High Labeling Index Research Articles

A primary intracranial neuroepithelial neoplasm with novel TCF3::BEND2 fusion: a case report

Astroblastoma, MN1-altered, is a rare circumscribed glial neoplasm that is composed of round, cuboidal, orcolumnar cells with astroblastic perivascular pseudorosettes, often associated with MN1::BEND2 and MN1::CXXC5 fusions. Atroblastoma-like gliomas harbouring EWSR1::BEND2 have been reported that they defined an epigenetically distinct subtype of astroblastoma. We report a case of a 19-year-old female with an intracranial neuroepithelial tumor featuring a novel TCF3::BEND2 fusion. This tumor, while classified as EWSR1::BEND2 gliomas based on DNA methylation, did not exhibit the MN1 alteration or typical astroblastoma morphology. The patient, initially diagnosed as ependymoma WHO grade 2 following surgery for an intracranial tumor four years prior, presented with a suspected recurrence. Magnetic resonance imaging identified a mixed solid-cystic lesion in the temporal area of the left lateral ventricle. For the recurrent tumor, the histological examination revealed the tumor cells predominantly exhibited a solid arrangement, with the solid areas primarily consisting of oval and short-spindle cells. In certain regions, loosely arranged short-spindle cells was observed. The tumor exhibited high cellular density, nuclear atypia, and frequent mitoses, but lacked the hallmark features typically associated with astroblastoma. Immunohistochemistry revealed patchy positivity for GFAP and OLIG2, diffuse positivity for EMA, and a high MIB-1 labeling index. Genome-wide DNA methylation profiling confirmed the tumor’s classification as EWSR1::BEND2 gliomas with a high-confidence match and revealed focal deletion of chromosome 9q. Targeted next-generation sequencing identified a TCF3::BEND2 fusion, validated by reverse transcription polymerase chain reaction and Sanger sequencing. This case broadens the genetic spectrum of high-grade neuroepithelial tumor and suggests that BEND2 alterations may serve as critical determinants for this EWSR1::BEND2 glioma subgroup within the methylation classifier.

BubR1 and cyclin B1 immunoexpression in pleomorphic adenoma and polymorphous adenocarcinoma of minor salivary glands

The immunoexpression of BubR1 and cyclin B1 in pleomorphic adenoma (PA) and polymorphic adenocarcinoma (PAC) in minor salivary glands is poorly studied. Thus, a retrospective and observational study was performed to provide a better understanding of the role and immunopositivity patterns of these proteins in these lesions. Sixteen cases of PA and 16 cases of PAC were selected. Parenchyma cells were submitted to quantitative immunohistochemical analysis through the labeling index. Cytoplasmic immunoexpression of BubR1 was observed in neoplastic cells from all analyzed PA and PAC cases. All PA cases and 93.7% of PAC exhibited nuclear immunoexpression of BubR1. Higher cytoplasmic and nuclear immunoexpression of BubR1 was observed in PAC (p = 0.001 and p = 0.122, respectively). Cytoplasmic immunoexpression of cyclin B1 was observed in all cases of PA and PAC, with a higher labeling index in the latter (p < 0.001). There was a significant positive correlation between nuclear and cytoplasmic BubR1 immunoexpressions (p < 0.001) in PA and a significant negative correlation between BubR1 and cyclin B1 cytoplasmic immunoexpressions (p = 0.014) in PAC. The higher cytoplasmic and nuclear immunoexpression of BubR1 in PACs suggests the continuous maintenance of neoplastic cells in the cell cycle and migration. Higher immunoexpression of cyclin B1 supports this lesion's enhanced proliferative and migration ability.

Fibroblast growth factor 5 expression predicts the progression of oral squamous cell carcinoma

Fibroblast growth factor (FGF) 5 is a member of the FGF family that functions as a regulator of tissue growth and regeneration. Aberrant FGF5 expression has been previously associated with the progression of a number of different malignancies. However, its potential role in oral cancer remains unclear. In this study, we explored the relationship between the expression of FGF5 protein in oral squamous cell carcinomas (OSCCs) and the clinicopathological parameters of OSCCs and whether the expression of FGF5 protein in OSCCs could be a prognostic factor for OSCC patients. The FGF5 protein expression was examined in 64 OSCC and 34 normal oral mucosal specimens by immunohistochemical staining. Stress induced upregulation and intracellular redistribution of FGF5 were verified using xenograft animal model and OSCC cell lines. The mean FGF5 protein labelling index was significantly higher in OSCC than in normal oral mucosal samples, with high FGF5 protein labelling index (>58%) being correlated with advanced stage and poor survival of OSCC patients. Apart from the peri-cytoplasmic staining pattern characteristic of paracrine growth factors, FGF5 protein was localized as distinct punctate structures in the cytoplasm of advanced stage or stressed-induced cells. This redistribution and upregulation of FGF5 protein could be sustained after termination of the stress induction in cell line and xenograft animal models. FGF5 can be induced by cellular stress and risk factors of OSCC, where high expression levels of FGF5 is potentially a useful parameter for predicting OSCC progression and patient survival.

