Mean Ki-67 Proliferation Index Research Articles

Pathological Insights into the Subclassification of Diffuse Large B-Cell Lymphoma (NOS)

Abstract Introduction Diffuse Large B-cell Lymphoma, NOS represents around 25-35% of adult Non- Hodgkin’s lymphoma worldwide. According to the 5th edition of WHO for Hematolymphoid neoplasms, DLBCL, NOS encompasses all biologically heterogeneous cases with no clear criteria for inclusion in a specific diagnostic category. The sixth and seventh decade are reported as the median age for DLBCL, NOS in developed countries and a lower median age in developing countries, with slight male predominance (1.2:1). DLBCL, NOS is further subclassified according to cell of origin (COO) using gene expression profiling (GEP) and various immunohistocehmical (IHC) algorithms into germinal center (GCB) and activated B-cell (ABC) subtypes, which carries a prognostic and therapeutic value. Objectives In our study, we have recorded and compared the demographic and pathological data of the DLBCL, NOS subtypes in Ain Shams University Hospitals over the period of three years. Materials and Methods Our retrospective study was conducted in the Department of Histopathology in Ain Shams University Hospitals from January 2020 till December 2022. We retrieved all available cases with a diagnosis consistent with DLBCL, NOS over the period of these three years. A total of 102 cases with available reports, H&E slides and paraffin blocks with sufficient tissue material were included in this study. We recorded the demographic and pathological data of the cases, re-examined available H& E and IHC slides, and applied immunohistochemical (IHC) staining of CD10, and multiple myeloma oncogene 1(MUM1) to remaining DLBCL cases with available paraffin blocks and sufficient tissue material for further subclassification of into GCB and ABC subtypes according to the Hans and modified Hans immuoalgorithms. Finally, we compared and analyzed the demographic and pathological data of both subtypes. Results DLBCL, NOS represented 35.3 % of all NHL cases and 26.19% of all lymphoma cases overall. Out of 102 cases of DLBCL, NOS, 38.2% were GCB while were 61.8 % ABC subtypes. The median age for DLBCL, NOS was 54.9 with male to female ratio of 1.3:1. The ABC subtype showed a higher median age and female affection predominance as compared to GCB. The most affected site overall was the cervical nodal group while stomach, spleen and liver were reported as the most commonly involved extranodal sites. The ABC subtype showed significant association with extra-abdominal nodal groups as compared to the GCB subtype (P = 0.02). The mean Ki-67 proliferation index for DLBCL, NOS was 70.42% while the ABC subtype exhibited higher Ki-67 index with a mean of 74.21 as compared to the GCB subtype with a mean of 69.1 (P = 0.08). A higher proportion of cases of the ABC subtype exhibited >70 % ki-67 proliferation index than the GCB subtype (P = 0.08). Tumor necrosis was noted in 34.8% of cases overall, with higher proportion of cases belonging to the ABC subtype (P = 0.45). Moreover, centroblastic morphological variant was the most common histology reported in both subtypes with less common histological features/variants observed in the ABC subtype; immunoblastic and anaplastic variants. Conclusion In conclusion, incidence of DLBCL, NOS in Ain Shams university hospitals was closely similar to recorded international incidence. According to COO, the ABC subtype was more frequent than the GCB subtype. The ABC subtype was associated with more nodal involvement with a significant predilection to extra- abdominal nodal groups. Moreover, the ABC subtype reported higher overall ki-67 proliferation index with more proportion of cases with > 70% proliferation index and more advanced histological features: immunoblastic/anaplastic variants and necrosis.

Meningiomlarda Ki-67 Proliferasyon İndeks Pozitiflik Sınır Değeri

Meningiomas are usually slow-growing grade 1 tumors according to World Health Organization (WHO) classification. Histological and molecular criterias were defined for the determination of meningiomas of high grade and more aggressive. The proliferation activity is also considered among histopathological criterias. A commonly used parameter for determining proliferation activity is the Ki-67 index. This study was formed retrospectively to identife the positivity limit (cut-off) value of the Ki-67 proliferation index in cases diagnosed with meningioma. The Ki-67 indices of a total 190 patients diagnosed with meningioma was compared with the histological degrees of the tumors. The ROC analysis method was used in the statistical analysis for Ki-67 values. The mean Ki-67 proliferation index was found to be 3% for grade 1, 8% for grade 2 and 17% for grade 3 in the cases diagnosed with meningioma in our center. The Ki-67 proliferation index, which can be used in addition to histopathological findings in the distinction of grade 1 and grade 2 meningiomas in our laboratory, was determined as a positivity limit value of 6,5 (p>0,05).

