Clinicopathological and Preclinical Findings of NUT Carcinoma: A Multicenter Study.

BACKGROUND: NUT carcinoma is a rare aggressive disease caused by BRD4/3-NUT fusion, and C-MYC upregulation plays a key role in the pathogenesis. Here, we report on the clinicopathological characteristics of Korean patients with NUT carcinoma and the in vitro efficacy of MYC-targeting agents against patient-derived NUT carcinoma cell lines. MATERIALS AND METHODS: Thirteen patients with NUT carcinoma were evaluated for p53, C-MYC, epidermal growth factor receptor (EGFR), HER2, and programmed cell death ligand 1 (PD-L1) by immunohistochemistry. The half maximal inhibitory concentration (IC50) values of NUT carcinoma cell lines (SNU-2972-1, SNU-3178S, HCC2429, and Ty-82) were determined using MYC-targeting agents, including bromodomain and extraterminal (BET) inhibitors (I-BET, OTX-015, AZD5153) and histone deacetylase (HDAC) inhibitors (vorinostat, romidepsin, panobinostat, CUDC-907). RESULTS: Primary tumor sites included head and neck (n = 9) and lung (n = 4). The patient age ranged from 8 to 73 years with the male/female ratio of 1.2:1. Nine patients died at 3-23.6 months (median, 10.6) after diagnosis. Eight patients had been misdiagnosed initially with other diseases. One patient with metastatic NUT carcinoma who received mass excision plus metastasectomy followed by chemoradiotherapy was a long-term survivor (>27 months). Although expressions of C-MYC (8/12, 73%) and p53 (12/12, 100%) were commonly observed, EGFR, HER2, and PD-L1 expressions were observed in 2 of 7 (29%), 2 of 8 (25%), and 1 of 12 (8.3%) patients, respectively. BET and HDAC inhibitors showed variable but limited in vitro efficacy. However, a dual HDAC/PI3K inhibitor, CUDC-907, was most potent against NUT carcinoma cells, with an IC50 of 5.5-9.0 pmol/L. Consistent with these findings, kinome short interfering RNA screening showed a positive hit for PI3KCA in NUT carcinoma cells. Panobinostat (IC50, 0.4-1.3 nmol/L) and a bivalent BET inhibitor, AZD5153 (IC50, 3.7-8.2 nmol/L), also showed remarkable efficacies. CONCLUSION: East Asian patients with NUT carcinoma showed dismal survival outcomes like Western patients, and CUDC-907 might be promising in NUT carcinoma treatment. IMPLICATIONS FOR PRACTICE: NUT carcinoma (NC) is a disease caused by BRD-NUT fusion leading to C-MYC upregulation. NC is often misdiagnosed and very aggressive, requiring development of effective therapeutic strategy. This article presents the clinicopathological features of the largest series of NCs in East Asians and preclinical sensitivities to MYC-targeting agents in NC cell lines. Patients with NC had grave outcomes and poor response to treatment. Among MYC-targeting agents, including BET and HDAC inhibitors, CUDC-907 (a dual PI3K/HDAC inhibitor) was most effective against NC cells, followed by panobinostat (an HDAC inhibitor) and AZD5153 (a bivalent BET inhibitor). CUDC-907 might be promising in NC treatment.

Macrometastasis in Papillary Thyroid Cancer Patients is Associated with Higher Recurrence in Lateral Neck Nodes.