High Grade Differentiated Follicular Cell-Derived Thyroid Carcinoma Versus Poorly Differentiated Thyroid Carcinoma: A Clinicopathologic Analysis of 41 Cases.

Criteria overlap for separating between malignant follicular epithelial cell-derived thyroid gland neoplasms with high grade features of increased mitoses and tumor necrosis but lacking anaplastic histology. Patterns of growth, nuclear features, tumor necrosis, and various mitotic index cutoffs are suggested, but a reproducible Ki-67-based labeling index has not been established. Forty-one cases diagnosed as poorly differentiated thyroid carcinoma (PDTC) or high grade differentiated follicular cell-derived thyroid carcinoma (HGDFCDTC) were reviewed, with histologic features, mitotic figure counts, and Ki-67 labeling index reviewed on cases within Southern California Permanente Medical Group from 2010 to 2021 to establish any potential outcome differences. There were 17 HGDFCDTC (nine papillary thyroid carcinoma; eight oncocytic follicular thyroid carcinoma), median age 64years, affecting nine females and eight males. Tumors were large (median, 6.0cm), usually unifocal (n = 13), with only one tumor lacking invasion. Tumor necrosis was present in all; median mitotic count was 5/2 mm2 (median Ki-67 labeling index 8.3%). Three patients had metastatic disease at presentation, with additional metastases in four patients (41.2% developed metastases); 11 were without evidence of disease (median 21.2months); with the remaining six patients alive (n = 4) or dead (n = 2) with metastatic disease (median 25.8months). Criteria associated with an increased risk of developing metastatic disease: widely invasive tumors; age ≥ 55years; male; advanced tumor size and stage; extrathyroidal extension; but not increased mitotic rate or higher labeling index. There were 24 PDTC, median age 57.5years, affecting 13 females and 11 males. Tumors were large (median, 6.9cm), with 50% part of multifocal disease, with three tumors lacking invasion. Insular/trabecular/solid architecture was seen in all tumors; tumor necrosis was present in 23; and median mitotic count was 6/2 mm2 (median Ki-67 labeling index 6.9%). Five patients had metastatic disease at presentation, with additional metastases in 3 patients (29.2% developed metastases); 16 were without evidence of disease (median, 48.1months); with the remaining 8 patients alive (n = 3) or dead (n = 5) with metastatic disease (median, 22.4months). Criteria associated with an increased risk of developing metastatic disease: widely invasive tumors; male; advanced tumor size and stage; extrathyroidal extension; but not increased mitotic rate or higher labeling index. HGDFCDTC shows tumor necrosis, a median Ki-67 labeling index of 8.3%, with a high percentage (41%) of patients developing metastatic disease. Extent of invasion (non-invasive, minimally invasive, angioinvasive, widely invasive) correlates strongly with developing metastatic disease. PDTC presents at a slightly younger age, with large tumors, often in a background of multifocal tumors, with tumor necrosis nearly always seen, a median Ki-67 labeling index of 6.9%, with 29% of patients developing metastatic disease. Separation between groups is meaningful as early metastatic disease is relatively common, but mitotic counts/labeling indices are not different between the groups nor able to potentially risk stratify development of metastatic disease.

S2075 Mixed Adeno-Neuroendocrine Carcinoma (MANEC) of Colon: Rare Differential Diagnosis for Iron Deficiency Anemia