Gemistocytic Differentiation in Isocitrate Dehydrogenase Mutant Astrocytomas: A Histopathological and Survival Analysis.

Gemistocytic differentiation is a rare histological feature seen in IDH mutant Astrocytomas. The 2021 World Health Organization (WHO) retains the diagnosis of IDH mutant Astrocytoma with its classical histology and tumors with the rare histological pattern of gemistocyticdifferentiation.Gemistocyticdifferentiation has historically been associated with a worse prognosis and shorter survival, and this prognostic difference has not been investigated in detail in our population. A population-based retrospective study included 56 patients with IDH mutant Astrocytoma with Gemistocytic differentiation and IDH mutant Astrocytoma diagnosed between 2010 and 2018 in our hospital. Demographic, histopathological, and clinical parameters were compared between the two groups. Gemistocyte percentage, perivascular lymphoid infiltrates, and Ki-67 proliferation index were also analyzed. A Kaplan-Meier analysis was done to analyze any prognostic difference in the overall survival time between the two groups. Patients with an IDH mutant Astrocytoma having gemistocyticdifferentiation had an average survival period of 2 years, while patients diagnosed with an IDH mutant Astrocytoma had an average survival time of approximately 6 years. There was a statistically significant decrease in survival time (p = 0.005) for patients with tumors with gemistocyticdifferentiation. The percentage of gemistocytes and the presence of perivascular lymphoid aggregates did not correlate with survival time (p = 0.303 and 0.602, respectively). Tumors with gemistocyticmorphology had a higher mean Ki-67 proliferation index (4.4%) than IDH mutant Astrocytoma (2.0%, p = 0.005). Our data suggest that IDH mutant Astrocytoma with Gemistocytic differentiation is an aggressive variant of IDH mutant Astrocytoma associated with a shorter survival time and an overall worse prognosis. This data might be helpful to clinicians in the future management of IDH mutant Astrocytoma with Gesmistocytic differentiation as an aggressive tumor.

Correlation of Somatostatin Receptor 1-5 Expression, [68Ga]Ga-DOTANOC, [18F]F-FDG PET/CT and Clinical Outcome in a Prospective Cohort of Pancreatic Neuroendocrine Neoplasms.

Simple SummaryThe need for prognostic and predictive biomarkers in pancreatic neuroendocrine neoplasms (PNENs) is great. Overexpression of somatostatin receptors (SSTRs) provides a molecular basis for imaging these tumors with 68Ga-labeled somatostatin (SST) PET/CT and for treatment with somatostatin analogs. We evaluated all 5 somatostatin receptors (SSTR1-5) with immunohistochemistry and prospectively compared the results with both [68Ga]Ga-DOTANOC and [18F]F-FDG PET/CT in a cohort of 21 non-functional (NF) PNENs. SSTR2 was the only SSTR subtype to correlate with [68Ga]Ga-DOTANOC PET/CT. High SSTR5 expression correlated with a low Ki-67 proliferation index, suggesting a better prognosis for these patients. Thus, our results confirm that SSTR2 has the highest impact on SSTR PET signaling of PNENs.Purpose: The aim of this study was to correlate immunohistochemical (IHC) tissue levels of SSTR1-5 with the receptor density generated from [68Ga]Ga-DOTANOC uptake in a prospective series of NF-PNENs. Methods: Twenty-one patients with a total of thirty-five NF-PNEN-lesions and twenty-one histologically confirmed lymph node metastases (LN+) were included in this prospective study. Twenty patients were operated on, and one underwent endoscopic ultrasonography and core-needle biopsy. PET/CT with both [68Ga]Ga-DOTANOC and [18F]F-FDG was performed on all patients. All histological samples were re-classified and IHC-stained with monoclonal SSTR1-5 antibodies and Ki-67 and correlated with [68Ga]Ga-DOTANOC and [18F]F-FDG PET/CT. Results: Expression of SSTR1-5 was detected in 74%, 91%, 80%, 14%, and 77% of NF-PNENs. There was a concordance of SSTR2 IHC with positive/negative [68Ga]Ga-DOTANOC finding (Spearman’s rho 0.382, p = 0.043). All [68Ga]Ga-DOTANOC-avid tumors expressed SSTR2 or SSTR3 or SSTR5. Expression of SSTR5 was higher in tumors with a low Ki-67 proliferation index (PI) (−0.353, 95% CI −0.654–0.039, p = 0.038). The mean Ki-67 PI for SSTR5 positive tumors was 2.44 (SD 2.56, CI 1.0–3.0) and 6.38 (SD 7.25, CI 2.25–8.75) for negative tumors. Conclusion: SSTR2 was the only SSTR subtype to correlate with [68Ga]Ga-DOTANOC PET/CT. Our prospective study confirms SSTR2 to be of the highest impact for SST PET/CT signal.

