Ki-67 Labeling Index Research Articles

A phase III study of combination therapy with everolimus plus lanreotide versus everolimus monotherapy for unresectable or recurrent gastroenteropancreatic neuroendocrine tumor (JCOG1901, STARTER-NET).

652 Background: There is limited evidence regarding the benefit of adding somatostatin analogs to molecular targeted agents for well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs). This phase III trial was conducted to compare everolimus plus lanreotide (EVE/LAN) with everolimus monotherapy (EVE) in patients with unresectable or recurrent GEP-NETs in the first-line setting. Methods: Patients with grade 1 or grade 2, nonfunctioning GEP-NETs with poor prognostic factors (Ki-67 labeling index (LI) 5-20% or diffuse liver metastases) were randomly assigned (1:1) to EVE (10 mg/day) or EVE/LAN (EVE + LAN 120 mg every 28 days). The primary endpoint was progression-free survival (PFS). The key secondary endpoint was overall survival (OS), and other secondary endpoints were objective response rate (ORR), disease control rate (DCR), and safety. The study was based on the hypothesis of an assumed median PFS of 11.0 months for EVE, expecting a 4-month improvement by EVE/LAN (HR: 0.73). The planned sample size was 250, requiring 195 events overall with a one-sided alpha level of 5%, a power of 70%, an accrual period of 5 years, and a follow-up period of 1.5 years. Results: Between April 2020 and June 2024, a total of 178 patients were enrolled, and the planned interim analysis was conducted in 145 patients (72 in the EVE and 73 in the EVE/LAN) in June 2024 with a data cut-off date of Nov 2023. The median PFS was 11.5 months in the EVE arm and 29.7 months in the EVE/LAN arm (HR 0.38 [99.91% CI 0.15–0.96], P = 0.00017 < the prespecified significance level of 0.00046, by the stratified log-rank test). The HR for OS was 0.97 (95% CI: 0.24-3.90). The ORR and DCR were 8.7% (6/69) and 87.0% (60/69) in the EVE arm and 26.8% (19/71) and 91.5% (65/71) in the EVE/LAN arm, respectively. Both hematologic and non-hematologic toxicities tended to be more frequent in the EVE/LAN arm than in the EVE arm. No treatment-related deaths were observed in either arm. Based on the efficacy results, the Data and Safety Monitoring Committee recommended early termination of the study. Conclusions: The EVE/LAN provides statistically significant prolongation of PFS compared with EVE monotherapy, and the safety profile of EVE/LAN was manageable. The EVE/LAN might be a new standard treatment in the first-line setting for well-differentiated grade 1/2 GEP-NETs with poor prognostic factors. Clinical trial information: jRCT1031200023.

P-04 A PATIENT WITH A GIANT ADRENAL MASS DETECTED DURING PREGNANCY

Abstract Introduction Although the frequency of adrenal incidentalomas is increasing, they are rarely detected due to lack of imaging during pregnancy. Here, we present a case of adrenal incidentaloma diagnosed during pregnancy. Clinical Case A 32-year-old female patient was diagnosed with a mass in the liver during obstetric ultrasonography performed in the 4th month of pregnancy and was referred to gastroenterology clinic for further examination, but any additional intervention could not be made because of patient’s refusion. She underwent an emergent caesarean section at 36th weeks of pregnancy. A mass approximately 15 cm in size, thought to be of adrenal origin, was detected in the retroperitoneal area posterior to the liver at the surgery. Abdominal MRI revealed a 188*121*113 mm non-adenomatous lesion, at right adrenal gland, containing cystic necrotic areas, and not suppressed in fat-suppressed series (figure 1A). At initial assesment by endocrinology, the patient denied any paroxysmal or persistent hypertension, weakness, weight gain and hirsutism. Physical examination was found normal, no signs of Cushing’s syndrome was observed. Laboratory testing including 24-hour urine catecholamines, basal cortisol, dehydroepiandrosterone sulfate (DHEA-S), adrenocorticotropic hormone (ACTH) were in reference ranges. The cortisol levels were supressed following the low-dose dexamethasone test. Adrenal carcinoma was suspected based to radiological features of the lesion. FDG uptake of the mass with a SUVmax: 16.9 was reported at PET-scan (figure 1B). Laparotomy for right adrenal gland was planned, but the patient disapproved once again. She underwent to adrenalectomy 18 months later after the mass was detected. Surprisingly, the pathology resulted as adrenocortical adenoma. Ki67 labeling index was found to be 3-4%, immunohistochemical staining of tissue specimens showed that synaptophysin and chromogranin A negative ( - ), but CD56 positive (++). The patient was lost for approximately 1 year and then aplied to our clinic with another unplanned pregnancy. She is doing well at the 32nd week of her second pregnancy. Conclusion Large and non-adenomatous masses detected during pregnancy are likely to be malignant and these masses are usually known with poor-prognosis. Rarely, as seen in our patient, huge adrenal masses may exhibit a benign behavior compatible with an uncomplicated long process despite suspicious radiological imaging features.Figure 1A:Abdominal MRI revealed a 188*121*113 mm non-adenomatous lesion, at right adrenal gland containing cystic necrotic areas. B:Increased uptake of FDG in the right adrenal region (SUVmax: 16.9)

