Low Labeling Index Research Articles

Mesothelioma of Uncertain Malignant Potential (MUMP) of the Tunica Vaginalis: Proposal for Reclassification as "Complex Mesothelial Tumor of the Tunica Vaginalis".

A well-differentiated papillary mesothelial tumor (WDPMT) and malignant mesothelioma are 2 well-recognized entities arising from the testis tunica vaginalis. Another mesothelial lesion exclusively seen at this site is mesothelioma of uncertain malignant potential (MUMP)-a lesion reminiscent of WDPMT yet demonstrating variable proportions of more complex architectural patterns that could be confused with invasion. MUMP was first described in 2010 with a total of 11 cases reported to date. Herein, we describe 19 additional patients who underwent hydrocelectomy, excision, and/or orchiectomy. Novel morphologic patterns found in addition to the 2010 series include spindle cells, keloidal-type collagen, and multicystic architecture lined by bland mesothelial cells. Clinical follow-up in 9 patients for more than 1 year (1.5 to 22.5y, median 4.5y) revealed no evidence of disease recurrence or metastases. Despite greater architectural complexity, MUMP has (1) bland cytology; (2) merging in with WDPMT areas; (3) low mitotic rate and Ki-67 nuclear labeling index; (4) retention of MTAP and BAP1 expression; and (5) benign clinical follow-up. If these cases were malignant mesotheliomas, one would have expected at least some of the patients to demonstrate disease recurrence/progression without adjuvant therapy within the available follow-up time, particularly with limited resection in most patients. Thus, we propose that "mesothelioma of uncertain malignant potential" be renamed as "complex mesothelial tumor of the tunica vaginalis." Using the term "complex" draws a contrast with the simple cuboidal lining and simple papillary architecture seen in WDPMT. Also, labeling the lesion as "tumor" removes the stigmata of "uncertain malignant potential" and "mesothelioma" that are alarming to patients and clinicians, and potentially could unduly lead to more extensive surgery in an attempt at "complete" resection. At the same time, not definitively labeling the lesion as benign allows recommendations for follow-up.

Low-Dose Acetylsalicylic Acid Treatment in Non-Skull-Base Meningiomas: Impact on Tumor Proliferation and Seizure Burden.

Simple SummaryMIB-1 index is an established immunohistochemical marker reflecting the proliferative potential in meningiomas. Cyclooxygenase-2 has been demonstrated to be positively correlated with MIB-1 index in meningiomas. In a recent investigation, we revealed that cranial non-skull-base meningiomas have increased proliferative potential and increased inflammatory burden compared to other anatomical locations of meningiomas. The role of nonsteroidal anti-inflammatory drugs (NSAIDs) regarding proliferative activity and location-specific symptoms in non-skull-base meningiomas is unclear so far. In the present investigation, we therefore analyzed the impact of low-dose (100 mg) acetylsalicylic acid (ASA) treatment on the MIB-1 index and baseline symptomatic epilepsy. We identified that elderly female non-skull-base meningioma patients with ASA intake had significantly lower MIB-1 indices. Furthermore, ASA intake significantly reduced the preoperative seizure burden in non-skull-base meningioma. We believe that further research on NSAID treatment in non-skull-base meningiomas is necessary to enhance a tailored treatment scheduling.MIB-1 index is an important predictor of meningioma progression and was found to be correlated with COX-2 expression. However, the impact of low-dose acetylsalicylic acid (ASA) on MIB-1 index and clinical symptoms is unclear. Between 2009 and 2022, 710 patients with clinical data, tumor-imaging data, inflammatory laboratory (plasma fibrinogen, serum C-reactive protein) data, and neuropathological reports underwent surgery for primary cranial WHO grade 1 and 2 meningioma. ASA intake was found to be significantly associated with a low MIB-1 labeling index in female patients ≥ 60 years. Multivariable analysis demonstrated that female patients ≥ 60 years with a non-skull-base meningioma taking ASA had a significantly lower MIB-1 index (OR: 2.6, 95%: 1.0–6.6, p = 0.04). Furthermore, the intake of ASA was independently associated with a reduced burden of symptomatic epilepsy at presentation in non-skull-base meningiomas in both genders (OR: 3.8, 95%CI: 1.3–10.6, p = 0.03). ASA intake might have an anti-proliferative effect in the subgroup of elderly female patients with non-skull-base meningiomas. Furthermore, anti-inflammatory therapy seems to reduce the burden of symptomatic epilepsy in non-skull-base meningiomas. Further research is needed to investigate the role of anti-inflammatory therapy in non-skull-base meningiomas.