PROGNOSIS IN IDH-MUTANT AND IDH-WILD TYPE GLIOBLASTOMA

Glioblastoma (GBM) is the most common brain tumor in adults with a poor prognosis and predominantly astrocytic differentiation. GBM is classified according to the isocitrate dehydrogenase (IDH) mutation according to the World Health Organization (WHO) Brain Tumors 2016 classification. IDH-1 gene mutations are evaluated immunohistochemically (IHC) and molecular methods in current pathology laboratory practice. The aim of this study was to determine the overall survival in GBM cases according to IDH-1 mutation status and Ki-67 proliferation index. Total of 53 patients diagnosed as GBM between 2007-2020 in Sivas Cumhuriyet University Faculty of Medicine, Department of Pathology were evaluated. Disease-free median survival of 7 (13%) GBM patients with IDH mutation was 2 months (2-year survival 14%), disease-free median survival 9 months (2-year survival 24 %) in GBM IDH-wild type cases. In cases with a higher Ki-67 proliferation index, the median disease-free survival were shorter. In conclusion statistically significant results could not be obtained between disease-free survival in GBM IDH-mutant type and GBM IDH-wild type. However, the mean Ki-67 proliferation index of GBM IDH-wild type cases was found to be much higher than GBM IDH-mutant cases. High Ki-67 proliferation index was found to be associated with a significantly shorter survival.

Ovarian incision enhances folliculogenesis: A rat model.

To determine whether performing incision on the surface of the ovarian cortex in rats advances follicular development. Five to seven separate superficial incisions were performed on the surface of right ovaries of 6-7-month-old albino Wistar rats. Daily 40 IU of gonadotropins were administered for 14 days. On the 15th day, both ovaries of the rats were removed. The right (incised) ovaries were compared with the contralateral ovaries in terms of ovary's weight, numbers of primordial, primary, secondary and antral follicles, their mean percentages and mean Ki-67 proliferation indices. A total of 22 ovaries were evaluated, with 11 right ovaries (incised) and 11 left ovaries (non-incised). The mean weight of ovaries was greater in the right ovaries than in the left ovaries; however, no statistical difference was found between them (0.77 ± 1.22 vs. 0.22 ± 0.08 gr, P = 0.159). The numbers of secondary and antral follicle were statistically higher in the right ovaries than in the left ovaries (4.4 ± 1.5 vs. 2.1 ± 1.6, P = 0.003 and 18.6 ± 8.7 vs. 11.3 ± 7.5, P = 0.046, respectively). The right ovaries also significantly differed from the left ovaries in terms of mean percentages of primordial and antral follicles (P < 0.05 for both). The mean Ki-67 proliferation index had a marginal difference between the groups (P = 0.064). Performing incisions on the surface of the ovarian cortex in rats may advance the ovarian follicular development. Future animal studies may provide more evidence regarding potential benefits of mechanical stimulation to the ovaries.

Radioembolization for neuroendocrine liver metastases is safe and effective prior to major hepatic resection.

Radioembolization (RE) is well established in the treatment of neuroendocrine liver metastases. However surgery is rarely performed after RE, although liver resection is the gold standard in the treatment of localized neuroendocrine liver metastases. Therefore, aim of the present study was to evaluate the safety and feasibility of liver resection after RE in a homogenous cohort. From a prospective surgical (n=494) and nuclear medical (n=138) database patients with NELM who underwent liver resection and/or RE were evaluated. Between September 2011 and December 2017 eight patients could be identified who underwent liver resection after RE (mean therapeutic activity of 1,746 Mbq). Overall and progression free survival were evaluated as well as epidemiological and perioperative factors. The surgical specimens were analyzed for necrosis, fibrosis, inflammation, and steatosis. The mean hepatic tumor load of patients, who had liver surgery after RE, was 31.4% with a mean Ki-67 proliferation index of 5.9%. The majority of these patients (7/8) received whole liver RE prior to liver resection, which did not increase morbidity and mortality compared to a surgical collective. Indications for RE were oncological (6/8) or carcinoid syndrome associated reasons (2/8). Mean overall survival was 25.1 months after RE and subsequent surgery. Tumor necrosis in radioembolized lesions was 29.4% without evidence of fibrosis and inflammation in hepatic tissue. This is the first study analyzing the multimodal therapeutic approach of liver resection following whole liver RE. This treatment algorithm is safe, does not lead to an increased morbidity and is associated with a favorable oncological outcome. Nonetheless, patient selection remains a key issue.