BACKGROUND: The use of routine central compartment neck dissection surgery for papillary thyroid carcinoma (PTC) is controversial. Although macroscopic central neck lymph node metastasis (CNLN) in PTC is a poor prognostic factor correlated with increased loco-regional recurrence, the significance of microscopic metastasis to the central lymph nodes is not established. Herein, we aimed to assess the influence of the size of CNLN on disease recurrence among PTC patients. METHODS: Data from 233 patients who underwent less than total thyroidectomy with CNLN dissection in 1989-1999 were retrospectively reviewed. The patients were assigned to three groups according to the central node metastasis: no metastasis (Group I), micrometastasis (<2 mm, Group II), and macrometastasis (≥2 mm, Group III). Clinicopathological features, recurrence rate, site of recurrence, and disease-free survival (DFS) were assessed. RESULTS: Of the 233 patients enrolled (mean follow-up period, 16.1 years), 134 (57.5%) had no central neck metastasis, 37 (15.9%) had micrometastasis, and 62 (26.6%) had macrometastasis. Demographics and tumour variables were similar among the three groups. Recurrence rates were 12.7, 16.2, and 43.5% in Groups I, II, and III, respectively (p < 0.001). Group III had a 3.2-fold increased relative risk of recurrence and a significantly decreased DFS compared to Group I. Group III showed significantly higher rates of lateral neck nodes metastasis than Groups I and II. CONCLUSIONS: In conclusion, macrometastasis significantly affects disease recurrence in PTC patients, whereas microscopic metastasis has only marginal effects. Macroscopic CNLN metastasis showed a significantly higher recurrence in the lateral neck node compared to micrometastasis.

Implications of NOVA1 suppression within the microenvironment of gastric cancer: association with immune cell dysregulation.

BACKGROUND: The neuronal splicing factor neuro-oncological ventral antigen 1 (NOVA1) is enriched in normal fibroblasts. Stromal spindle cells such as fibroblasts are major components of tissue inflammation and tertiary lymphoid structures within the microenvironment that contribute to the survival and growth of cancer cells. In the present study, we investigated changes of NOVA1 expression in tertiary lymphoid structures in early and advanced gastric cancer microenvironments in terms of tumor progression and immune regulation. METHODS: Using immunohistochemistry, we analyzed NOVA1 expression in tumor cells, T cells, and stromal spindle cells as well as infiltrating densities of CD3+ T cells, forkhead box P3 positive (FOXP3+) regulatory T cells, CD68+ macrophages, CD163+ M2 macrophages, and myeloperoxidase-positive neutrophils in 396 surgically resected gastric cancer tissues. RESULTS: Suppressed NOVA1 expression in tumor cells, T cells, and stromal spindle cells was closely related to decreased infiltration of FOXP3+ regulatory T cells, increased infiltration of CD68+ macrophages and CD163+ M2 macrophages, more advanced tumor stage, and inferior overall survival rate. In addition, low infiltration of CD3+ T cells and FOXP3+ regulatory T cells and high infiltration of CD68+ macrophages were associated with inferior overall survival. Specifically, weak NOVA1 expression in tumor cells was independently related to more advanced tumor stage and inferior overall survival. CONCLUSIONS: NOVA1 suppression was frequently noted in the gastric cancer microenvironment, and attenuated NOVA1 expression in tumor cells was associated with tumor progression and poor prognosis. This finding seems to be related to immune dysfunction through changes in the immune cell composition of T cells and macrophages.

Chondroblastoma of the temporomandibular joint lateral capsule: a case report.

AIM: Chondroblastoma is a rare, benign bone tumor that accounts for approximately 1% of all primary bone tumors. Chondroblastoma that occurs at the temporomandibular joint can exhibit symptoms similar to those associated with other temporomandibular disorders. This case study aims to present an eight-year followup of chondroblastoma occurring at the temporomandibular joint. METHODOLOGY: The patient presented swelling in the left temporomandibular joint and trismus. Based oncomputed tomography and magnetic resonance imaging findings, a provisional diagnosis of synovial chondromatosis was made. Complete excision of the lesion was performed under general anesthesia. RESULTS: After histopathological examination, the lesion was finally diagnosed as chondroblastoma. Currently, 8 years after the operation, the patient has not experienced any symptoms or any notable complications. CONCLUSIONS: Although chondroblastoma is a benign tumor, it shows aggressive characteristics with bone invasion. Therefore, precise diagnosis and proper treatment planning is crucial for successful treatment of chondroblastoma.