S1489 Solid Pseudopapillary Pancreatic Tumor: Preoperative Malignant Potential and Gender Differences

INTRODUCTION: Solid pseudopapillary tumor (SPT) is a rare tumor that was first described by Virginia Frantz in 1959. It is found most commonly in females in the second or third decade of life, and less commonly found in males. We herein present two cases of SPT, one discovered in a young female and the other in an elderly male, followed by literature review of this interesting disorder of the pancreas with emphasis on preoperative predictors of malignancy and gender differences in presentation. CASE DESCRIPTION/METHODS: Case 1 is a 30 years old healthy female who presented with right lower abdominal pain and vomiting that persisted for days after a night of moderate alcohol consumption. Basic labs were unrevealing, and ultimately a computerized tomography (CT) of the abdomen discovered a 3.2 × 2.8 × 1.8 cm pancreatic tail mass with cystic and solid components. On endoscopic ultrasound fine needle biopsy (EUS-FNB), lesion was anechoic and hypoechoic, measuring 3.1 × 2 cm. Immunohistochemical staining was positive for CD56, CD 10, CD 117, and B-Catenin consistent with SPT. The patient was referred to surgery and ultimately underwent an uncomplicated distal pancreatectomy. The surgical pathology was consistent with SPT. Case 2 is a 64 years old male with hyperlipidemia, chronic obstructive pulmonary disease and atrial fibrillation who presented with diffuse abdominal pain, nausea and vomiting. Basic labs were unrevealing, and CT revealed a 2.3 cm mass in pancreatic head. Subsequent magnetic resonance imaging showed a cystic mass with some solid debris. EUS-FNA with biopsy showed hypoechoic mass with smooth margins measuring 2.1 × 2.1cm. Immunohistochemical staining was positive for CD 56, CD 10, vimentin, androgen receptor, cylcin D1. Ki-67 stain demonstrated low proliferative labeling index. The patient ultimately underwent a robotic Whipple surgery. Pathologic evaluation was consistent with SPT. DISCUSSION: SPT is a pancreatic neoplasm with low malignant potential. Factors that predict malignancy preoperatively have been studied. Additionally, Males and females can have different presenting features of the tumor. However, given its low incidence, proven risk factors and the extent of impact have been challenging to discover. Furthermore, some malignant features can be missed on preoperative evaluation. Therefore, a large multicenter prospective or metanalysis study might be needed to better assess and differentiate demographic and clinical risk factors that can help in determining prognosis.Figure 1.: Image A: Cystic mass lesion with rim calcification in the tail of the pancreas in female patient.Figure 2.: Image B: Hypodense lesion in pancreatic head in male patient.Figure 3.: Image C: Pancreatic head cystic mass on MRCP in male patient.

WT1 Clone 6F-H2 Cytoplasmic Expression Differentiates Astrocytic Tumors from Astrogliosis and Associates with Tumor Grade, Histopathology, IDH1 Status, Apoptotic and Proliferative Indices: A Tissue Microarray Study.

