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The aim of the present study was to compare the efficiency of tissue microarray (TMA) results using immunohistochemistry markers applied to a variety of core sizes and full sections of gastrointestinal stromal tumors (GIST) using performance measures such as core loss rate and concordance rate. Six primary antibody markers (c-Kit, CD34, smooth muscle actin (SMA), S-100, p53, and Ki-67) were used with the TMA technique to analyze 0.6 mm, 2 mm, and 3 mm punch cores of GIST samples from 67 patients. No statistical association was found between core size and loss rate (P= 0.512). TMA results for the 0.6 mm, 2 mm, and 3 mm core showed that all core sizes could statistically significantly reflect full sections with regard to c-Kit, SMA, and S-100 antibodies, but that the 3 mm core section was the most representative except for CD34. With regard to p53 and Ki-67 staining, the 0.6 mm core section was not representative, but the 2 mm and 3 mm core sections could statistically significantly represent full section results. Among them, the 3 mm core section was more accurate than the 2 mm core section. Use of a single 3 mm core size in TMA is suitable for evaluating large numbers of protein and nuclear stains with regard to immunohistochemistry for GIST.

Sebaceoma is a rare benign tumor arising from the sebaceous gland of the skin. Sebaceoma often occurs on the head and neck but rarely on the ears. We present the case of a 78-year-old female patient with a two-year history of a protruding mass in her left ear. Physical examination revealed a well-circumscribed plaque in the crus of the helix of the left ear. A wide local excisional biopsy was taken, and the mass was subjected to histopathologic assessment. While the mass showed cytological findings indicating sebaceoma, it also presented malignant features architecturally and immunohistochemically. Based on these findings, the tumor was regarded as a sebaceoma of borderline malignancy. [ABSTRACT FROM AUTHOR]

Mitotic counts in the World Health Organization (WHO) grading system have narrow cutoff values. True mitotic figures, however, are not always distinguishable from apoptotic bodies and darkly stained nuclei, complicating the ability of the WHO grading system to diagnose well-differentiated neuroendocrine tumors (NETs). The mitosis-specific marker phosphohistone H3 (PHH3) can identify true mitoses and grade tumors reliably. The aim of this study was to investigate the correspondence of tumor grades, as determined by PHH3 mitotic index (MI) and mitotic counts according to WHO criteria, and to determine the clinically relevant cutoffs of PHH3 MI in rectal and nonrectal gastrointestinal NETs. Mitotic counts correlated with both the Ki-67 labeling index and PHH3 MI, but the correlation with PHH3 MI was slightly higher. The PHH3 MI cutoff ≥4 correlated most closely with original WHO grades for both rectal NETs. A PHH3 MI cutoff ≥4, which could distinguish between G1 and G2 tumors, was associated with disease-free survival in patients with rectal NETs, whereas that cutoff value showed marginal significance for overall survival in patient with rectal NETs. In conclusion, the use of PHH3 ≥4 correlated most closely with original WHO grades. [ABSTRACT FROM AUTHOR]

Tonsillar squamous cell carcinomas (TSCCs) are the most common human papillomavirus- (HPV-) associated oropharyngeal cancers with poor prognosis. Homeodomain-interacting protein kinase 2 (HIPK2) is a central regulator of p53, which participates in apoptosis during the DNA damage response. HIPK2 is involved in HPV-associated uterine cervical and cutaneous carcinogenesis through its binding of HPV E6, thereby preventing apoptosis and contributing to tumor progression. However, its clinical and prognostic significance in TSCC remains unclear. HIPK2 mRNA levels were analyzed in 20 normal tonsils and 20 TSCC specimens using real-time reverse transcription polymerase chain reaction. Immunohistochemistry of HIPK2 was performed in 79 resected specimens. HIPK2 was expressed in 57% of the TSCCs, and HIPK2 protein expression and HIPK2 mRNA levels were higher in TSCCs than in normal tonsils. HIPK2 overexpression was associated with poorly differentiated carcinoma and low alcohol consumption and was an independent prognostic factor for overall survival and disease-free survival (DFS) in TSCC and a negative independent prognostic factor for DFS in patients receiving postoperative radiotherapy. HIPK2 overexpression had a significant association with poorer DFS in HPV-positive TSCCs, but not in HPV-negative tumors. HIPK2 overexpression may be a potential prognostic marker for predicting prognoses and a high risk of recurrence, particularly in patients with HPV-positive TSCC. [ABSTRACT FROM AUTHOR]

The incidence of endometrial cancer is rapidly increasing worldwide, and its molecular classification has gained importance for new therapeutic approaches. This study sought to examine the clinicopathologic features and immune markers associated with the DNA mismatch repair (MMR) status and MLH1 promoter methylation status of endometrial cancer patients. A total of 173 patients with primary endometrial cancer who had received a hysterectomy were evaluated for four MMR proteins (MLH1, MSH2, MSH6, and PMS2), immune markers (CD8, programmed cell death protein 1 (PD-1), and programmed death-ligand 1 (PD-L1)) and p53 by immunohistochemistry (IHC), followed by an MLH1 methylation test. Patients were classified into MMR deficiency or proficiency, sporadic cancer, or probable Lynch syndrome (PLS), and the clinicopathologic features (including the expression of peritumoral immune markers) and prognosis of each group were compared. Patients with MMR deficiency or PLS showed an increase in immune markers compared those with MMR proficiency or sporadic cancer, respectively, and PLS demonstrated higher immune marker expression than MLH1 promoter methylation. Regarding prognosis, patients with MMR deficiency showed significant adverse overall survival (OS) when in stages I and II. Practical molecular classifications based on p53 staining results, in addition to MMR or PLS status, revealed an increased predictive ability for OS compared with the European Society of Medical Oncologists (ESMO) risk groups. The results of this study suggest that PLS may be a better candidate for an immune checkpoint inhibitor than MMR deficiency. The practical molecular classification contributes not only to the screening of Lynch syndrome, but also assists in predicting the prognosis in endometrial cancer. [ABSTRACT FROM AUTHOR]