Large nested variant of urothelial carcinoma of urinary bladder: a clinicopathological analysis of five cases

Objective: To investigate the clinicopathologic features, diagnosis and differential diagnosis of large nested variant of urothelial carcinoma (LNUC) of urinary bladder. Methods: The clinical and pathologic data of five cases of LNUC of urinary bladder diagnosed between January 2014 and December 2018 at the Department of Pathology, Zhejiang Provincial People's Hospital were analyzed by immunohistochemistry (IHC) and Sanger sequencing. The relevant literature was reviewed. Results: All five patients were male with a mean age of 63 years (range, 48 to 81 years). The mean tumor size was 3.4 cm (range, 1.7 to 4.7 cm). Histologically, the invasive LNUC tumor cells formed medium to large sized nests of varying shapes, from regular round, bulbous, oval to irregularly fused, branched, dumbbell shaped glands, with mild stromal reaction. In all five cases, focal central necrosis and microcystic changes in the tumor nests were identified. Cytologically, the tumor cells were low grade in four cases; the remaining case was overall low grade with focal high grade areas. Mitoses were scarce. All cases possessed surface urothelial tumors, including three low-grade papillary carcinomas, one high-grade papillary carcinoma and one carcinoma in situ. Three of the LNUC were accompanied by small nested variant of urothelial carcinoma and two by conventional high grade invasive urothelial carcinoma. Perineural involvement and angiolymphatic invasion were each noted in four tumors. Radical cystectomy was performed in four cases with TNM stages as followings: pT3aN0M0 in two cases, pT4aN0M0 and pT4aN1M0 in one case each. The remaining case had transurethral bladder resection and was of pT2 stage. By IHC, all five cases were positive for CK7 and p40; four were positive for GATA3; two were positive for CK20; and the mean Ki-67 proliferation index was 18%. TERT promoter mutation status were successfully performed in three cases, with one showing mutation (C228T) and two were wild type. All patients received postoperative chemotherapy. At a follow-up of 2 to 11 months, one patient died of unrelated causes, two patients developed metastases, and two were alive with no evidence of disease. Conclusions: LNUC is a histologic subtype of urothelial carcinoma with deceptively benign features but aggressive behavior, and appreciation of its unique infiltration patterns can aid in diagnosis and differential diagnosis. LNUC tends to coexist with small nested variant of urothelial carcinoma, suggesting these may represent different manifestations of the same urothelial carcinoma subtype.

Frequency and Role of CDKN2A Deletion in High-Risk Pituitary Neuroendocrine Tumors.

The underlying mechanisms of aggressive pituitary neuroendocrine tumors (pitNETs) are still unclear. The p16 protein, encoded by the CDKN2A tumor suppressor gene on chromosome 9p21, is commonly reported to be lost in numerous types of cancer. For this reason, this study examined to examine the status of homozygous deletion of CDKN2A in high-risk pitNETs. Thirty-eight high-risk pitNETs (30 male, 8 female) were analyzed for CDKN2A deletion by fluorescent in situ hybridization (FISH). Demographic characteristics such as sex, patient age at operation, and sellar magnetic resonance imaging findings including tumor size and invasion status were recorded. The frequency of CDKN2A homozygous deletion by FISH was 3/38 (7.89%) in the high-risk pitNET group. All of these three cases with CDKN2A homozygous deletion were invasive densely granulated lactotroph tumors (p= 0.000). CDKN2A deletion was not correlated with patient age, sex, cavernous sinus invasion (CSI), and tumor size (p> 0.05). The Ki-67 proliferation index was significantly correlated with CDKN2A homozygous deletion (p= 0.003). The mean Ki-67 proliferation index was 10.7% in pitNETs with CDKN2A homozygous deletion and the Ki-67 proliferation index in the whole study group was 4.1%. CSI was significantly correlated with the morphofunctional tumor types including lactotroph tumor, invasive null cell tumor, and invasive gonadotroph tumor (p= 0.021). These findings suggest a close correlation between inactivation of p16 gene and invasive lactotroph tumors. Further investigations are needed to expand on the mechanism of p16 (CDKN2A) gene deletion in high-risk pitNETs.