Introduction: Colonic Mixed adenoneuroendocrine carcinoma (MANEC) is a rare but highly aggressive tumor. In English Literature only 10 cases or less have been reported of this neoplasm, with the prognosis still unfavorable. Mixed adenoneuroendocrine carcinomas, by definition, are comprised of at least 30% of both a neuroendocrine and an adenocarcinomatous component. Cases are typically diagnosed at advanced stages, and the age of presentation is younger than the average age of colorectal adenocarcinoma (∼60 years old). Metastasis can occur anywhere but usually seen in the liver, regional lymph nodes and rarely peritoneum. The tumor neuroendocrine markers and immunophenotype are essential for the diagnosis, for example chromogranin, synaptophysin, CDX-2, and CD56. Case Description/Methods: A 53-year-old women with a history of abdominal pain was diagnosed with NET via histopathology of the cecum. The patient was referred to us by her hematologist which he ordered CT/pelvis due to her new onset of iron deficiency anemia and CT scan showed irregular bowel wall thickening of proximal ascending colon with infiltration and nodularity of surrounding fat suspicious of colon neoplasm. The patient has diabetes mellitus and hypertension other than that she had no significant history of past illness. A colonoscopy and biopsy were performed that showed poorly differentiated carcinoma with ulceration in large bowel mucosa, morphologically, high grade poorly differentiated malignant neoplasm was noted with ulceration. Histopathology and Immunohistochemical studies show the tumor cells are positive for AE1/3, CK7, synptophysin, CDX-2, while negative for CK20, chromogranin, CD56. Ki-67 shows a high labeling index (−95%). The negative stain of tumor cells for MLH-1 and PMS2 can be associated with microsatellite instability related germ line mutation. The differential diagnosis includes poorly differentiated adenocarcinoma, mixed adenoneuroendocrine carcinoma and large cell endocrine carcinoma. A definitive classification depends on the total resection specimen (Figure 1). Discussion: Mixed adenoneuroendocrine carcinoma of the colon is a neoplasm consisting of 2 components coexisting simultaneously within a tumor. It is a very rare carcinoma that presents at a younger age than colorectal adenocarcinoma. Unfortunately, it is diagnosed usually at late stages when metastasis has occurred. If detected at early stages curative surgery can be the treatment. The prognosis Is poor due to late diagnosis and dual nature of the tumor.Figure 1.: Histology and Immunohistochemical studies.

Clinicopathologic significance of DNA replication licensing factors in head and neck diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) harbors defects in the proliferation pathway. We performed multiparameter analysis of proteins expressed during different cell cycle phases and correlated them with clinical parameters of head and neck DLBCLs. Thirty-nine DLBCLs were staged and immunohistochemically stained with MCM2, Ki67, and geminin. The receiver operating characteristic curve and its area under the curve were calculated, and sensitivity vs specificity curve analysis was performed. The highest labeling index was in MCM2, followed by Ki67 and geminin (P < .001). All pairs showed significant differences (P < .001). The best cutoff points to differentiate limited from advanced disease were 68% and 45% for MCM2 and Ki67, respectively. There was no acceptable cutoff for geminin (area under the curve=0.667, P=.134). MCM2/Ki67 (P=.293) and geminin/Ki67 (P=.233) ratios did not differ between the stages. The median (interquartile range) of the geminin/Ki67 ratio was 0.57 (0.68), translating to a reduced G1. We suggest a role for cell cycle-related proteins in the biology and behavior of DLBCLs. MCM2 and Ki67 cutoffs can be a potential option to differentiate limited from advanced disease, where imaging and laboratory techniques are unavailable. The G1 decrease and the significantly higher MCM2 expression compared to Ki67 indicate replication disturbances, making factors involved in the G1 phase targets for treatment.

Isolation of low grade urinary bladder tumors carrying bad prognosis using KI-67 labeling index

Introduction: Even among low grade bladder tumors, there are some which have been found to carry bad prognosis for progression, recurrence and survival. Accurately pinpointing these cases at the time of diagnosis just with the help of routine histopathology is problematic. Ki-67 immunostaining may potentially be of help in identifying such cases, making administration of additional treatment modalities like chemotherapy and radiotherapy possible. There is scarcity of such studies in our country. The present study aims to correlate Ki-67 labeling index with the histopathological type and grade, pathological stage and mitotic index of urinary bladder tumors. Objective: Objective of the study is to consider the possibility of using Ki-67 labeling index to identify those low grade urinary bladder tumors which carry bad prognosis. Materials and Methods: All trans-uretheral resection of bladder tumor (TURBT) specimens in our institute were analyzed for their histopathological grade, pathological stage, mitotic index and Ki-67 labeling index in the period extending from from August 2015 to December 2016. The clinical data were analyzed retrospectively and statistically. SPSS Version 23 (SPSS Inc.,Chicago, IL, USA) software was utilized for all statistical analyses. Chi-square analysis was utilized for comparison of groups. Results with P Results: Ki-67 expression in Low grade urothelial carcinoma (LGUC) showed variation from 1.4% to 41%. The papillary urothelial neoplasm of low malignant potential (PUNLMP) cases showed variation from 16 -17%. And the only case of transitional cell papilloma in the study was found to have expression of 9%.Conclusion: Cases of high (more than 20%) Ki-67 MIB-1 labeling index can be segregated even from among those cases with low histopathological grade, low mitotic index and pTa histopathological stage. Such cases are candidates for multimodality treatment including radiotherapy, chemotherapy etc. Keywords: Bladder tumors,

Programmed death ligand 1 protein expression is positively correlated with the solid predominant subtype, high MIB-1 labeling index, and p53 expression and negatively correlated with epidermal growth factor receptor mutations in lung adenocarcinoma