Objectives:This tissue microarray (TMA) immunohistochemical (IHC) study elucidates the role of Wilms’ tumor 1 protein (WT1) in diagnosis and prognostication of astrocytic tumors. Methods:IHC was applied to 75 astrocytic lesions (18 astrogliosis and 57 astrocytic tumors) using antibodies directed against WT1 clone 6F-H2, isocitrate dehydrogenase 1(IDH1), Bcl2 and Ki67. WT1 IHC staining was evaluated and scored blindly by 2 pathologists. Bcl2 and Ki67 scores and labelling indices were assessed and IDH1 status determined. Statistical analysis was performed using the appropriate methodology. Results:WT1 cytoplasmic expression was detected in 89.5% of astrocytic tumors but not in astrogliosis. Positive WT1 differentiated astrocytic tumors (92.6% accuracy) and grade II diffuse astrocytomas (93.5% accuracy) from astrogliosis with high sensitivity, specificity and positive predictive values (p<0.001). Increased WT1 score significantly associated higher Bcl2 and Ki67 labelling indices, increasing WHO tumor grade and tumor’s histopathologic type (p<0.05) showing staining pattern variability by tumor entity and cell type. Glioblastomas, gliosarcomas and subependymal giant cell astrocytomas were the most frequently WT1 expressing tumors with frequent +3 WT1 score. About 21.4% of pilocytic astrocytomas had +3WT1 score in association with increased Bcl2 and Ki67 indices. Low WT1 scores in grade II and III diffuse astrocytomas were linked to the high frequency of IDH1 positivity, and were associated with low Bcl2 and Ki67 labelling indices. In glioblastomas, WT1 significantly associated poor prognostic variables: older age, negative-IDH1 status, high Bcl2 and Ki67 labelling indices (p=0.04, <0.001, =0.001 and <0.001 respectively). Conclusions:WT1 clone 6F-H2 is a highly accurate positive surrogate marker to differentiate astrocytic tumors notably the challenging grade II diffuse astrocytoma from astrogliosis. It significantly associates with poor prognostic variables including IDH1 negativity, high apoptotic and proliferative indices and depends on tumor’s histopathologic entity more than its grade. Evaluation of WT1 expression seems essential to tailor patient’s therapy.

Clinical and cytopathological characteristics of HTLV-1+ hodgkin lymphoma.

BackgroundHuman T‐lymphotropic virus‐1 (HTLV‐1)+ Hodgkin lymphoma (HL) is difficult to differentiate from adult T‐cell leukemia/lymphoma (ATLL) with HL‐like histology (HL‐like ATLL).MethodsCytological and immunohistological features, HTLV‐1 proviral DNA integration, and rearrangements of the T‐cell receptor (TCR) Cβ1 gene were examined in 11 HTLV‐1+ patients with HL‐like disease.ResultsSix patients were classified as HTLV‐1+ HL and five as HL‐like ATLL in accordance with genetic findings of HTLV‐1 proviral DNA integration and rearrangements of the TCR Cβ1 gene. Small ordinary looking lymphocytes with round nuclei were detected in the background of six patients with HTLV‐1+ HL, which were immunohistochemically negative for CD25 and CC chemokine receptor (CCR)4 and had a low MIB1 labeling index (mean: 28.3%). In the HL‐like ATLL specimens, small‐ and medium‐sized atypical lymphocytes with indented and irregular‐shaped nuclei were found, and were diffusely positive for CD25 and CCR4, with high MIB1 labeling (mean: 76%). Both groups had scattered CD30+ and CD15+ Hodgkin and Reed Sternberg (RS) giant cells, with or without CD20 expression and Epstein‐Barr virus infection. The 50% overall survival period was significantly longer for the HTLV‐1+ HL group (180 months) than for the HL‐like ATLL group (7.8 months; P = .004).ConclusionsHTLV‐1+ HL showed typical small lymphoid cells with a low MIB1 labeling index in a background of Hodgkin and RS cells, with some scattered CD25+ and CCR4+ lymphocytes. In HTLV‐1 endemic areas, distinguishing HTLV‐1+ HL from HL‐like ATLL is important because of their differing treatment strategies and prognoses.

MON-628 Noninvasive Encapsulated Papillary RAS-Like Thyroid Tumor (NEPRAS) as a Possible Novel Subtype of Borderline Tumor