Snail1 is stabilized by O-GlcNAc modification in hyperglycaemic condition.

Protein O-phosphorylation often occurs reciprocally with O-GlcNAc modification and represents a regulatory principle for proteins. O-phosphorylation of serine by glycogen synthase kinase-3ß on Snail1, a transcriptional repressor of E-cadherin and a key regulator of the epithelial-mesenchymal transition (EMT) programme, results in its proteasomal degradation. We show that by suppressing O-phosphorylation-mediated degradation, O-GlcNAc at serine112 stabilizes Snail1 and thus increases its repressor function, which in turn attenuates E-cadherin mRNA expression. Hyperglycaemic condition enhances O-GlcNAc modification and initiates EMT by transcriptional suppression of E-cadherin through Snail1. Thus, dynamic reciprocal O-phosphorylation and O-GlcNAc modification of Snail1 constitute a molecular link between cellular glucose metabolism and the control of EMT.

Oncologic safety of pylorus-preserving gastrectomy in the aspect of micrometastasis in lymph nodes at stations 5 and 6.

BACKGROUND: Pylorus-preserving gastrectomy (PPG) is a function-preserving gastrectomy for early gastric cancers (EGCs) that are preoperatively assessed as pN0 tumors and located in the middle portion of the stomach. In PPG, dissection of the lymph nodes at stations 5 and 6 is frequently incomplete, and this may be worrisome in terms of oncologic safety. METHODS: We examined lymph nodes collected from stations 5 and 6 from 196 patients who had undergone conventional distal gastrectomy (CDG) for EGC located in the middle portion of the stomach and from 24 patients who had undergone PPG. RESULTS: The average number of lymph nodes collected at station 5 was significantly lower with PPG than with CDG (0.08 vs. 1.32, respectively; P = 0.008). However, such a difference was not noted for station 6 nodes. The rate of macrometastasis was very low in all station 5 nodes (1 of 220, 0.45%) and station 6 nodes (1 of 220, 0.45%). Immunohistochemical analysis of cytokeratin in 109 cases of the CDG group and 21 cases of the PPG group showed that micrometastasis of single isolated tumor cell type was observed in only one station 6 lymph node of a patient who was initially diagnosed with pN0 EGC. There were no cases of micrometastasis in station 5 nodes. CONCLUSIONS: The possibility of micrometastasis to station 5 and/or 6 lymph nodes may be negligible for EGC located in the middle portion of the stomach, and PPG thus might be the oncologically safe procedure when considering micrometastasis in remaining nodes in vivo at stations 5 and 6.

Lysyl-tRNA synthetase (KRS) expression in gastric carcinoma and tumor-associated inflammation.

BACKGROUND: Lysyl-tRNA synthetase (KRS) is an aminoacyl-tRNA synthetase (ARS) that is essential for protein synthesis during ligation of specific amino acids to their cognate tRNAs. Aberrant expression of ARSs is associated with various human cancers. METHODS: Using immunohistochemical detection, the present study analyzed the clinical relevance of KRS expression in tumor cells and tumor-associated inflammatory cells (TAI) in 457 patients who underwent curative radical surgery and standard adjuvant therapy and who were observed on long-term follow-up. RESULTS: High expression of KRS in tumor cells (tumor-KRS(+)) was noted in 43.3 % (198 of 457) of cases. High expression of KRS in tumor-associated inflammatory cells (TAI-KRS(+)) including macrophages/monocytes, CD4-positive T cells, and/or neutrophils was observed in 37.2 % (170 of 457) of cases. Status of KRS in the tumor and TAI revealed an association with the known clinicopathological parameters for prognosis of gastric cancer. Tumor-KRS(+) status correlated to shorter overall survival, especially in stage III to IV cancers (P = 0.003), while TAI-KRS(+) status correlated significantly to longer overall survival in gastric cancer (P = 0.049). Cases with tumor-KRS(+) and TAI-KRS(-) status showed significantly reduced survival rates compared to those of other cases (P = 0.010), and status of tumor-KRS(+) and TAI-KRS(-) was revealed as an independently poor prognostic factor of overall survival (P = 0.001). CONCLUSIONS: KRS-related inflammation can be identified in a subset of gastric cancer. This may be a possible mechanism of immune surveillance against tumor progression. In addition, expression status of KRS in tumor and TAI may be an independent prognostic marker for gastric cancer patients.