Programmed death ligand 1 (PD-L1) protein expression is a proposed predictive biomarker of immunotherapy; thus, identification of the clinicopathological and molecular characteristics associated with PD-L1 expression is important and necessary. We examined PD-L1 immunohistochemical expression and its relationships with the clinicopathological and molecular characteristics of patients with surgically resected nonsmall cell lung carcinoma. PD-L1 expression differed according to the histological subtype. Among 633 patients with adenocarcinoma, 523 (82.6%) had no PD-L1 expression, 78 (12.3%) low expression, and 32 (5.1%) high expression. PD-L1 expression was more common in men (p<0.001), in smokers (p=0.002), and in patients with a more advanced stage (p=0.002), the solid predominant subtype (p<0.001), no epidermal growth factor receptor(EGFR) mutations (p<0.001), a high MIB-1 labeling index (p<0.001), and positive p53 immunohistochemical expression (p<0.001). In a multivariate logistic regression analysis, the solid predominant subtype (odds ratio [OR]=4.92, 95% confidence interval [CI]: 2.72-8.89, p<0.001), no EGFR mutations (OR=2.27, 95% CI: 1.35-2.7, p=0.002), a high MIB-1 labeling index (OR=2.78, 95% CI: 1.72-4.55, p<0.001), and p53 positivity (OR=2.13, 95% CI: 1.34-4.36, p=0.042) were significantly and independently associated with PD-L1 expression. The combination of the solid predominant subtype with a high MIB-1 labeling index was strongly associated with positive expression of PD-L1. In the 193 patients with squamous cell carcinoma, 92 (47.7%) had no PD-L1 expression, 57 (29.5%) low expression, and 44 (22.8%) high expression. There were no significant correlations between PD-L1 expression and the evaluated clinicopathological or molecular characteristics of these patients. These results, indicating associations of PD-L1 with various clinicopathological or molecular characteristics in adenocarcinoma but not squamous cell carcinoma, may be useful for selecting patients with a good response to immune checkpoint inhibitors.

Solitary peritoneal metastasis of gastrointestinal stromal tumor: A case report

BACKGROUNDA gastrointestinal stromal tumor (GIST) is a mesenchymal tumor of the gastrointestinal tract that is most commonly found in the stomach. Recurrence of GISTs mostly occurs in the liver or peritoneum, and in most cases, multiple metastases occur. As a solitary peritoneal metastasis is rare, an appropriate treatment strategy has not been established. Here, we report a case of solitary peritoneal metastasis after complete resection of gastric GIST.CASE SUMMARYA 76-year-old woman was diagnosed with stomach GIST and underwent laparoscopic local resection using the CLEAN-NET method. As the recurrence risk was intermediate, adjuvant imatinib therapy was not administered. Two years after surgery, routine computed tomography revealed an abdominal mass between the dorsal side of the right hepatic lobe and right kidney. Other imaging tests did not reveal any abnormalities. Laparoscopic observation showed that the tumor was located at the retroperitoneum, and intraperitoneal dissemination was not found. Therefore, we performed laparoscopic tumor resection. Immunohistochemically, the tumor was positive for c-kit and CD34 and had a relatively high mitotic index and MIB-1 Labeling index. We administered adjuvant imatinib therapy. There was no evidence of recurrence 3 years after the operation.CONCLUSIONThis is the first reported case of a solitary recurrence of GIST in the peritoneum treated with complete laparoscopic resection.

Recurrence Interval Within 1 Year Leads to Death in Patients with Grade 2 Meningioma

Grade 2 meningioma is more likely to recur than grade 1 meningioma. Recurrence decreases overall survival in patients with grade 2 meningioma. However, the clinical course of grade 2 meningioma with several repeated recurrences is poorly understood. The purpose of this study was to clarify the clinical characteristics of grade 2 meningioma with repeated recurrences. This study included 28 patients with grade 2 meningioma treated at our institution from January 1994 to December 2017. The relationship between survival and factors including age, sex, number of recurrences, malignant transformation, radiation therapy, tumor location, MIB-1 labeling index, Simpson grade, Karnofsky Performance Status, and surgical interval were analyzed. The average age at the initial operation was 53.4 years. The number of recurrences was 3.7 times on average during the follow-up of 113.9 months after the initial operation. An increasing number of recurrences resulted in shortening of the surgical interval, increase in the MIB-1 labeling index, and decrease in Karnofsky Performance Status. In fatal cases, the average surgical interval before death was approximately 1 year. Three factors were related to poor prognosis: number of recurrences (odds ratio, 1.620; P= 0.030), malignant transformation (odds ratio, 10.625; P= 0.019), and high MIB-1 labeling index (odds ratio, 1.089; P= 0.044). Shortening of the surgical interval within 1 year because of multiple recurrences led to death in patients with grade 2 meningioma. Malignant transformation was the most potent among the poor prognostic factors.