Background: A subset of thyroid tumors was classified into borderline/precursor tumors in the latest World Health Organization (WHO) classification. However, these tumors were defined only in terms of follicular structure, including hyalinizing trabecular tumor (HTT), noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), and uncertain malignant potential (UMP). As papillary microcarcinoma was proposed to be renamed to papillary microtumor (PMiT), there would be no reasons for restricting borderline/precursor tumors to the follicular growth pattern. Clinical Case: A 26-year-old man was incidentally found to have a 23 mm nodule in his thyroid. After undergoing left lobectomy, histological findings revealed extremely delicate nuclear changes in a noninvasive encapsulated papillary growth-patterned tumor. Tumor cells showed nuclear enlargement, irregularity, elongation, and overlapping as well as a few nuclear grooves. Nuclear pseudoinclusions were absent and chromatin characteristics were insufficient (nuclear score 2 according to Nikiforov et al. (1)). The patient was diagnosed with an encapsulated conventional papillary thyroid carcinoma by a local pathologist; however, a second-opinion consultation endorsed a follicular adenoma with papillary hyperplasia. In a third-opinion consultation, immunohistochemical analyses revealed a low MIB-1 labeling index and negative staining for cytokeratin 19 and BRAFV600E, which supported the expected indolent clinical behavior. Remarkably, mutational analysis identified a heterozygous point mutation of the KRAS gene but not the BRAF genes. Eventually, we speculated that this tumor could be a possible example of a novel borderline tumor with a papillary architecture, which does not qualify as NIFTP or UMP under the current WHO criteria. The patient refused additional surgery (complete thyroidectomy), and developed no recurrence or distant metastasis for 24 months. Conclusion: We reported a significant observer variation in a noninvasive encapsulated papillary growth-patterned tumor with delicate nuclear changes and a KRAS mutation. We speculated that our case could be an example of a novel borderline tumor with a papillary structure. Further studies using a larger number of patients are needed to elucidate this disease entity, because the possible introduction of terminology such as “noninvasive encapsulated papillary RAS-like thyroid tumor (NEPRAS)” without the word “cancer” could relieve psychological burdens of the patients similar to NIFTP. Reference: (1) Nikiforov YE, et al. Nomenclature Revision for Encapsulated Follicular Variant of Papillary Thyroid Carcinoma: A Paradigm Shift to Reduce Overtreatment of Indolent Tumors. JAMA Oncol. 2016;2:1023-9.

Encapsulated Papillary Thyroid Tumor with Delicate Nuclear Changes and a KRAS Mutation as a Possible Novel Subtype of Borderline Tumor.

Although papillary thyroid carcinoma (PTC)–type nuclear changes are the most reliable morphological feature in the diagnosis of PTC, the nuclear assessment used to identify these changes is highly subjective. Here, we report a noninvasive encapsulated thyroid tumor with a papillary growth pattern measuring 23 mm at its largest diameter with a nuclear score of 2 in a 26-year-old man. After undergoing left lobectomy, the patient was diagnosed with an encapsulated PTC. However, a second opinion consultation suggested an alternative diagnosis of follicular adenoma with papillary hyperplasia. When providing a third opinion, we identified a low MIB-1 labeling index and a heterozygous point mutation in the KRAS gene but not the BRAF gene. We speculated that this case is an example of a novel borderline tumor with a papillary structure. Introduction of the new terminology “noninvasive encapsulated papillary RAS-like thyroid tumor (NEPRAS)” without the word “cancer” might relieve the psychological burden of patients in a way similar to the phrase “noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP).”

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.

Assessment of Histopathological Grade and Ki-67 Expression in Tobacco and Non-tobacco Habitual Buccal Mucosa Cancer

Although there are various risk factors in the literature, the established primary risk factor for oral cancer is tobacco and betal-nut chewing habits. It is believed that pathogenesis of oral cancer depends on the aetiology. To assess the histopathological grade and Ki-67 expression in tobacco (smoking/smokeless) and non-tobacco (betal nut/pan masala) habitual buccal mucosa cancer. The cross-sectional study was carried out in Regional cancer centre, Tamilnadu. Proliferative marker, Ki-67 expression was determined by immunohistochemistry using biotin-streptavidin method. The study includes 117 buccal mucosa cancer patients (61 male and 56 female). According to WHO grading system, high frequency observed with well differentiated squamous cell carcinoma 48 (41%) followed by moderate 46 (39.3%) and poorly differentiated 23 (19.7%). The cut-off value 50% was used to categorize Ki-67 expression into low and high labelling index (LI); 96 (82%) buccal mucosa cancer and 4 (3.4%) adjacent normal mucosa patients showed high Ki-67 expression. The present study showed highly significant association of histopathological tumor grade and Ki-67 expression by Chi square and paired t test p < 0.05. All the patients were grouped as tobacco 87 (74.4%) and non-tobacco habitual 30 (25.6%) in 3:1, respectively. Further, the risk habits identified with significant differences of tumor grade (p = 0.028) and Ki-67 at p < 0.05. Thus, the study revealed that the nature of cell differentiation and proliferation was strongly related to consumption of carcinogen in both tobacco and non-tobacco form. Therefore, histopathological grade and Ki-67 could be used as a reliable biomarker to understand the biological behaviour of risk habits which might helpful for further treatment therapeutics.