Evaluation of Ki67 in pathological prognostic staging of breast cancer: a tertiary care center study

ABSTRACT Background The rising global burden of breast cancer demands early detection and effective treatment, with a focus on prognostic and predictive markers. The eighth edition of the American Joint Committee on Cancer staging manual introduced a new prognostic staging system to increase the predictive power of the existing anatomical staging system of breast cancer. The current study aimed to establish the correlation between Ki67 expression with molecular subtypes and with the pathological prognostic stage of invasive ductal carcinoma. Materials and Methods A total of 40 patients were included in the study with samples from 32 modified radical mastectomies and 8 biopsies. Hematoxylin and Eosin staining, histopathological analysis and Ki67 immunostaining were conducted. Descriptive and inferential statistical analyses were performed. Results Bloom Richardson Grade II was the predominant histological grade. In Grade II cases, 15 of 24 had a Ki67 labeling index of 26–45%, while 6 exceeded 45% (p = 0.001). Pathological prognostic staging reclassified 27 cases, with 24 (75%) downstaged, 3 (9.38%) upstaged, and 5 (15.63%) retaining their clinical stage. Conclusions Ki67 immunohistochemistry is an effective tool for assessing proliferative activity of invasive ductal carcinoma, aiding in pathological prognostic stage stratification and offering insights into tumor biology.

High correlation between Ki-67 expression and a novel perfusion MRI biomarker diffusion-derived vessel density (DDVD) in endometrial carcinoma.

This study aimed to investigate the feasibility of diffusion-derived vessel density (DDVD) in characterizing tumor microvasculature in endometrial carcinoma (EC), and to explore the correlations with Ki-67 proliferation status and histological type based on DDVD values. There were in total 81 EC patients. There were 64 cases of non-aggressive histological type, and 17 cases of aggressive histological type. Ki-67 labeling index was low (<50%) in 35 cases and high (≥50%) in 46 cases. DDVD(b0b20) is calculated according to: DDVD(b0b20)=Sb0/ROIarea0 - Sb20/ROIarea20, where Sb0 and Sb20 refer to the tissue signal when b is 0 or 20s/mm2. Intraclass correlation coefficient (ICC); two-tailed independent samples t-test and Mann-Whitney U test, and Receiver operating characteristic area under the curve (AUC) were applied for statistical analysis. Endometrial carcinoma showed lower DDVD(b0b20) values (34.9±21.2, au/pixel) compared with myometrium (65.3±37.4, P<0.001). Tumors with Ki-67 high-proliferation or aggressive histological type had higher DDVD values than those with Ki-67 low-proliferation (44.17 (median) vs. 16.08, P<0.001]] or non-aggressive histological type (47.92 vs. 30.77, P=0.002). DDVD(b0b20) ROC curve analysis shows AUC of 0.842 for distinguishing between Ki-67 low- and high-expression, and AUC of 0.771 for distinguishing between non-aggressive and aggressive histological types. DDVD(b0b20)>32.9 and DDVD(b0b20)>50.1 provided a specificity of 85% for identifying Ki67 high expression (sensitivity 78.3%) and histological aggressive type (sensitivity 47.1%), respectively. DDVD can act as an imaging marker reflecting Ki-67 proliferation and histological aggressiveness of EC, thus helping pretreatment risk assessment in EC.

Immunophenotype of uterine tumor resembling ovarian sex cord tumor (UTROSCT): Case series and meta-analysis of the literature.