Sebaceous carcinoma (SC) represents a rare, aggressive eyelid malignancy with poor prognosis and is a possible component of Muir-Torre syndrome. However, genetic features as driver mutations or potential therapeutic targets are not fully elucidated. Recent a few studies have shown that SCs have concurrently multiple mutations including RAS/RAF/MAPK and PI3K/Akt pathways via next-generation sequencing in western population. Because we recently demonstrated absence of KRAS mutations in Korean eyelid SCs, we extended our previous study to the analysis of NRAS , BRAF , PIK3CA , and CTNNB1 mutations, and the examination of related protein expressions in 15 eyelid SCs. Repeated molecular analysis by peptide nucleic acid-mediated PCR clamping method, PNA clamping-assisted fluorescence melting curve analysis, and direct sequencing revealed that all eyelid SCs had wild type alleles of NRAS , BRAF , and PIK3CA in hotspot exon locations. Only silent mutations in the CTNNB1 gene (p.Q61Q) were identified. Using immunohistochemistry and microsatellite instability analysis, they harbored all intact mismatch repair gene proteins with microsatellite stability. Membranous and cytoplasmic β-catenin staining was found in all tumors, whereas the one third of those tumors showed cyclin D1 overexpression, of which 40% and 80% showed p53 expression and p16 expression, respectively. The lack of KRAS , NRAS , BRAF , and PIK3CA mutation in our study may suggest that a subset of eyelid SCs is unlike that of eyelid SCs of western countries. The mismatch repair gene proteins and microsatellite instability analysis as a screening test for Muir-Torre syndrome may be limited in the Korean eyelid SCs. [ABSTRACT FROM AUTHOR]

Objective Monoclonal antibodies targeting programmed cell death-1 (PD-1)/programmed death ligand 1 (PD-L1) demonstrated promising clinical response. The predictive/prognostic value of PD-1/PD-L1 immunohistochemistry (IHC) has been evaluated in many cancer types. However, the prognostic value of PD-1/PD-L1 IHC has not been evaluated in endometrial cancer. Methods We conducted a retrospective study to quantify the IHC CD8, PD-1, and PD-L1 expressions in immune cells at center of tumor (CT), invasive margin (IM), and/or tumor cell in 183 primary endometrial cancer samples from a single cohort, followed by their reciprocal combinations, including compartmental differences, and correlated them with overall survival (OS) and progression-free survival (PFS). Results In repeated Cox multivariable models adjusted by clinicoimmunopathologic factors, high CT-PD-L1 was an independent adverse prognostic factor for PFS in all patients and in the microsatellite-stable subgroup. Immune marker ratios revealed independently shorter PFS for high CT-PD-L1/CT-CD8 and CT-PD-L1/CT-PD-1 ratios. Classification of endometrial cancer into four groups based on CT-CD8 and CT-PD-L1 revealed significantly different survival among groups. Conclusions The high PD-L1/CD8 ratio and the high expression of PD-L1 on immune cells were independent poor prognostic factors for PFS in endometrial cancer, providing insights into the tumor microenvironment. [ABSTRACT FROM AUTHOR]

Hepatocyte growth factor (HGF) and MET are candidates of targeted therapies for cancer patients. Although MET and HGF are commonly expressed in biliary tract cancers, their expression and gene copy number status and their association with KRAS mutations have not been investigated in pancreatobiliary-type ampullary adenocarcinomas (A-ACs), one of the aggressive periampullary cancers. MET and HGF expressions and MET copy number status were examined by performing immunohistochemistry (IHC) and silver in situ hybridization (SISH) in 62 surgically resected, paraffin-embedded tumors, respectively. High MET and HGF protein expressions were detected in 24 (38.7%) and 15 (24.2%) tumors. High MET expression was associated with KRAS mutation. However, there were no associations of high MET/HGF expression alone with other clinicopathological feature or survival. MET SISH positivity was detected in 19 tumors (30.6%), where 84.2% were due to high trisomy or polysomy and only 3 cases (15.8%) were MET gene amplification. The overall MET protein overexpression was well correlated with MET SISH positivity. The concurrent MET SISH positivity and KRAS mutation, not each alone, was an independent poor prognostic factor of disease-free survival only in pancreatobiliary subtype of A-ACs, but not in intestinal subtype. Concurrent MET SISH positivity and KRAS mutation may predict a high risk of recurrence in pancreatobiliary subtype of A-ACs, indicating those markers could be potent candidates for a new therapeutic target in this cancer type. MET IHC can be used as a reliable tool screening for MET copy number status in ampullary cancers. [ABSTRACT FROM AUTHOR]