Uterine cervical mesonephric hyperplasia with focal cystic change masquerading clinicopathologically as lobular endocervical glandular hyperplasia to malignancy

IntroductionAlthough uterine cervical mesonephric hyperplasia (MH) arising from mesonephric remnants is a well-known but uncommon entity, it might pose a clinicopathological diagnostic challenge to distinguish from lobular endocervical glandular hyperplasia (LEGH) or adenocarcinoma, if MH rarely presents as a lobular and/or cystic mass with expansion of the cervical wall. However, few papers have described the detailed clinicopathological characteristics of MH compared to those benign to malignant lesions. Case presentationAn early forties Japanese female presented with a history of increased vaginal watery discharge. Multiple cystic lesions measuring less than 3 mm in diameter generated a high signal intensity on T2-weighted MRI, in the bilateral aspects of the variably enlarged uterine cervix. A gross examination of a hysterectomy specimen revealed bilateral small multicystic lesions, filled partly with secreted fluids, measuring approximately 25 × 7 × 5 mm, respectively, located in the superficial to relatively deep cervical wall. A microscopic examination showed that these lesions predominantly consisted of a lobular proliferation of small to medium-sized tubules and cysts containing occasionally periodic acid-Schiff-positive eosinophilic/pink secreted materials, lined by bland-looking cuboidal to flattened epithelium. Immunohistochemically, these lining cells were specifically positive for CD10 in a characteristic luminal staining pattern, whereas negative for MUC6, and had a low MIB-1 labeling index. We ultimately made a diagnosis of cervical MH, lobular type, with focal cystic change. ConclusionWe should be aware that, since gynecologists/pathologists might misinterpret MH as LEGH to malignancy, including the malignant counterpart of MH, a wide panel of immunohistochemical antibodies can be helpful supplemental tools.

Quality assurance trials for Ki67 assessment in pathology.

Ki67 is a broadly used proliferation marker in surgical pathology with an obvious need for standardization to improve reproducibility of assessment. Here, we present results of the so far only existing round robin tests on Ki67, organized annually in Germany, Austria, and Switzerland from 2010 to 2015 with up to 160 participating laboratories (QuIP). In each quality assessment trial, eight probes from each breast cancer, neuroendocrine tumor, and malignant lymphoma were compiled on a tissue microarray (TMA). TMAs were stained in the participants' laboratories with antibodies and procedures also applied in their daily routine. Participating pathologists were expected to assign Ki67 values to one of four different categories for each tumor type. All local stainings and evaluations were reassessed by the organizing panel and compared to a preset standard. On average, 95% of participants reached the benchmark of over 80% concordance rates with the Ki67 category pre-established by the panel. Automatization and type of antibody did not affect the success rate. Concordance rates differed between tumor entities being highest in each tumor type with either very high or very low labeling indices. Lower rates were seen for intermediate Ki67 levels. Staining quality improved during the observation period as did inter-observer concordance with 85% of participants achieving excellent agreement (kappa>0.8) in the first year and over 95% in 2015. In conclusion, regular external quality assurance trials have been established as a tool to improve the reproducibility and reliability of the prognostic and predictive proliferation marker Ki67.

Effect of menopause on hormonal receptors in ampullae of the fallopian tube with a special reference to the p53 signature.