Large cell neuroendocrine carcinoma with a solitary brain metastasis and low Ki-67: a unique subtype

IntroductionStage IV large cell neuroendocrine carcinoma (LCNEC) of the lung generally presents as disseminated and aggressive disease with a Ki-67 proliferation index (PI) 40–80%. LCNEC can be subdivided in two main subtypes: the first harboring TP53/RB1 mutations (small-cell lung carcinoma (SCLC)-like), the second with mutations in TP53 and STK11/KEAP1 (non-small-cell lung carcinoma (NSCLC)-like). Here we evaluated 11 LCNEC patients with only a solitary brain metastasis and evaluate phenotype, genotype and follow-up.MethodsEleven LCNEC patients with solitary brain metastases were analyzed. Clinical characteristics and survival data were retrieved from medical records. Pathological analysis included histomorphological analysis, immunohistochemistry (pRB and Ki-67 PI) and next-generation sequencing (TP53, RB1, STK11, KEAP1 and MEN1).ResultsAll patients had N0 or N1 disease. Median overall survival (OS) was 12 months (95% confidence interval (CI) 5.5–18.5 months). Mean Ki-67 PI was 59% (range 15–100%). In 6/11 LCNEC Ki-67 PI was ≤40%. OS was longer for Ki-67 ≤40% compared to >40% (17 months (95% CI 11–23 months) vs 5 months (95% CI 0.7–9 months), P = 0.007). Two patients were still alive at follow-up after 86 and 103 months, both had Ki-67 ≤40%. 8/11 patients could be subclassified, and both SCLC-like (n = 6) and NSCLC-like (n = 2) subtypes were present. No MEN1 mutation was found.ConclusionStage IV LCNEC with a solitary brain metastasis and N0/N1 disease show in the majority of cases Ki-67 PI ≤40% and prolonged survival, distinguishing them from general LCNEC. This unique subgroup can be both of the SCLC-like and NSCLC-like subtype.

Diffuse Large B-Cell Lymphoma in Kenya: MYC, BCL2, and the Cell of Origin.

PURPOSEDiffuse large B-cell lymphoma (DLBCL) is the most commonly diagnosed non-Hodgkin lymphoma in adults in Kenya. Cell of origin (COO) and double expression of MYC and BCL2 are two important prognostic factors for DLBCL. A small subset (5% to 10%) of DLBCL cases show positivity for CD5 and are associated with poor prognosis, whereas CD30 antigen, seen in up to 10% of cases, may be a useful target for therapy. We sought to determine the prevalence of MYC/BCL2 double expression, COO, and proportion of Epstein-Barr virus positivity among patients with DLBCL diagnosed at a tertiary referral laboratory in Kenya.PATIENTS AND METHODSAll cases of DLBCL diagnosed from 2012 through 2015 in our pathology department were analyzed. Tumor tissue microarray sections were stained with CD20, CD3, CD5, CD30, BCL2, BCL6, CD10, MUM1, MYC, and Ki67, classified for COO on the basis of the Hans algorithm, and subjected to Epstein-Barr virus-encoded small RNAs in situ hybridization.RESULTSAmong 165 DLBCL cases, the median age was 50 years, and there was no sex predilection. Only 18 (10.9%) cases showed double expression for MYC and BCL2. Germinal center B (GCB)-cell type DLBCL accounted for 67 cases (40.6%) and 97 cases (59.4%) were classified as non-GCB. The mean Ki67 proliferation index was significantly higher in the double-expressing (45%) and non-GCB groups (36%) compared with the non–double-expressing group (29%) and GCB group (26%). Sixteen cases (9.7%) were Epstein-Barr virus-encoded small RNAs positive, 12 (75%) of which were non-GCB.CONCLUSIONDLBCL in Kenya is seen in much younger patients with the poor prognostic non–GCB-type accounting for 59.4% of cases. MYC and BCL2 double expression was seen in fewer tumors than reported in the literature and in significantly older patients.

Impact of Multifocality and Molecular Markers on Survival of Glioblastoma

Several parameters like extent of resection and MGMT promotor methylation in glioblastoma (GBM) are known to influence survival. Other elements like multifocality and proliferation indices are not commonly used. The aim of the present study was to analyze routinely and not routinely assessed prognostic markers for survival of patients suffering from GBM in a single center. Adult cases with GBM operated at our institution were included in this survey. The association of age, Karnofsky performance status (KPS), MGMT promotor methylation, Ki67 proliferation index, IDH1/2 mutational status, and multifocality on overall survival (OS) was analyzed in univariate and multivariate cox regression models. We analyzed 565 patients with a mean age of 62.2 (18-84) years. Median OS was 12.5 months. MGMT promoter methylation and IDH 1/2 mutation were associated with significant better OS (P < 0.01). In 48 cases (8.5%), the tumor was localized in both hemispheres, which was associated with a significant worse OS than tumor infiltration of 1 hemisphere (P= 0.039). Mean Ki67 proliferation index increased to 18% when both hemispheres were infiltrated. Multivariate analysis for OS revealed IDH 1/2 wildtype (adjusted odds ratio [aOR] 4.3), higher age (aOR 4.2), unmethylated MGMT promotor (aOR 3.5), preoperative KPS score <70 (aOR 1.9), and multifocality (aOR 2.1) as independent parameters for worse survival. This study confirms well-known parameters like MGMT promoter methylation, IDH 1/2 mutational status, KPS, and age as independent prognostic factors for survival and reveals multifocality as further independent prognostic marker for survival. The dismal prognosis of multifocal involvement is associated with an increasing Ki67 proliferation index.