Scattered psammomatous calcifications around papillary thyroid carcinoma.

BACKGROUND: Although psammomatous calcification is a characteristic pathologic feature of papillary thyroid carcinoma (PTC), the clinical meaning of histologically determined scattered psammomatous calcifications around PTC is unknown. OBJECTIVE: The aim of this study was to evaluate the clinical significance of scattered psammomatous calcifications around PTC. MATERIALS AND METHODS: Between January 2009 and July 2009, a total of 546 patients who underwent total thyroidectomy for PTC were enrolled. They were classified into two groups: patients with scattered psammomatous calcifications and patients without psammomatous calcifications. The clinical findings, preoperative diagnostic findings, and histopathologic features were compared between the two groups. RESULTS: Scattered psammomatous calcifications around PTC were found in 209 patients (38 %), and mostly in younger patients (p = 0.007), those with infiltrative tumor margin (p = 0.022), those with capsule invasion (p = 0.013), and those with lymph node metastasis (p < 0.001). No statistical significance was found in gender, tumor size, multiplicity, and coexisting lymphocytic thyroiditis. CONCLUSIONS: Although further studies with large-scale, long-term follow-up will be necessary to validate the relationship between scattered psammomatous calcifications and prognosis, scattered psammomatous calcification around PTC may have correlations with the aggressiveness of the PTC.

Atypical teratoid/rhabdoid tumor arising in pleomorphic xanthoastrocytoma: a case report.

Atypical teratoid/rhabdoid tumor (AT/RT) is a rare, highly malignant, true rhabdoid tumor in the central nervous system predominantly presenting in young children.AT/RT typically shows rhabdoid cells which can also be seen in other tumors, but it is differentiated from other tumors by the specific genetic alteration involving the SMARCB1 gene. Only a few cases of AT/RT arising in low-grade glioma have been reported. A 13-year-old girl presented with headache, dizziness, nausea and vomiting.A 4.7 cm cerebellar mass was found on MRI.The mass was totally removed. Histologically, the tumor revealed two distinct morphologic appearances: central areas of AT/RT containing rhabdoid cells and sarcomatous component in the background of pleomorphic xanthoastrocytoma(PXA). Immunohistochemically, PXA areas retained nuclear expression of INI-1 and low Ki-67 proliferation index, whereas AT/RT component showed loss of INI-1 nuclear expression and markedly elevated Ki-67 proliferation index. Epithelial membrane antigen (EMA), smooth muscle actin (SMA), and p53 protein were positive only in AT/RT. BRAF V600E mutation was identified in PXA by real-time polymerase chain reaction.We report a rare case of AT/RT arising in PXA which is supposed to progress by inactivation of INI-1 in a pre-existing PXA.

Prognostic implications for high expression of oncogenic microRNAs in advanced gastric carcinoma.