Abstract P4-09-08: Tumor mutational burden in Japanese patients with triple negative breast cancer

Abstract Background: Immune checkpoint inhibitors (ICIs) has become a new promising treatment in the field of cancer therapy. Therefore, it is important to identify predictors of effect for ICIs in breast cancers (BC). PD-L1 expression and the abundance of TILs were known to be related to tumor mutational burden (TMB). TMB is associated with clinical benefit to ICIs in patients with melanoma, lung and colon cancer. However, the significance of TMB is unclear in BC. In this study, we assessed TMB using the TruSightOncology 500 panel (TSO500) (Illumina, San Diego), which the US Food and Drug Administration had designated as a breakthrough device, and identify characteristics of higher TMB tumors in triple negative breast cancer (TNBC), one of the most clinically aggressive subtypes. Methods: This study included 30 patients with primary TNBC underwent resection without neoadjuvant chemotherapy. DNA was extracted from FFPE tissue. Next-generation sequencing assay was performed by using the TSO500. The DNA of 523 genes for assessment of small variants, as well as biomarkers related to response to immunotherapy, such as TMB and MSI. TMB was measured in synonymous and/or non-synonymous mutation (mut) per megabase (mb). Total TMB levels were divided into three groups: low (1-5 mut/mb), intermediate (int) (6-19 mut/mb), and high (≥20 mut/mb). PD-L1 were assessed in IHC staining and PD-L1 positivity was defined as PD-L1 expression in ≥1% of tumor cells. TILs were assessed in HE staining and TILs were defined as TILs-high for ≥50% stromal TILs and TILs-low for &amp;lt;50% stromal TILs. Results: The median age of patients was 63 years old (range: 32-81). The median TMB was 8.56 mut/mb (2.35-14.22). Among the 30 tumors, 8 (26.7%) were TMB-low, 22 (73.3%) were TMB-int, and none was TMB-high. TMB-int tumors had more aggressive features than TMB-low tumors. In TMB-int tumors, nuclear grade 3 were 72.7%, high labeling index of Ki-67 (≥20%) were 54.5%, and PD-L1 positivity on tumor cells were 68.2%. Whereas, PD-L1 positivity were 25.0% in TMB-low tumors (p=0.03). TILs-high were 72.7% in TMB-int and TILs-low were 75.0% in TMB-low (p=0.02). Twelve patients in TMB-int (54.5%) and 1 patient in TMB-low (12.5%) were treated by anthracycline based chemotherapy as an adjuvant chemotherapy. Six patients with TMB-int had recurred within 5 years and 3 of them died. Meanwhile, no one with TMB-low had recurred and died. Conclusions: Findings of our study demonstrated that higher TMB in TNBC might be a poor prognostic factor. We could expect this breakthrough device to be useful for the treatment strategy in patients with TNBC. Citation Format: Kanako Kurata, Makoto Kubo, Yuan Yuan, Yurina Harada, Takafumi Morisaki, Akiko Shimazaki, Saori Hayashi, Hitomi Kawaji, Kazuhisa Kaneshiro, Mai Yamada, Masaya Kai, Masafumi Nakamura. Tumor mutational burden in Japanese patients with triple negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-09-08.

Neuropeptide depletion in the amygdala in sudden unexpected death in epilepsy: A postmortem study.

Sudden unexpected death in epilepsy (SUDEP) is typically unwitnessed but can be preceded by seizures in the period prior to death. Peri-ictal respiratory dysfunction is a likely mechanism for some SUDEP, and central apnea has been shown following amygdala stimulation. The amygdala is enriched in neuropeptides that modulate neuronal activity and can be transiently depleted following seizures. In a postmortem SUDEP series, we sought to investigate alterations of neuropeptidergic networks in the amygdala, including cases with recent poor seizure control. In 15 SUDEP cases, 12 epilepsy controls, and 10 nonepilepsy controls, we quantified the labeling index (LI) for galanin, neuropeptide Y (NPY), and somatostatin (SST) in the lateral, basal, and accessory basal nuclei and periamygdala cortex with whole slide scanning image analysis. Within the SUDEP group, seven had recent generalized seizures with recovery 24hours prior to death (SUDEP-R). Galanin, NPY, and SST LIs were significantly lower in all amygdala regions in SUDEP cases compared to epilepsy controls (P<.05 to P< .0005), and galanin LI was lower in the lateral nucleus compared to nonepilepsy controls (P<.05). There was no difference in the LI in the SUDEP-R group compared to other SUDEP. Higher LI was noted in epilepsy controls than nonepilepsy controls; this was significant for NPY in lateral and basal nuclei (P<.005 and P<.05). A reduction in galanin in the lateral nucleus in SUDEP could represent acute depletion, relevant to postictal amygdala dysfunction. In addition, increased amygdala neuropeptides in epilepsy controls support their seizure-induced modulation, which is relatively deficient in SUDEP; this could represent a vulnerability factor for amygdala dysfunction in the postictal period.