Visual qualitative evaluation of diffusion-weighted imaging, apparent diffusion coefficient quantification and Ki-67 proliferation index for predicting atypia in surgical meningiomas

Object. The goal in this study was to investigate the efficiency of qualitative evaluation using DW imaging, ADC quantification, and Ki-67 proliferation labeling index in grading intracranial meningiomas compared to our reference standard histopathology.Methods. From our database, we enrolled 35 consecutive patients with pathologic report of a meningioma, conventional MR imaging, contrast-enhanced MR imaging, DW imaging and ADC maps.Results. Eight patients (23%) had atypical meningioma (5 women and 3 men; mean age: 57.1±15.8 years); 27 (77%) had low-grade-typical (19 women, 8 men; mean age: 54.3±14.0 years). The most frequent histological subtype was the meningothelial type in both low-grade (37%) and atypical meningiomas (59%). The mean Ki-67 proliferation index for low-grade and atypical meningiomas were 2.31±1.44% (range: 1-5) and 7.37 ± 2.72% (range: 3-10), respectively. Meningiomas with Ki-67 proliferation index higher than 4% (except one) were atypical (p&amp;lt;0.001). In visual qualitative evaluation; diffusion restriction was significantly more common in atypical meningiomas (p&amp;lt;0.05). In quantitative evaluation, benign and atypical tumor groups had no significant difference in mean ADC values (p=0.471). Conclusion. We suggest that visual qualitative evaluation of DW imaging may be helpful to predict atypia and the risk of recurrence in patients with surgically treated meningiomas.

Gastrointestinal Stromal Tumors: A Clinicopathological and Immunohistochemical Study of 65 Cases.

The clinical behavior of gastrointestinal stromal tumors is divergent. The aim of the present study was to define the clinicopathological features that determine the patient's outcome. Sixty-five gastrointestinal stromal tumors were reviewed with their histological, immunohistochemical and clinical features and compared with their clinical outcome statistically. Tumors were located in the stomach (n=39, 60%), small intestine (n=22, 33.8%) and large intestine (n=4, 6.2%). Immunohistochemically, CD 117 positivity was found in 90.8%, whereas CD34, Smooth muscle actin, Desmin and S100 positivity was found in 73.3%, 61.7%, 11.7% and 28.3% of tumors respectively. All six ''CD 117-negative'' cases expressed DOG-1. The mean Ki-67 proliferation index was 8.69%±12.76. Liver metastasis was detected in seven cases. A significant association was detected between decreased mean survival time and increased tumor size (p < 0.001), large bowel localization (p=0.047), mitosis (p < 0.001), the presence of necrosis (p=0.001), metastasis (p=0.033), Ki-67 proliferation index (p=0.002) and risk category (p < 0.001). CD 34 positivity was mostly seen in the stomach (p=0.001), and CD 34 positive tumors had longer overall survival (92.85.±5.77 months versus 67.21±13.68 months) (p=0.046). Higher Ki-67 proliferation index (≥6%) was also correlated with the presence of metastases (p=0.015). Our study indicates that in addition to well-known risk factors such as increased tumor size, high mitotic activity and metastasis; higher Ki-67 proliferation index, the presence of necrosis, and CD34 negativity also correlate with shorter survival time.

Aggressive digital papillary adenocarcinoma: A clinicopathological study of 19 cases

Aggressive digital papillary adenocarcinomas (ADPA) are malignant tumors of sweat glands having recurrence/metastatic potential. We sought to describe the clinical/histopathological characteristics of a series of ADPA. This is a retrospective case series of 19 ADPA. The tumors occurred in 17 men and 2 women (mean age: 47years). They involved digits (15), big toe (3), andpalm (1), and measured from 3 to 30mm. They were mostly solid and cystic, with papillary projections and tubular structures. Atypia was mostly mild to moderate. Tumors tested positive for p63, keratin 7, keratin77 (eccrine duct-specific), PHLDA1, and epithelial membrane antigen in most cases, andfor carcinoembryonic antigen, smooth muscle actin, S100 protein, estrogen, progesterone, and androgen receptors in 50%. Mean Ki67 proliferation index was 15%. Local recurrence was observed in 4 cases. One patient had axillary lymph node metastasis. Histopathologic parameters were not predictive of evolution. Conservative surgical treatment, performed in 7 of 19 cases, did not result in more recurrences than amputation. The study was retrospective and the number of cases is small. ADPA are histologically variable, but papillary projections are always present. Keratin 77 expression suggests an eccrine origin. P63 is helpful to exclude metastasis. Conservative surgery may be sufficient in some cases.