This study aimed to define the frequency of positivity of several immunohistochemical markers in uterine tumor resembling ovarian sex cord tumor (UTROSCT). All consecutive UTROSCT cases were retrieved from consultation files of one of the authors. Histological and immunohistochemical slides were reviewed. In addition, three electronic databases were searched from their inception to January 2024 for all studies assessing the immunophenotype of UTROSCT. Exclusion criteria were: sample size < 10 patients, overlapping patient data, reviews. Endometrial stromal tumors with sex cord-like areas (formerly called "type I UTROSCT") were excluded. Immunohistochemical markers assessed in ≥ 10 cases in at least 3 different series were included. For each marker, pooled positivity rate was calculated by using a random effect model; mean labeling index was calculated for Ki67. Thirty UTROSCT cases were retrieved Six studies were included, and 30 new cases were obtained, with a total of 181 UTROSCTs. Fourteen immunohistochemical markers were assessed. Pooled positivity rates were (in descending order): CD56 = 97 %, progesterone receptor = 91 %, estrogen receptor = 85.5 %, WT1 = 84 %, wide-spectrum cytokeratins = 78.7 %, CD99 = 77 %, desmin = 74.5 %, calretinin = 70.6 %, smooth muscle actin = 56.4 %, inhibin = 44.5 %, CD10 = 41 %, caldesmon = 21.9 %, Melan-A/MART-1 = 10.4 %. Mean Ki67 labeling index was 8.7 %. Immunophenotypically, UTROSCT is less consistent than ovarian sex cord tumors and overlaps with other mesenchymal and epithelial tumors; an integrated clinico-pathological and immunohistochemical evaluation appears necessary for a correct diagnosis.

Appendiceal Neuroendocrine Tumor: Clinicopathologic Characteristics of Six Cases and Review of the Literature.

Appendiceal neuroendocrine tumors (ANETs) are the most prevalent type of appendiceal neoplasm and the fifth most common neuroendocrine tumor in the gastrointestinal tract. In this study, we described the clinicopathological features of patients with ANET. We reviewed the clinicopathological findings and histopathological reports of six patients diagnosed with ANET between January 2014 and December 2023 at Korea University Medical Center, Anam Hospital. Six cases, comprising three males and three females, were diagnosed during procedures for lower abdominal pain or other medical reasons. Most tumors were less than 1 cm in size and located at the tip of the appendix. One patient had a large tumor (4.1 cm) with lymph node metastasis. Four tumors extended to the muscularis propria, whereas two infiltrated the subserosal soft tissue. The tumor cells exhibited a typical trabecular and nested pattern with monotonous round or oval nuclei. All patients had a mitotic count of less than 2 per 10 high-power fields and a Ki-67 labeling index of less than 1%, classifying them as having G1 well-differentiated tumors. Immunohistochemical staining showed that all cases were positive for CD56 and synaptophysin, and four were positive for chromogranin A. No recurrence or distant metastasis was observed during follow-up. ANETs are relatively uncommon and mostly benign in terms of prognosis. Because of their malignant potential, meticulous examination of appendectomy specimens is warranted to identify the presence of ANETs.

Distribution and clinicopathological characteristics of G-CSF expression in tumor cells and stromal cells in upper tract urothelial carcinoma

Abstract Background Urothelial carcinoma (UC) is a common type of malignant disease; however, the diagnostic and prognostic markers of upper urinary tract urothelial cancer (UTUC) remain poorly understood because of its rarity. Methods To clarify the clinicopathological significance of granulocyte-colony stimulating factor (G-CSF) in UTUC, we analyzed the expression and distribution of G-CSF in 112 upper tract urothelial carcinoma (UTUC) samples with immunohistochemistry. Results In normal urothelium, G-CSF expression was weak or absent, whereas high expression of G-CSF was observed in UTUC tissues, both in tumor cells (TCs) and stromal cells (SCs). G-CSF expression in the TCs and SCs was associated with nodular/flat morphology, high grade, advanced T stage, and lymphovascular invasion in UTUC. G-CSF expression in SCs was associated with poor prognosis and was an independent prognostic factor. Public data showed that G-CSF expression was also associated with decreased progression-free survival and disease-specific survival. A prognostic model was constructed by incorporating the presence or absence of G-CSF expression along with clinicopathologic factors, which allowed for a more accurate prediction of poor prognosis. We further showed that G-CSF expression was associated with a high Ki-67 labeling index and with PD-L1, HER2, and p53 expression in UTUC. Conclusion G-CSF expression in TCs and SCs may play a crucial role in UTUC tumor progression. Notably, stromal G-CSF expression showed significant prognostic value, even when compared to major clinicopathological factors, suggesting that the evaluation of G-CSF expression may contribute to clinical decision-making in patients with UTUC.

Small cell lung carcinoma metastatic to the stomach: Commonly overlooked, limited treatment options.