An institutional review of 10 cases of spinal hemangiopericytoma/solitary fibrous tumor.

Spinal hemangiopericytoma is very rare tumors with only a few case reports and one case series. We have treated ten patients between 2004 and 2017 and, thus, present a retrospective review of our patients with a focus on clinical presentation, radiological features, management, pathology, and outcome. Histopathological data were reviewed in all the cases and clinical and follow-up details were collected from data available in our department. There were five males and five females, including one pediatric patient. The mean age of the patients was 34.7 years (Range 12-52 years). Dorsal, cervical, and lumbar spine involvement were found in five, four, and one patient, respectively. Intradural extramedullary tumor was the most common tumor and all patients presented motor weaknesses. Gross total resection of the tumor was done in seven patients and six patients received postoperative radiotherapy. Histopathology showed anaplastic tumor in two cases with high MIB-1 labelling index. Most patients were positive for CD34, vimentin, mic-2, and bcl-2. While the seven patients who underwent gross total resection improved significantly and were self-ambulatory in the follow-up period, two patients who underwent subtotal resection expired due to tumor metastasis. Spinal hemangiopericytoma is a very rare tumor. We present a series of cases treated at our institute for the same. Gross total resection is the goal and radiotherapy should be given in case of residual tumor or high-grade tumors. Prognosis is good after gross total excision and functional recovery can be expected in most patients.

Gastric leiomyosarcoma: A common tumor in an uncommon location

A previously healthy 51-year-old female presented with gradually worsening, 10/10 non-radiating epigastric abdominal pain associated with nausea, bilious vomiting, and weight loss. Computed tomography (CT) of the abdomen with intravenous contrast showed a large 10.7 × 9.5 cm exophytic mass in the antrum/body of the stomach (Figure 1A). An upper endoscopic evaluation revealed a large fungating, infiltrative, and ulcerated mass in the gastric body (Figure 1B). Histopathology of the biopsied mass was notable for spindle cells with a fascicular pattern, moderate nuclear atypia, abundant eosinophilic cytoplasm, and numerous mitotic figures. Immunohistochemistry analysis revealed that the tumor was diffusely positive for smooth muscle actin (SMA) (Figure 2A), desmin (Figure 2B), and calponin (Figure 2C). Ki-67 stain (Figure 2D) showed a high labeling index of 60% indicating a high-grade leiomyosarcoma. There was a complete lack of reactivity with DOG-1 and CD-117 (c-KIT) which excluded the diagnosis of a gastrointestinal stromal tumor (GIST). No evidence of metastatic disease and no lymph node involvement were noted in the head, abdomen, or thorax on the respective CT scans which were done for staging. Due to the large size of the tumor, the patient was started on a neoadjuvant chemotherapy regimen consisting of doxorubicin, ifosfamide, and mesna to reduce tumor burden with a future plan for surgical excision.

SEL1L plays a major role in human malignant gliomas.

Suppressor of Lin‐12‐like (C. elegans) (SEL1L) participates in the endoplasmic reticulum‐associated protein degradation pathway, malignant transformation and stem cell biology. We explored the role of SEL1L in 110 adult gliomas, of different molecular subtype and grade, in relation to cell proliferation, stemness, glioma‐associated microglia/macrophages (GAMs), prognostic markers and clinical outcome. SEL1L protein expression was assessed by immunohistochemistry and Western blotting. Genetic and epigenetic alterations were detected by molecular genetics techniques. SEL1L was overexpressed in anaplastic gliomas (World Health Organization [WHO] grade III) and in glioblastoma (GB, WHO grade IV) with the highest labelling index (LI) in the latter. Immunoreactivity was significantly associated with histological grade (p = 0.002) and cell proliferation index Ki‐67/MIB‐1 (p = 0.0001). In GB, SEL1L co‐localised with stemness markers Nestin and Sox2. Endothelial cells and vascular pericytes of proliferative tumour blood vessels expressed SEL1L suggesting a role in tumour neo‐vasculature. GAMs consistently expressed SEL1L. SEL1L overexpression was significantly associated with TERT promoter mutations (p = 0.0001), EGFR gene amplification (p = 0.0013), LOH on 10q (p = 0.0012) but was mutually exclusive with IDH1/2 mutations (p = 0.0001). SEL1L immunoreactivity correlated with tumour progression and cell proliferation, conditioning poor patient survival and response to therapy. This study emphasises SEL1L as a potential biomarker for the most common subgroup of TERT mutant/EGFR amplified/IDH‐WT GBs.

