC. In smokers alone, although p16-positive OPSCC smokers showed weaker Th2/Treg predominant cytokine expressions than p16-negative OPSCC smokers, the prognoses of both groups were equally poor. As for p16-positive OPSCC patients alone, p16-positive nonsmokers showed a significantly better prognosis than p16-positive smokers, but the immune responses of both groups were all weakly Th2/Treg predominant. Overall, higher Th1 and lower Th2/Treg proinflammatory cytokine expressions are associated with a better prognosis for OPSCC. HPV may be related to increased Th1, decreased Th2/Treg responses, and a good prognosis, while smoking may be related to increased Th2/Treg, decreased Th1 responses, and a poor prognosis in OPSCC. The impact of smoking on immune deviation may be weaker than that of HPV, but the impact of smoking on prognosis may be stronger than that of HPV in OPSCC.

Meningeal seeding from glioblastoma multiforme treated with radiotherapy and temozolomide.

Extracranial and meningeal seeding of glioblastoma multiforme is rare. We report herein a case of glioblastoma in a 41-year-old man who underwent surgical resection, concomitant chemoradiotherapy (CCRT) and seven courses of adjuvant chemotherapy with temozolomide. The patient then complained of intermittent severe lower back pain and gait disturbance. Imaging studies demonstrated that although the intracranial residual tumors were well-controlled by the treatment, meningeal seeding involving the brainstem and spinal cord was present. The patient died 2 months after the diagnosis of spinal seeding. This case illustrates the need for consideration of extracranial metastasis if a patient is symptomatic, even if the intracranial tumor appears responsive to treatment. We suggested that the prophylactic craniospinal irradiation may be considered in patients at high risk of meningeal seeding immediately after surgery.

Pseudorosette-Like Proliferations of the Endometrium.

The endometrium displays a wide spectrum of appearances in both neoplastic and non-neoplastic tissue. Unusual proliferations are not infrequently encountered and may lead to misinterpretation. In this study, we investigated pseudorosette-like proliferations (PLPs) found within the endometrial stroma which, to our knowledge, have not been previously reported. Nineteen endometrial samples with PLPs were identified over a period of 5 yr. Characteristics of the endometrium in which the PLPs were arising as well as patient information were recorded for each case. In addition, residual tissue from 10 of the cases was immunostained for cytokeratin, CD10, smooth muscle actin, S-100, and caldesmon to better characterize the lesions. In all cases the endometrium was in the proliferative phase and none of the patients reported the use of exogenous hormones. In 89% (17 of 19) of the cases, PLPs were present as a single focus; 2 cases showed multiple PLPs. Of the 10 immunostained cases, 90% (9 of 10) showed strong/diffuse staining for smooth muscle actin. Six cases showed negative or weak (1+) staining for CD10, whereas 3 showed moderate (2+) and 1 showed strong (3+) staining. In all cases the PLPs were negative for cytokeratin AE1/AE3, S-100, and caldesmon. These studies suggest that PLPs are benign proliferations with smooth muscle differentiation.

Computer-generated surface and tone enhancements to distinguish neoplastic from non-neoplastic colon polyps less than 1 cm in diameter.

BACKGROUND AND STUDY AIMS: Computer-generated enhancements, which can highlight the surface and color of a colonic lesion, may be helpful to predict the histology; however, it remains unclear whether this technology can distinguish neoplastic from non-neoplastic colon polyps when the polyps are <1 cm without magnification. PATIENTS AND METHODS: Images of colorectal polyps less than 1 cm in diameter were obtained from 54 patients who underwent non-magnified colonoscopy with surface enhancement (SE) and tone enhancement (TE). We calculated the sensitivity, specificity, and accuracy in the prediction of histology. Inter- and intra-observer consistency was evaluated by inviting four endoscopists to rate 45 static images. RESULTS: Overall sensitivity, specificity, and accuracy following the sequence of SE, TE colon, and TE pit pattern modes were 87.7% (95% confidence interval 81.3-94.1%), 84.1% (76.9-91.3%), and 86.1% (79.4-92.8%), respectively. For each modality, the results were 75.0% (68.7-81.3%), 82.7% (77.2-88.2%), and 77.2% (71.1-83.3%) for SE; 71.1% (64.5-77.7%), 78.8 (72.8-84.8), and 73.3% (66.8-79.8%) for TE colon mode; and 75.0% (68.7-81.3%), 80.8% (75.0-86.8%), and 76.7% (70.5-82.9%) for TE pit pattern mode. Their inter- and intra-observer agreements were all fair (κ range 0.522-0.568) and good (0.605-0.694), respectively. When the same rater evaluated the same lesion under different modalities, eight of 45 (18%) polyps yielded discordant interpretations, and the possibility of incorrect diagnoses was the highest with the TE colon mode. CONCLUSION: Computer-generated enhancements are satisfactory in predicting the histology of small colon polyps without the need for magnification. This advantage is mostly related to the pit pattern enhancement.