BACKGROUND: Aberrant expressions of specific microRNAs are recently known in many malignancies, including gastric carcinoma. The prognostic implication of oncogenic microRNA dysregulation was investigated in advanced gastric carcinomas undergoing radical resection and adjuvant systemic chemotherapy, and observed on long-term follow-up. METHODS: The expression levels of miR-20a, miR-21, miR-25, miR-93, miR-103, miR-106a, miR-106b, miR-130b, miR-155, miR-221, and miR-222 were analyzed in formalin-fixed paraffin-embedded (FFPE) cancer tissues of 91 patients, using reverse transcription real-time PCR. RESULTS: The high expression of miR-20a, miR-25, miR-93, miR-103, miR-106a, miR-106b, miR-130 was associated with lymph node metastasis (P < 0.05), and high expression of miR-155 was related to tumor penetration through serosa and lymph node metastasis (P < 0.05). Cases with high expression of miR-222 (P = 0.014) showed reduced 5-year survival rates. The high expression of miR-222 and miR-221 showed correlation with shorter metastasis-free survival (P = 0.039 and 0.033, respectively), and miR-222 high expression was related to reduced overall survival (P = 0.012). CONCLUSIONS: The high expression of miR-20a, miR-25, miR-93, miR-103, miR-106a, miR-106b, miR-130, miR-155, miR-221, and miR-222 in AGC tissues may be a high risk factor associated with tumor penetration through serosa, lymph node metastasis, distant metastasis, and poor long-term survival in patients undergoing radical resection and adjuvant systemic chemotherapy.

Diffuse sclerosing variant of papillary thyroid carcinoma: sonography and specimen radiography.

The purpose of this pictorial essay is to show the limitations of sonography and complementary usefulness of specimen radiography in detecting microcalcifications of the diffuse sclerosing variant of papillary thyroid carcinoma, which mostly manifests as diffusely scattered microcalcifications in the thyroid gland.

Diffuse follicular variant of papillary thyroid carcinoma in a 69-year-old man with extensive extrathyroidal extension: a case report.

Diffuse follicular variant papillary thyroid carcinoma (DFVPTC) is a rare variant papillary thyroid carcinoma. DFVPTC typically occurs in young females, extensively involves one lobe or both lobes entirely with frequent nodal metastasis and vascular invasion. In contrast to the other subtypes of follicular variant, DFVPTC has biologically aggressive behavior. We present a case of DFVPTC arising in a 69-yr-old male patient. He presented hoarseness for a few months. Following diagnosis of malignancy on aspiration cytology, total thyroidectomy with neck dissection was performed. The tumor involved both lobes of thyroid, encroaching the surrounding structures including tracheal cartilage and esophagus. Multiple lymph node metastasis and vascular invasion were also found. The patient passed away due to the unexplained bleeding of surgical site.

Trouble-makers in cytologic interpretation of the uterine cervix.

The development and standardization of cytologic screening of the uterine cervix has dramatically decreased the prevalence of squamous cell carcinoma of the uterine cervix. Advances in the understanding of biology of human papillomavirus have contributed to upgrading the histologic diagnosis of the uterine cervix; however, cytologic screening that should triage those that need further management still poses several difficulties in interpretation. Cytologic features of high grade intraepithelial squamous lesion (HSIL) mimics including atrophy, immature metaplasia, and transitional metaplasia, and glandular lesion masquerades including tubal metaplasia and HSIL with glandular involvement are described with accentuation mainly on the differential points. When the cytologic features lie in a gray zone between the differentials, the most important key to the more accurate interpretation is sticking to the very basics of cytology; screening the background and cellular architecture, and then scrutinizing the nuclear and cytoplasmic details.

Clinical and ultrasonographic findings affecting nondiagnostic results upon the second fine needle aspiration for thyroid nodules.