Small cell lung carcinoma metastatic to the stomach, whether synchronous or metachronous, is a rare phenomenon accounting for < 0.5% of lung cancers. Hence it can be overlooked by clinicians resulting in delayed diagnosis. This manuscript comments on Yang et al's article which reported 3 such cases. The main diagnostic features are based on routine morphology comprised of small cells with hyperchromatic nuclei, scant cytoplasm, brisk mitoses and necrosis. This can be supplemented by immunohistochemistry demonstrating positivity for cytokeratin, thyroid transcription factor-1 and neuroendocrine markers as well as a high Ki-67 labelling index. Imaging modalities such as positron emission tomography/contrast computed tomography help to confirm lung origin and rule out the possibility of extra-pulmonary small cell carcinoma. The predominant mechanism of spread is most likely hematogeneous. Prognosis is generally poor since this represents stage 4 disease but survival can be improved by chemo/radiotherapy and palliative surgery in select cases. Though outcomes have not changed much in the last several decades, the recent Food and Drug Administration approval of immune checkpoint inhibitors was a significant milestone as was the delineation of small cell lung carcinoma molecular subtypes. Liquid biopsies are increasingly being used for biomarker studies in clinical trials to assess treatment response and prognosis.

Significance and limitations of routine p16/Ki-67 immunohistochemistry as a diagnostic tool for high-grade squamous intraepithelial lesions of the uterine cervix.

To evaluate the diagnostic utility and limitations of routine p16 and Ki-67 immunohistochemistry (IHC) in detecting high-grade squamous intraepithelial lesions (HSILs) in the uterine cervix. We reviewed 2,061 cervical biopsy records, including 271 morphologically indeterminate squamous lesions, evaluated using p16/Ki-67 IHC for HSIL detection or exclusion. HSIL was diagnosed based on p16 positivity and a high Ki-67 labeling index (Ki-LI). In cases that remained inconclusive after IHC, follow-up histological and/or cytological outcomes were assessed. p16/Ki-67 IHC established a definitive diagnosis of either HSIL or non-HSIL in 74.2% (201/271) of morphologically indeterminate cases, whereas 25.8% (70/271) remained inconclusive. p16/Ki-67 IHC contributed to the diagnosis of HSIL in 120 cases, representing 11.9% (120/1,011) of all HSILs cases and 44.3% (120/271) of morphologically indeterminate cases. Among the 70 inconclusive cases, 58 had available follow-up data, of which 22 were subsequently diagnosed with HSIL, including 12 within 1 month of the initial biopsy. HSIL outcomes were more frequent in cases with suspicious HSIL on the initial biopsy (66.7 [12/18]). Based on the p16/Ki-LI status, patients with HSIL outcomes were categorized into three groups: p16-positive/low Ki-LI (54.2 [13/24]), p16-negative/high Ki-LI (50.0 [5/10]), and p16-negative/low Ki-LI (16.7 [4/24]). Multiple comparisons revealed a significant difference between the p16-positive/low Ki-LI and p16-negative/low Ki-LI groups (Benjamini-Yekutieli adjusted P=0.0435), whereas no significant difference was found between other groups. IHC using p16/Ki-67 significantly improved the diagnostic performance for HSIL. In cases that remain inconclusive after IHC, IHC-based risk stratification offers a valuable approach for surveillance, thus mitigating delays in HSIL diagnosis.

Elevated expression of REV7 correlates with poor prognosis in lung adenocarcinoma and its inactivation in carcinoma cells enhances chemosensitivity.

REV7 is a multifunctional protein involved in the DNA damage response, cell cycle regulation, gene expression, or primordial germ cell maintenance. REV7 expression in tumor cells is associated with clinical aggressive features and chemoresistance in several human malignancies, however, the clinicopathological significance of REV7 in lung adenocarcinoma (LUAD) has not been studied yet. In this study, we investigated the significance of REV7 expression in LUAD using clinical materials and cell lines. REV7 expression in 142 invasive LUADs were determined using immunohistochemistry, and the relationship between REV7 expression and clinicopathological features was analyzed. High levels of REV7 expression in tumor tissues were positively associated with progressive tumor behavior as assessed by Ki-67 labeling indexes (p < 0.001), maximum standardized uptake values on positron emission tomography (p = 0.005), pathological stage (p = 0.031), N factor (p = 0.048), recurrence (p = 0.038), and disease-specific death (p = 0.020). The REV7-high-expression group showed poorer relapse-free survival (RFS) (p = 0.025) and overall survival (OS) (p = 0.019) compared to the REV7-low-expression group, and REV7 was a significant prognostic factor for RFS and OS. CRISPR/Cas9-mediated REV7-knockout and siRNA-mediated REV7 knockdown were carried out using the LUAD cell lines A549 and H1975, respectively, and it was demonstrated that REV7 inactivation led to slower cell growth, attenuated activation of AKT signaling, and enhanced chemosensitivity compared with control cells. These results suggest that REV7 is a potential predictive biomarker for poor prognosis in invasive LUAD and a possible molecular target for LUAD management.