Ki67--An unsuitable marker of gastric cancer prognosis unmasks intratumoral heterogeneity.

Background and ObjectivesDue to contradictious findings of previous studies regarding Ki67's value in gastric cancer (GC), we reevaluated the expression of Ki67 in whole tissue sections (WTS) and tissue microarrays (TMAs) of GC testing the following hypotheses: does Ki67 show intratumoral heterogeneity; are TMAs representative in the determination of the Ki67 proliferation index (PI); is the Ki67 PI subject to an intralaboratory variability; and is the Ki67 PI related to clinico‐pathological patient characteristics and/or prognostically relevant in GC.MethodsCorresponding WTS and TMAs samples from 315 GCs were stained immunohistochemically. The Ki67 PI evaluated on WTS was correlated with the Ki67 PI evaluated on TMAs, sample age, clinico‐pathological characteristics, and patient survival.ResultsThe overall amount of Ki67‐positive tumor cells did not depend on sample age. Three distinct, partly heterogeneous Ki67 expression patterns were observed. The mean Ki67 PI evaluated on TMAs differed on average minus 16.9% from the Ki67 PI evaluated on WTS. Ki67 in WTS correlated significantly with the Laurén phenotype and tumor grade, but not with patient survival.ConclusionTMAs carry the risk of a systematic underestimation of the Ki67 PI. Ki67 has no prognostic value in GC but might be a potential indicator of intratumoral heterogeneity. J. Surg. Oncol. 2016;113:46–54. © 2015 The Authors. Journal of Surgical Oncology published by Wiley Periodicals, Inc.

Ki-67 Labeling Indices in 'Classic' versus 'Blastoid' Mantle Cell Lymphomas--Proposed Cutoff Values for Routine Diagnostic Workup.

Mantle-cell lymphoma (MCL) is a unique entity of peripheral B-cell lymphoma that has a discrete morphologic, immunologic, and genetic phenotype, with more common 'classic' and less frequent 'blastoid' and 'pleomorphic' variants, associated with an aggressive clinical course. The aim of this study was to analyze proliferation (Ki-67) indices of 'classic' (c-MCL) and 'blastoid' (b-MCL) variants of a cohort of MCL and to suggest cut off values for the Ki-67 proliferation index in these two subsets. MCL cases diagnosed over 4 1/2 years at Section of Histopathology, Department of Pathology and Laboratory Medicine, Aga Khan University Hospital, Karachi were retrieved and reviewed. Ki-67 labelling was scored and analysed. A total of 90 of cases of MCL were scrutinized. Mean age±SD was 60.2±12.5 years and the male to female ratio was 4:1, with 67 (75%) cases of c-MCL and 23 (25%) cases of b-MCL. Most samples were lymph node biopsies (n=68), whereas the remainder were from various extranodal sites The mean Ki-67 proliferation index was 29.5%±14.4% in classic variants and 64.4±15.2% for the blastoid variant, the difference being statistically significant (p=0.029). It was concluded that differential cut-off values of Ki-67 labeling may be used in more objective way to reliably classify MCL into classic or blastoid variants by diagnostic pathologists. We propose a <40 proliferative index to be suggestive of c-MCL and one of >50 for the blastoid variant.

O10.02 * MITOTIC INDEX, MICROVASCULAR PROLIFERATION AND NECROSIS DEFINE THREE GROUPS OF 1P/19Q CO-DELETED ANAPLASTIC OLIGODENDROGLIOMAS ASSOCIATED WITH DIFFERENT GENOMIC ALTERATIONS