BACKGROUND: The purpose of this study was to investigate the clinical and ultrasonographic (US) findings affecting the nondiagnostic cytology and malignancy rate in thyroid nodules with nondiagnostic cytology upon a second ultrasound-guided fine needle aspiration (US-FNA). MATERIALS AND METHODS: A total of 1124 nodules in 1081 patients (M:F=111:970; mean age, 48.5 years) with 2 or more US-FNAs were included. Clinical and US features were compared between the nodules with nondiagnostic results and diagnostic results from their second FNA using univariate and multivariate analyses. The malignancy rate was analyzed in terms of nondiagnostic cytology. RESULTS: Among 458 nondiagnostic results of the initial FNA, 94 nodules (20.5%) still had nondiagnostic results on the second FNA. Having cystic portion>50% (odds ratio [OR]=2.845, P=.0001), nondiagnostic cytology of the first FNA (OR=2.813, P<.0001), a nodule size≤5 mm (OR=1.742, P=.0331), or hypoechogenicity (OR=1.512, P=.0404) were factors significantly affecting the incidence of nondiagnostic results in the second US-FNA based on multivariate analysis. The malignancy rate was 11.4% in the nodules with nondiagnostic results in the first FNA and 3.2% in the nodules with serial nondiagnostic results in both the first and second FNAs. CONCLUSIONS: The high probability of nondiagnostic results from a second FNA should be considered if a nodule shows cystic portion greater than 50%, nondiagnostic cytology on the first FNA, a nodule size≤5 mm, or hypoechogenicity. The malignancy rate of thyroid nodules with 2 consecutive nondiagnostic results was 3.2%.

Expression of hMLH1, hMSH2 and hMSH6 in small intestinal carcinomas.

BACKGROUND/AIMS: Although primary small intestinal carcinoma (SIC) is morphologically similar to colorectal carcinoma and shares many of the genetic changes of carcinogenesis, little is known about the role of defective mismatch repair (MMR) genes involved in the SIC. The aim of this study is to investigate the role of defective MMR genes and correlation between clinicopathological factors and loss of MMR protein in SIC. METHODOLOGY: A total of 195 SIC cases were collected from 20 institutions in Korea and tissue microarrays (TMA) were made. The loss of expression of hMLH1, hMSH2 and hMSH6 was examined by immunohistochemistry (IHC). RESULTS: The loss of expression of hMLH1, hMSH2 and hMSH6 was identified in 25/193 (13.0%), 25/193 (13%) and 29/195 (15%), respectively. The loss of hMSH2 expression was associated with retroperitoneal seeding. Patients with loss of hMSH6 expression had a tendency to invade deeply and a higher frequency of pancreas invasion. The loss of hMSH6 expression was associated less frequently with peritumoral adenoma. There was no survival difference by MMR protein expression status. CONCLUSIONS: The loss of MMR protein was associated with some distinct clinicopathological features. MMR pathway seems to be major pathway in carcinogenesis of SICs. MMR defect seems to be related with sporadic-microsatellite instability (MSI).

Prognostic significance of angiogenesis by Chalkley counting in node negative cancer of the ampulla of Vater.

Angiogenesis is essential for tumor growth and metastasis. Currently, the Chalkley assay with CD34 immunostaining is the proposed standard method for angiogenesis quantification in solid tumor sections. The purpose of this study was to evaluate the expression of CD34 and its prognostic significance using the Chalkley method in node negative carcinoma of the ampulla of Vater. Between January 1997 and December 2006, 56 node negative patients who had curative resection for carcinoma of the ampulla of Vater were retrospectively reviewed. The Chalkley count was expressed as the mean value of the three counts for each tumor and further divided into two groups according to the mean value of the Chalkley count: low < 4 or high ≥ 4. The mean Chalkley count value was 4.0 (± 3.1). In the low Chalkley group, the 1- and 3-yr recurrence rates were 18.3%, 47.6% respectively; in the high Chalkley group, the 1- and 3-yr recurrence rates were 26.5% and 60.6% respectively. Only high Chalkley count had statistical significance as a factor in recurrence of node negative ampulla of Vater carcinoma. Assessment of angiogenesis may have an important role in the prognostic evaluation of node negative cancer of the ampulla of Vater.

Digital Dermatopathology and Its Application to Mohs Micrographic Surgery.

Digital pathology is being gradually adopted in hospitals due to technological advances. We propose that digital pathology can be used in Mohs micrographic surgery (Mohs surgery) to precisely check residual tumor cells in frozen tumor margin tissues. This would aid surgeons and pathologists in accurately recording tumor margins and give patients the benefit of shorter operation time.