Syringocystadenocarcinoma of the perianal region: a case report

IntroductionSyringocystadenocarcinoma papilliferum is an extremely rare malignant adnexal tumor that typically arises from a papilliferous syringocystadenoma (World Health Organization classification of skin tumors, 2018.). This tumor predominantly occurs in the cephalic region.Case presentationWe present the case of a 68-year-old Moroccan male with no significant medical history who presented with a slowly progressing skin mass in the perianal region. Despite the chronic nature of the swelling, the patient remained in overall good health. Physical examination revealed a firm 2.3-cm mass in the perianal area, with no other remarkable findings. The patient underwent surgical excision of the mass. Macroscopic examination showed a solid-cystic, rounded mass. Microscopic examination revealed a malignant adnexal tumor with apocrine differentiation and papillary architecture. Immunohistochemistry was positive for p63, cytokeratin 7 (CK7), and smooth muscle actin, with a Ki67 labeling index in 60% of tumor cells, and negative for p16. The diagnosis of syringocystadenocarcinoma papilliferum was confirmed. A further surgical resection was performed, and the patient’s postoperative course was unremarkable.ConclusionSyringocystadenocarcinoma papilliferum is an extremely rare tumor, with its occurrence in the perianal region being particularly uncommon. This case contributes to the limited literature on this malignancy, highlighting its clinical and pathological features.

Correlation of dynamic contrast-enhanced ultrasonography and the Ki-67 labelling index in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant and aggressive tumor, and high Ki-67 expression indicates poor histological differentiation and prognosis. Therefore, one of the challenges in diagnosing preoperatively patients with PDAC is predicting the degree of malignancy. Dynamic contrast-enhanced ultrasonography (DCE-US) plays a crucial role in abdominal tumor diagnosis, and can adequately show the microvascular composition within the tumors. However, the relationship between DCE-US and the Ki-67 labelling index remains unclear at the present time. To predict the correlation between Ki-67 expression and the parameters of DCE-US. Patients with PDAC who underwent DCE-US were retrospectively analyzed. Patients who had received any treatment (radiotherapy or chemotherapy) prior to DCE-US; had incomplete clinical, imaging, or pathologic information; and had poor-quality image analysis were excluded. Correlations between Ki-67 expression and the parameters of DCE-US in patients with PDAC were assessed using Spearman's rank correlation analysis. The diagnostic performances of these parameters in high Ki-67 expression group were evaluated according to receiver operating characteristic curve. Based on the Ki-67 labelling index, 30 patients were divided into two groups, i.e., the high expression group and the low expression group. Among the relative quantitative parameters between the two groups, relative half-decrease time (rHDT), relative peak enhancement, relative wash-in perfusion index and relative wash-in rate were significantly different between two groups (P = 0.018, P = 0.025, P = 0.028, P = 0.035, respectively). The DCE-US parameter rHDT was moderately correlated with Ki-67 expression, and rHDT ≥ 1.07 was more helpful in accurately diagnosing high Ki-67 expression, exhibiting a sensitivity and specificity of 53.8% and 94.1%, respectively. One parameter of DCE-US, rHDT, correlates with high Ki-67 expression. It demonstrates that parameters obtained noninvasively by DCE-US could better predict Ki-67 expression in PDAC preoperatively.