BACKGROUND: The aim of this study was to correlate histological features and molecular characteristics in anaplastic oligodendrogliomas (AO). METHODS: The histological characteristics of 203 AO patients enrolled in the French national network POLA were analyzed. The genomic profiles of 191 cases were studied using genomic arrays. IDH mutational status was assessed by immunohistochemistry and direct sequencing. RESULTS: 1p/19q co-deletion was present in 79% of cases and was associated with alpha-internexin expression (p < 10-4), IDH1/2 mutation (p < 10-4), chromosome 4 loss (p < 10-3), and better overall survival (p < 10-4). Based on mitotic index, microvascular proliferation (MVP) and necrosis, 3 groups of 1p/19q co-deleted AO were identified: AO with more than 5 mitoses per 10-HPF, no MVP and no necrosis, (1), AO with MVP and no necrosis (2) and AO with MVP and necrosis (3). Compared to group 1, group 2 and 3 AO had a higher mean Ki-67 proliferation index and a higher rate of 9p and 9q losses. Compared to group 2, group 3 AO had a higher number of chromosomal alterations including chromosome 4 loss. In the subgroup of 157 1p/19q co-deleted AO, chromosomal instability was associated with shorter progression free survival (p = 0.024) and shorter overall survival (p = 0.023). CONCLUSIONS: The present study shows that oligodendroglioma with classic histological features remains a molecularly heterogeneous entity and should be stratified according to 1p/19q status because of its major prognostic relevance. Moreover, 1p/19q co-deleted AO are also heterogeneous. Interestingly, mitotic index, MVP and necrosis help to classify them into three groups associated with distinct genomic alterations.

Correlation of apparent diffusion coefficient with Ki-67 proliferation index in grading meningioma.

A noninvasive method to predict aggressiveness of high-grade meningiomas would be desirable because it would help anticipate tumor recurrence and improve tumor management and the treatment outcomes. The Ki-67 protein is a marker of tumor proliferation, and apparent diffusion coefficient (ADC) is related to tumor cellularity. Therefore, we sought to determine whether there is a statistically significant correlation between ADC and Ki-67 values in meningiomas and whether ADC values can differentiate various meningioma subtypes. MRI examinations and histopathology of 68 surgically treated meningiomas were retrospectively reviewed. Mean ADC values were derived from diffusion imaging. Correlation coefficients were calculated for mean ADC and Ki-67 proliferation index values using linear regression. An independent unpaired Student t test was used to compare the ADC and Ki-67 proliferation index values from low-grade and more aggressive meningiomas. A statistically significant inverse correlation was found between ADC and Ki-67 proliferation index for low-grade and aggressive meningiomas (r(2) = -0.33, p = 0.0039). ADC values (± SD) of low-grade meningiomas (0.84 ± 0.14 × 10(-3) mm(2)/s) and aggressive (atypical or anaplastic) meningiomas (0.75 ± 0.03 × 10(-3) mm(2)/s) were significantly different (p = 0.0495). Using an ADC cutoff value of 0.70 × 10(-3) mm(2)/s, the sensitivity for diagnosing aggressive meningiomas was 29%, specificity was 94%, positive predictive value was 67%, and negative predictive value was 75%. ADC values correlate inversely with Ki-67 proliferation index and help differentiate low-grade from aggressive meningiomas.

Mitotic index, microvascular proliferation, and necrosis define 3 groups of 1p/19q codeleted anaplastic oligodendrogliomas associated with different genomic alterations.

The aim of this study was to correlate histological features and molecular characteristics in anaplastic oligodendrogliomas (AOs). The histological characteristics of 203 AO patients, enrolled in the French national network POLA, were analyzed. The genomic profiles of 191 cases were studied using genomic arrays. IDH mutational status was assessed by immunohistochemistry and direct sequencing. 1p/19q codeletion was present in 79% of cases and was associated with alpha-internexin expression (P < 10(-4)), IDH1/2 mutation (P < 10(-4)), chromosome 4 loss (P < 10(-3)), and better overall survival (P < 10(-4)). Based on mitotic index, microvascular proliferation (MVP), and necrosis, 3 groups of 1p/19q codeleted AOs were identified: (group 1) AO with more than 5 mitoses per 10-HPF, no MVP, and no necrosis; (group 2) AO with MVP and no necrosis; and (group 3) AO with MVP and necrosis. Compared with group 1, groups 2 and 3 AOs had a higher mean Ki-67 proliferation index and a higher rate of 9p and 9q losses. Compared with group 2, group 3 AOs had a higher number of chromosomal alterations including chromosome 4 loss. In the subgroup of 157 1p/19q codeleted AOs, chromosomal instability was associated with shorter progression-free survival (P = .024) and shorter overall survival (P = .023). The present study shows that oligodendrogliomas with classic histological features remain a molecularly heterogeneous entity and should be stratified according to 1p/19q status because of its major prognostic relevance. Moreover, 1p/19q codeleted AOs are also heterogeneous. Interestingly, mitotic index, MVP, and necrosis help to classify them into 3 groups associated with distinct genomic alterations.