Adult capillary hemangioma of the liver: case report and literature review.

Primary hepatic capillary hemangioma in adults is very rare. Here, we report a case of hepatic capillary hemangioma in a 71-year-old woman. She had abnormal liver function tests, and abdominal sonography revealed a 2-cm nodular lesion and fatty liver. Computed tomography scan revealed a hypervascular tumor. During 2 years' follow-up, the hepatic tumor enlarged to 3 cm in diameter. Serological tests showed no evidence of chronic viral hepatitis or increased level of alpha-fetoprotein. In fear of hepatocellular carcinoma, she received atypical hepatectomy. Microscopically, the tumor turned out to be a capillary hemangioma in a background of steatohepatitis. We searched the literature, and only six similar cases were found. We made a brief review of this rare disease entity and described its clinicopathological features.

Myxoid adrenal cortical carcinoma presenting as primary hyperaldosteronism: case report and review of the literature.

The authors report a case of myxoid adrenal cortical carcinoma (ACC) clinically manifesting as primary hyperaldosteronism. The 82-year-old female patient had a history of hypertension and was sent to the emergency room because of change in consciousness. Ventricular fibrillation occurred, and severe hypokalemia was found. Increased renal loss of potassium, high serum aldosterone level, low renin activity, and a huge tumor in the left suprarenal area were revealed when tests were conducted to determine the cause of her hypokalemia. Left adrenalectomy was performed. The tumor measured 13 cm in diameter and showed a heterogeneous cut surface with gelatinous material. Microscopically, the lesion was composed of polygonal cells with eosinophilic cytoplasm and arranged in arborizing cords in a myxoid background. Capsular and vascular invasion were observed. The tumor stained positive for synaptophysin, melan-A, vimentin, and α-inhibin but negative for cytokeratin. A primary myxoid ACC was diagnosed, which is a rare histological variant. The authors review 13 other reported cases. Most of these were functional tumors causing Cushing syndrome, and only 2 cases presented as primary hyperaldosteronism. All cases had similar microscopic and immunohistochemical features. Distal metastases and local recurrence were not uncommon. Close clinical follow-up is imperative.

Drain tube migration into the anastomotic site of an esophagojejunostomy for gastric small cell carcinoma: short report.

BACKGROUND: Intraluminal migration of a drain through an anastomotic site is a rare complication of gastric surgery. CASE PRESENTATION: We herein report the intraluminal migration of a drain placed after a lower esophagectomy and total gastrectomy with Roux-en-Y anastomosis for gastric small cell carcinoma. Persistent drainage was noted 1 month after surgery, and radiographic studies were consistent with drain tube migration. Endoscopy revealed the drain had migrated into the esophagojejunostomy anastomotic site. The drain was removed from outside of abdominal wound while observing the anastomotic site endoscopically. The patient was treated with suction via a nasogastric tube drain for 5 days, and thereafter had an uneventful recovery. CONCLUSIONS: Though drain tube migration is a rare occurrence, it should be considered in patients with persistent drainage who have undergone gastric surgery.

Myocardial infarction due to giant cell arteritis: a case report and literature review.

Giant cell arteritis occurs mainly in the cranial arteries, especially in the temporal area, and rarely in the coronary arteries. Here, we present a case of coronary artery giant cell arteritis in a 51-year-old woman who complained of atypical chest pain. Radionuclide angiography showed dilated left ventricle with global hypokinesia. Despite medical treatment, she suffered progressive heart failure and finally was given a heart transplant. The pathologic examination revealed myocardial infarction due to coronary giant cell arteritis. Unusual giant cell arteritis should be considered in the differential diagnoses of myocardial infarction.