ROLE OF H3K27me3 AND Ki67 LABELLING INDEX IN ASSESSING THE BIOLOGICAL BEHAVIOUR OF MENINGIOMAS

Meningiomas are non-malignant neoplasms primarily originating from arachnoid cells and are classified into three grades [1, 2, and 3] based on histological features according to the WHO classification. However, this classification system is imperfect especially for grade 1 and 2 meningiomas as many grade 1 tumors recur. Meningiomas are hence a histologically diverse class of tumors exhibiting more unpredictable behaviour. Therefore, more improved classification is required, possibly using novel and more dependable biomarkers. In this study, we aim to investigate the role of the H3K27me3 and Ki67 labelling index in assessing the biological behaviour of meningiomas. The study was conceived, with the primary objective of examining the expression of H3k27me3 and Ki67 labelling index in grade 1/2 meningiomas with atypical features to ascertain if this potentially impacts patient prognosis. Upon obtaining clearance from the Institutional Ethical Committee (IEC), the authors studied 81 cases of meningiomas including 11 recurrent cases. The study used immunohistochemistry to evaluate the Ki67 index and H3K27me3 immunohistochemistry. The Ki67 labelling Index was determined by counting the positively stained MIB-1 cells and categorizing them into <5%, 5-10% and > 10%. The H3k27me3 staining was evaluated by finding the product of the tumor cells showing positive staining and the intensity of staining. Based on the product of the two, the cases were subdivided into Negative [0], Low [1-4] and high expression [5-9] of H3K27me3. The results showed that presence of atypical morphological features including necrosis and prominent nucleoli in grade 1 meningioma and low expression of H3K27me3 was significantly associated with higher grade, recurrence, and shorter progression-free survival (Kaplan Meier curves showed higher negative slope). The study also found that a higher Ki67 labelling Index was associated with recurrence and poor prognosis. This suggest that the H3K27me3 and Ki67 labelling Index can be useful prognostic markers in meningiomas, particularly in challenging grade 1 and 2 cases and recurrent meningiomas. The study highlights the importance of the H3K27me3 and Ki67 Labelling Index in assessing the biological behaviour of meningiomas. The findings provide valuable insights into the prognosis and treatment of meningiomas, emphasizing the need for further research to validate these markers and develop targeted therapeutic strategies.

Multilineage Pituitary Neuroendocrine Tumors Expressing TPIT and SF1: A Clinicopathological Series of Six Tumors.

Tumors of adenohypophysial hormone-secreting cells, now classified as pituitary neuroendocrine tumors (PitNETs), have been subclassified based on cell differentiation. Normal adenohypophysial cells have three lineages of differentiation driven by the transcription factors PIT1, TPIT, and SF1 which are responsible for the regulation of hormone gene expression; PIT1 drives expression of GH, PRL, and TSH, TPIT is required for POMC expression that gives rise to ACTH, and SF1 is the transcription factor responsible for FSH and LH expression. The vast majority of PitNETs follow these three lineage differentiation pathways but rare PitNETs show either no lineage differentiation or express biomarkers of more than one lineage. The recent WHO classification continued the terminology "plurihormonal" for tumors that have features of more than one lineage but a better term is "multilineage" since some tumors may express more than one lineage-specific transcription factor without the hormones that are driven by those factors. Recent data indicate that tumors with expression of PIT1 and SF1 are the most common multilineage PitNETs. Here we report the existence of rare PitNETs that express TPIT and SF1. The 6 patients (5 female, 1 male; mean age 54.8years; range 35-84years) represent less than 1% of patients in our series of PitNETs. Most patients had clinically silent tumors with no evidence of hormone excess and variable degrees of hypopituitarism; two had Cushing disease. All patients had macrotumors with a mean tumor size of 2.46cm (range 1.1-5.0cm). Crooke's hyaline change was identified in the nontumorous adenohypophysis of the two patients with Cushing disease. The mean Ki67 labeling index was 2.91% (range 2.03-3.94%). All tumors were negative for PIT1 and PIT1-lineage hormones (GH, PRL, and TSH). TPIT was focal in one tumor, and the remaining tumors had diffuse reactivity in more than 50% of tumor cells. SF1 expression was focal in 5 tumors and diffuse in one. Three tumors had variable expression of at least one gonadotropin (FSH or LH). GATA3 was expressed in two tumors. Variable ER-alpha expression was noted in three tumors. CAM5.2 was positive in all tumors. With the exception of two tumors causing Cushing disease, p27 expression was intact. Our study confirms that multilineage PitNETs expressing TPIT and SF1 occur but are extremely rare; they can be clinically non-functional or can cause Cushing disease. Irrespective of functional status of a PitNET, routine application of pituitary transcription factors is warranted to identify these tumors. Data on the molecular correlates and clinical significance are still needed for these rare multilineage PitNETs.