Cribriform-Morular Variant of Papillary Thyroid Carcinoma Shows High Ki-67 Labeling Indices, despite Its Excellent Prognosis

Objective: This study aimed to demonstrate that the cribriform-morular variant (CMV) of papillary thyroid carcinoma (PTC) has high Ki-67 labeling indices, despite its excellent prognosis. Methods: We examined 21 CMV-PTCs and 5 conventional PTCs (C-PTCs) resected at Kuma Hospital between 2008 and 2018. All of the patients with CMV-PTC were women. Their ages ranged from 17 to 35 years, with a mean of 25.2 years. An immunohistochemical study using β-catenin, estrogen receptor (ER), and Ki-67 was performed. For apoptotic analysis, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining was performed. Results: All CMV-PTCs were encapsulated with thick fibrous connective tissue. Eleven and one CMV-PTCs exhibited capsular invasion and extrathyroidal invasion, respectively. Two patients showed regional nodal metastasis. The Ki-67 labeling index ranged from 4.8 to 36.4% (mean 15.2%). Apoptotic cells were counted, which showed 2–52 positive cells (mean 12.6) per 10 high-power fields. The Ki-67 labeling index was positively correlated with the apoptotic cell count (r = 0.48, p = 0.030). Ki-67 labeling indices of CMV-PTCs were significantly higher than those of C-PTCs (p = 0.0027). Ages and tumor sizes did not have significant correlations with Ki-67 labeling indices or apoptotic cell counts. Conclusion: This study is the first to demonstrate disproportionally high Ki-67 labeling indexes in a large number of CMV-PTC cases, despite the fact that these cases had favorable prognoses. The favorable prognosis of CMV-PTC may be attributable to encapsulation and nuclear ER expression.

Gastric leiomyosarcoma in a 3-year-old boy

Abstract A 3-year-old boy presented with anemia and a palpable abdominal tumor. The operative finding was a 10.5×9.6×4.6-cm tumor that infiltrated the anterior wall of the stomach. Local excision was performed. The tumor was histopathologically diagnosed as leiomyosarcoma with immunoreactivity for alpha-smooth muscle actin and muscle actin, but not for CD34, c-kit, and S-100. The tumor was characterized as highly malignant because of its size, high mitotic count, nuclear atypia, and high MIB-1 labeling index. After 6 months of follow-up, recurrence developed in the remnant stomach and liver metastasis was observed. Partial gastrectomy and lateral segment resection of the liver were performed. Subsequently, multiple recurrences in the remnant liver and peritoneal dissemination occurred. The patient underwent follow-up without adjuvant therapy and was well for more than 10 years after liver metastases and peritoneal dissemination after the initial surgery. This case represents the different biological behavior of pediatric gastrointestinal leiomyosarcoma compared to adult gastrointestinal leiomyosarcoma.

The dilemma of extensive unilocular radiolucent lesions of the jaws - value of immunohistochemistry as a diagnostic marker and prognostic Indicator

IntroductionLarge Unilocular radiolucent lesions of the jaws often present a dilemma to both, the Oral Pathologist and the Maxillofacial surgeon with regards to their accurate diagnosis as well as their most appropriate treatment modality. A precise identification as to whether the lesion is a cyst or a tumor is imperative before any treatment is instituted. Once the correct diagnosis and likely prognosis are established, a management protocol can be planned which will completely eliminate the lesion, while at the same time, ensure least possible morbidity for the patient, such as pathological jaw fractures, persisting neurological deficits, esthetic deformity, functional debility, recurrence/persistence of the lesion, etc. Aim & objectivesTo establish the value of Immunohistochemistry (IH) as a Diagnostic marker and Prognostic indicator for extensive Unilocular radiolucent lesions of the jaws. To assess its role as an adjunct to Histopathological Examination (HPE) in distinguishing Odontogenic tumours from the cysts, by identifying the former using IH Tumor Markers; and in aiding in selection of the most appropriate and effective treatment option for each of such ambiguous lesions, based on their prognosis as indicated by the expression of lH Cell Proliferation Markers. Materials and methodThirty cases of large Unilocular Radiolucent lesions of the jaws (Maxilla/Mandible) were managed over a period of three years. Histopathological examination (HPE) and Immunohistochemical (IH) analysis were carried out of the biopsy specimens in all the cases. Calretinin, an Immunohistochemical Tumor marker, was used to distinguish between Odontogenic cysts and tumours. Ki-67 and Proliferating Cell Nuclear Antigen (PCNA), Immunohistochemical Cell Proliferation markers, provided information on the aggressive potential of the lesions.On the basis of the above information, an appropriate management protocol was established for each of these different lesions. Nerve sparing enucleation and curettage was employed for the established cases of Odontogenic Cysts; Enucleation and curettage, peripheral ostectomy, followed by chemical cauterization was employed for the Unicystic Ameloblastomas and other Odontogenic tumours with a low Ki-67 and PCNA Proliferation Index (PI)/Labelling index (LI ≤ 3); Marginal resection was carried out for the tumours with a higher Labelling Index (LI >3 ≤5), and Segmental resection (including partial/complete Maxillectomy, Hemimandibulectomy with/without disarticulation) for the aggressive pathologies with high Labelling Index (LI > 5). ResultsOf the thirty cases of large Unilocular radiolucent lesions of the Maxilla and Mandible, thirteen were diagnosed as Dentigerous cysts, one as Dentigerous cyst showing Ameloblastomatous transformation; two as Unicystic Ameloblastomas, one as the Mural variant of Unicystic Ameloblastoma; four as Follicular Ameloblastomas, two as Plexiform Ameloblastomas; four as Acanthomatous Ameloblastomas; one as Ameloblastic Fibroma and two as Adenomatoid Odontogenic Tumours. The predictive and prognostic indication of the Immunohistochemical markers correlated well with the post treatment findings. ConclusionIn cases of extensive Unilocular lesions of the jaws, where ambiguity often exists in both diagnosis and appropriate treatment plan to be employed, Immunohistochemistry can serve as an invaluable tool in establishing the precise diagnosis, guiding the treatment plan, as well as indicating the likely prognosis of these lesions.