Fine Needle Aspiration Cytology vs. Core Needle Biopsy for Thyroid Nodules: A Prospective, Experimental Study Using Surgical Specimen.

Purpose: To evaluate and compare the diagnostic outcomes of ultrasonography (US)-guided fine needle aspiration (FNA) and core needle biopsy (CNB) performed on the same thyroid nodule using a surgical specimen for direct comparison. Materials and Methods: We included 89 thyroid nodules from 88 patients from February 2015 to January 2016. The inclusion criterion was thyroid nodules measuring ≥ 20 mm (mean size: 40.0 ± 15.3 mm). Immediately after surgical resection, FNA and subsequent CNB were performed on the surgical specimen under US guidance. FNA and CNB cytopathologic results on the specimen were compared with the surgical diagnosis. Results: Among the 89 nodules, 30 were malignant and 59 were benign. Significantly higher inconclusive rates were seen in FNA for malignant than benign nodules (80.0% vs. 39.0%, p < 0.001). For CNB, conclusive and inconclusive rates did not differ between benign and malignant nodules (p = 0.796). Higher inconclusive rates were seen for FNA among cancers regardless of US features, and in the subgroup of size ≥ 40 mm (62.5% vs. 22.9%, p = 0.028). Eleven cancers were diagnosed with CNB (36.7%, 11/30), while none was diagnosed using FNA. Conclusion: In this experimental study using surgical specimens, CNB showed a potential to provide improved diagnostic sensitivity for thyroid cancer, especially when a conclusive diagnosis is limited with FNA.

Evaluation of intratumoral HER-2 heterogeneity by fluorescence in situ hybridization in invasive breast cancer: a single institution study.

This study aimed to determine the incidence and characteristics of HER-2 gene heterogeneity in invasive breast cancer in a single institution. Included were 971 cases of primary invasive breast cancer diagnosed between 2008 and 2010. Fluorescence in situ hybridization (FISH) image files were retrospectively reviewed and HER-2 gene heterogeneity was defined as more than 5% but less than 50% of analyzed invasive tumor cells with a HER-2/Chr17 ratio higher than 2.2, according to the College of American Pathologists guidelines. HER-2 gene heterogeneity was identified in 24 (2.5%) cases. The mean proportion of invasive tumor cells with a HER-2/chromosome 17 ratio higher than 2.2 was 11.6% (range: 5%-25%). Of 24 cases, HER-2 gene status was not amplified in 8, showed borderline amplification in 2, and amplification in 14. All HER-2 amplification cases were low-grade. In conclusion, HER-2 gene heterogeneity of invasive breast cancer is identified in routine FISH examination. This may affect the results of HER-2 gene amplification status in FISH studies.

Tumor margin histology predicts tumor aggressiveness in papillary thyroid carcinoma: a study of 514 consecutive patients.

Histologic patterns at tumor margins may be related to prognosis in several malignancies. We investigated tumor aggressiveness with respect to tumor margin histology in patients with papillary thyroid carcinoma (PTC). Five hundred fourteen consecutive patients who underwent surgery for primary PTC between January and July 2009 were assigned to two groups, one with an infiltrative pattern (I-type, n = 347) at tumor margins and one with an expanding pattern (E-type, n = 167). Tumor aggressiveness was assessed by analyzing relationships between these patterns and known prognostic factors. The analysis showed that unfavorable prognostic factors such as tumor multiplicity (P = 0.002), extrathyroidal extension (P < 0.001), lateral neck lymph node metastasis (P < 0.001) and advanced TNM stage (P = 0.001) were significantly more prevalent in patients with I-type PTC than in those with the E-type. Central neck node metastases were more prevalent without statistical significance in the I-type patients (P = 0.376). Tumor margin histology was not related to gender or tumor size. These results suggest that histologic patterns at tumor margins predict aggressiveness in PTC.