SURG-50. CLINICAL EXPERIENCE AND PATHOLOGICAL FEATURES IN AUTOPSY CASES TREATED WITH TUMOR TREATING FIELDS

Abstract BACKGROUND Since 2017 Tumor Treating Fields (TTF) was approved for primary glioblastoma in Japan. In this study, we reviewed clinical experience and the pathological characteristics of autopsy cases treated with TTF. METHODS From March 2018 to April 2022, 67 patients (36 males and 31 females, median age 68 years) with primary glioblastoma, IDH-wild type treated at our institution were included in the analysis. RESULTS Twenty-eight patients (19 males and 9 females, median age 66 years) met the TTF indication criteria for induction, 19 cases (67.9%) were 65 years or older, and 14 cases (50.0%) indicated MGMT promoter methylation. The mean duration of TTF treatment was 7.2 months. The main reasons for discontinuation were tumor recurrence in 11 patients (40.7%), skin symptoms in 8 patients (29.6%), and psychological distress in 6 patients (22.2%). Only 12 patients (42.9%) underwent TTF treatment over 18 hours per day, because of discomfort of wearing pad and concern about srrounding. Median PFS and OS in the used patients were 9.9 and 17.7 months, respectively. Autopsies were performed in 3 of the 16 deaths. Histopathological examination of tumor specimen indicate that the Ki-67 labeling index was higher in brainstem (33.6%) than in the supratentorial primary lesion (23.6%). DISCUSSION Comparing to the previous report (Stupp R et al., JAMA. 2017), our cases contained a large number of patients over 65 years old with shorter mean duration of TTF treatment, and shorter OS. After TTF treatment, the Ki-67 labeling index was higher on infratentorial than on supratentorial in the autopsy specimens, suggesting the anti-tumor effect of TTF for the supratentorial lesion. RESULTS High proliferative activity of infratentrial lesion was suggested as a typical form of progression for TTF treatment.

EXTH-81. A RARE CASE OF RELENTLESSLY PROGRESSIVE METASTATIC PINEOCYTOMA MANAGED WITH SEQUENTIAL MULTIMODAL THERAPY

Abstract BACKGROUND Pineocytoma is a rare pineal parenchymal WHO grade 1 tumor, typically well-managed with surgical resection alone. With gross total resection (GTR), 91% 1-year and 84% 5-year survival rates have been reported. Recurrent pineocytoma is rare and optimal management in that setting is unknown, in part owing to the rarity of the condition. METHODS We report an atypical course of pineocytoma in a 58-year-old male involving metastatic disease. RESULTS A pineal mass was identified upon MRI of the brain obtained for vision changes. Patient underwent GTR, pathology was consistent with pineocytoma, WHO grade 1. Ki-67 labeling index was low at 1-2%. Despite low-grade pathology, two years later, surveillance imaging demonstrated recurrence in the pineal region and a second lesion in the right thalamus. The patient underwent gamma knife surgery (GKRS) to both lesions. Three years later, he developed three new lesions in the right cerebellum and again underwent GKRS. Subsequent surveillance imaging identified new lesions in the right cerebellum and along ventricular walls, treated with further GKRS. Nine years after initial diagnosis, focal nodular leptomeningeal metastases were discovered, along with progression at the primary tumor site. Patient was treated with GKRS to the nodular deposits followed by pembrolizumab. Further disease progression as noted despite immunotherapy. Patient was treated with 6 cycles of temozolomide chemotherapy and at further progression 3 cycles of lomustine. Upon additional progression, further radiation therapy was administered with bevacizumab to reduce risk of radiation necrosis. Patient remains on surveillance 13 years after initial diagnosis with visual changes and mild headache representing only clinical issues. CONCLUSIONS Although exceedingly rare, pineocytoma is capable of metastasizing to brain parenchyma and the leptomeninges, as demonstrated in our patient. However, our case demonstrates prolonged survival is possible even in the setting of relentlessly progressive metastatic disease with utilization of multimodality treatment.

Association Between Gross Features and Coexistence of BRAFV600E and TERT Promoter Mutations in Papillary Thyroid Carcinomas: A Combined Analysis Incorporating Clinicopathologic Features.

Background: The coexistence of v-Raf murine sarcoma viral oncogene homolog B1 (BRAFV600E) and telomere reverse transcriptase promoter (TERT-p) mutations is considerably associated with aggressiveness and poor prognosis in papillary thyroid carcinoma (PTC). However, the association between gross findings and genetic alterations in PTC remains unknown. We aimed to investigate the association between clinicopathologic features, including macroscopic features, and the coexistent BRAFV600E and TERT-p mutations in patients with PTC. Methods: We retrospectively analyzed 375 cases of PTC surgically resected between January 2018 and October 2023 at a single institution, based on the presence of BRAFV600E and TERT-p double mutation. Clinicopathologic features, including gross features on the cut surface of tumors, were evaluated. Subsequently, the association between clinicopathologic features and mutation status was statistically examined. Cox proportional hazard models were used to analyze the impact of molecular pathological features on disease-free survival (DFS). Results: The BRAFV600E and TERT-p double mutation was identified in 78 (20.8%) patients among the PTC cases and was significantly correlated with shorter DFS. Multivariable analysis revealed that factors such as relatively older age (≥55 years) (odds ratio [OR] = 12.083, 95% confidence interval [CI] 4.498-32.456), larger tumor size (>2.0 cm) (OR = 2.722, CI 1.104-6.712), lobulated tumor margins (OR = 16.114, CI 3.155-82.296), papillary excrescences on the cut surface (OR = 17.573, CI 3.462-89.201), solid-cut surface (OR = 4.012, CI 1.084-14.849), minimal extrathyroidal extension (ETE) (OR = 4.156, CI 1.209-14.282), gross ETE (OR = 6.517, CI 1.734-24.490), and Ki-67 labeling index (LI) (≥5%, OR = 12.145, CI 4.354-33.877) were significantly associated with the double mutation. Conclusions: The BRAFV600E and TERT-p double mutation in PTC was significantly associated with relatively old age, larger tumor size, lobulated configuration in tumor margin, papillary excrescences on the cut surface, solid-cut surface, ETE, and high Ki-67 LI. These features are suggestive of the presence of the double mutation and should be analyzed at the molecular level in patients with PTC.