SAT-478 Successful Management of an Atypical Prolactinoma with Radiotherapy

INTRODUCTION: Prolactinomas are the most common pituitary adenoma and are usually slow growing tumors with a good response to medical therapy with dopamine agonists. Atypical adenomas are a variant, defined by invasive growth, high Ki-67/MIB-1 proliferative index, and high p53. These tumors are often recurrent and difficult to treat with standard therapy and surgery. The objective of this case is highlight successful treatment of an atypical aggressive prolactinoma with radiotherapy. CASE: A 63 year-old male initially presented with rapid development of visual defects and headache. He was found to have a prolactin-secreting pituitary macrodenoma with upward displacement of the optic chiasm, and bitemporal hemianopsia on formal visual field testing. He underwent transphenoidal resection of the tumor. Despite treatment on cabergoline patient had increasing prolactin levels, peripheral vision loss, and recurrence on imaging requiring a second surgery. Pathology consistent with an atypical prolactinoma with increased nuclear pleomorphism (increased mitoses up to 2 mitoses/10 HPF), high proliferation labeling index using Ki67 (11%). Despite carbergoline (up to 8mg/week), prolactin continued to rise (>4700 ng/mL) and developed severe compression of the optic chiasm leading to a third surgical resection. He was initiated on pasireotide but within 6 weeks had continued growth of tumor. Adjunctive radiotherapy was decided to be the best option, as patient was resistant to further surgical interventions. Fractionated radiation therapy was given, opposed to stereotactic given the proximity to the optic apparatus. He completed radiation therapy with 5040 cGy and has had a marked response. His prolactin continues to trend down, MRI with interval decrease in size, and visual field testing with improvement clinically. CONCLUSION: This case highlights the aggressive nature of these tumors, and resistance to therapy. Labeling of Ki67 have been demonstrated to correspond with the rate of invasive growth, and aggressive behavior. Despite prolactinomas having previously been described as poor responders to fractionated radiation therapy with variable success rates, this is an option that should be considered in those who have failed multiple other treatment modalities.

The Analysis of Cell Cycle-related Proteins in Ovarian Clear Cell Carcinoma Versus High-grade Serous Carcinoma.

In Japan, the frequency of ovarian clear cell carcinoma (CCC) is twice as high as that in the United States and Europe. Often, patient prognosis with CCC is poor because of chemoresistance. Here, we focus on the cell cycle, which is one of the mechanisms of chemoresistance. To detect the informative markers and improve the strategy of chemotherapy for CCC, we performed immunohistochemical staining of cell cycle-related proteins in ovarian malignant tumors. We detected that each of the 29 samples of CCC and high-grade serous carcinoma (HGSC) were necessary to reveal the significant differences in immunostaining and prognosis. We performed the immunostaining analysis using the antibodies of cell cycle-related proteins such as Ki-67, Cdt1, MCM7, and geminin. The positive rate of Cdt1 in the CCC group was significantly higher than that in the HGSC group (P<0.0001). However, the positive rate of geminin in the HGSC group was significantly higher than that in the CCC group (P<0.0001). The overall survival of CCC patients with high labeling index of Cdt1 was significantly worse than that of CCC patients with low labeling index of Cdt1 (P=0.004). The study results suggested that the cancer cells of CCC and HGSC exist in the G1 phase and S, G2, and M phases, respectively. The differences in cell cycle of CCC might be one of the reasons for chemotherapy resistance. Further investigations are necessary to reveal the usefulness of Cdt1 as a biomarker in CCC.