Programmed Death-Ligand 1 (PD-L1) and Ki-67 Labeling Index: Correlation with Tumor Grade and Recurrence

Background: Meningiomas are common primary brain tumors with variable clinical behavior. While most are benign, a subset exhibits aggressive characteristics and a high recurrence rate. This study aimed to investigate the association of Programmed Death-Ligand 1 (PD-L1) and Ki-67 labeling index with histopathological grade and recurrence in meningioma. Methods: A retrospective study was conducted on 139 cases of meningioma diagnosed between January 2020 and December 2023. PD-L1 expression was evaluated using immunohistochemistry (IHC) and scored using the combined positive score (CPS). Ki-67 labeling index was determined as the percentage of tumor cells with positive nuclear staining. The association of PD-L1 and Ki-67 with histopathological grade and recurrence was analyzed. Results: PD-L1 expression was positive in 66.7% of cases and was significantly associated with recurrence (p = 0.006). A higher Ki-67 labeling index (&gt;4%) was observed in 68.9% of cases and was also significantly associated with recurrence (p = 0.013). No significant association was found between PD-L1 expression or Ki-67 labeling index and histopathological grade. Conclusion: PD-L1 expression and Ki-67 labeling index may serve as potential prognostic markers for predicting recurrence in meningioma. Further studies are needed to validate these findings and explore their potential therapeutic implications.

Rare presentations of glioblastoma multiforme in the septum pellucidum: illustrative case.

Glioblastoma multiforme (GBM), a high-grade primary brain tumor, presents a formidable challenge in neuro-oncology because of its aggressive nature, infiltrative growth, and limited response to treatment. The septum pellucidum represents an uncommon and unexpected location for GBM, adding complexity to the diagnosis and management of this rare intracranial malignancy. A 69-year-old male with a previous history of prostate carcinoma presented to an outside hospital with a 2-week history of a "trance-like state" and cognitive decline. Initial head computed tomography showed prominent ventricles without distinct mass lesions. Upon admission, magnetic resonance imaging demonstrated a mass within the inferior septum pellucidum extending to the third and both lateral ventricles. Biopsy findings indicated a GBM, World Health Organization central nervous system tumor grade 4, with immunopositivity for glial fibrillary acidic protein and a Ki-67 labeling index of 60%-70%. Identifying only 5 cases in more than 60 years of literature, this systematic review illustrates the diverse clinical presentations, diagnostic advancements, and management approaches for septum pellucidum GBM. https://thejns.org/doi/10.3171/CASE23770.

The role of the Ki-67 labelling index as an independent prognostic factor in indonesian glioma patients.

Gliomas are the most common type of brain tumor. However, interpreting glioma morphology is subjective, and identifying mitosis can be challenging. This can impact the determination of the patient's tumor grade, therapy, and prognosis. In addition, the Ki-67 expression level, which reflects the tumor cells' ability to proliferate, is closely related to the patient's survival. This study aims to find a correlation between Ki-67 expression and the overall survival (OS) of glioma patients in the Indonesian population. Ninety-one glioma patients from Sardjito General Hospital were collected for formalin-fixed embedded paraffin (FFPE) samples, and the Ki-67 labeling index (LI) was calculated by determining the percentage of labeled nuclei per 1000 cells using a 40x objective lens in a randomized area (average method). The OS was calculated from the day of pathology diagnosis until death or the last follow-up (for censored cases). Kaplan-Meier survival analysis was used to analyze the OS. Individuals aged ≥60 with high-grade tumors, infratentorial gliomas, and a Ki-67 LI ≥10% had a shorter OS. The p-values associated with these factors were 0.001, 0.018, and 0.006, respectively. In multivariate analysis, age and tumor grade did not significantly correlate with OS. Glioma patients with a Ki-67 LI ≥10% have a significantly shorter OS than those with a lower Ki-67 LI, indicating that Ki-67 LI is an independent prognostic factor in Indonesian glioma patients.