ObjectivesAge-related changes in the expression of hormonal receptors have not been well examined in the fallopian tube (FT). We herein report the effect of menopause on the hormone receptors in ampullae of the FTs (AFTs), in comparison with cortical inclusion cysts (CICs) of the ovary.MethodsA total of 84 AFTs and 16 fimbriae of FTs, which were obtained from 26 premenopausal and 58 postmenopausal women; and 27 postmenopausal CICs were immunohistochemically studied for the expression of p53, Ki-67, estrogen receptor-alpha (ER-α), and progesterone receptor A (PRA). Apoptotic cells were identified using a TUNEL assay.ResultsPostmenopausal AFTs showed a significantly lower labeling index (LI) for Ki-67 (P<0.001), apoptosis (P=0.03), and PRA (P<0.001) than premenopausal AFTs. No significant correlation with immunohistochemical markers was found in premenopausal AFTs, but the LI for PRA was positively correlated with that for Ki-67 (P=0.004) and inversely with that for p53 (P=0.023) in postmenopausal AFTs. The expression of immunohistochemical markers was closely correlated between ampullae and fimbriae of the FT. The p53 signature (p53S) was detected in five postmenopausal AFTs (mean age: 70.2 years) and was not detected in any CICs. The immunohistochemical profile of p53S was low expression of Ki-67, apoptosis, and PRA, and high expression of ER-α. The expression of PRA in CICs was significantly higher than that in AFTs (P=0.001).ConclusionThe expression of PRA was significantly lower in postmenopausal AFTs than in premenopausal AFTs, whereas the expression of PRA was well preserved in postmenopausal CICs.

Epithelioid schwannoma of the skin displaying unique histopathological features: a teaching case giving rise to diagnostic difficulties on a morphological examination of a resected specimen, with a brief literature review

BackgroundEpithelioid schwannoma as a rare variant poses a challenge to all pathologists, as this uncommon entity is extremely difficult to conclusively diagnose by morphological analyses on a resected sample alone owing to its unique histopathological features. However, few papers have described the detailed clinicopathological characteristics of epithelioid schwannoma.Case presentationA 65-year-old female presented with a history of a flat and slightly elevated firm and tan plaque accompanied by occasional tenderness, measuring 10 × 8 mm, in the right joint of her hand 1 year before resection. A gross examination of a locally resected specimen revealed an encapsulated nodular lesion, yellow-whitish in color, partly filled with blood. A microscopic examination showed that the tumor predominantly consisted of a solid proliferation of epithelioid cells having mildly enlarged and round to partially spindled nuclei and abundant vacuolated or clear cytoplasm with very few mitotic figures and modest nuclear size variation, associated with focal hyalinized, cystic and hemorrhagic degeneration. This well-demarcated tumor was surrounded by dense, hyalinized and layered fibrocollagenous stroma. Immunohistochemically, these tumor cells were diffusely positive for S-100 protein and had a very low MIB-1 labeling index, and type IV collagen was strongly reactive with reduplicated basal lamina of them. We ultimately made a diagnosis of cutaneous epithelioid schwannoma.ConclusionWe should be aware that, since pathologists might misinterpret epithelioid schwannoma as other soft tissue tumors, including its malignant counterpart, a wide panel of immunohistochemical antibodies can be powerful supplementary tools for identifying a very rare entity of conventional schwannoma.

MCMs expression in lung cancer: implication of prognostic significance.

Minichromosome Maintenance (MCM) proteins play essential roles in various cancers. We previously reported that MCM7 could be a prognostic biomarker in non-small cell lung cancer (NSCLC). The purpose of current study is to explore roles of other MCM proteins in NSCLC and their correlation with clinico-pathologic parameters of NSCLC patients. We evaluated the expression of MCM2, MCM5 and MCM6 immunohistochemically in 571 primary NSCLC samples. High expression of MCM2, MCM5 and MCM6 was detected in 42.2%, 38.3% and 52.9% of tumor tissues, respectively. The expression of MCM2, MCM5 and MCM6 was significantly associated with gender (P = 0.00004, 0.00004, 0.008), tumor type (P < 0.00001, < 0.00001, 0.00001) and smoking history (P = 0.009, 0.00043, 0.002). MCM2 and MCM5 were detected more in central-type lung cancer (P< 0.006, 0.016). Higher labeling index (LI) of MCM2 was observed more frequently in aged patients (P = 0.023) and in those at later stage (P = 0.001). Higher MCM5 LIs was detected more in patients with distant metastasis (P = 0.008). Kaplan-Meier curves indicated that early-stage (stage I/II) patients with higher MCM2 LIs had a poorer OS compared to those with lower LIs (P = 0.021). And lung squamous cell carcinoma (SCC) patients presenting high MCM5 expression had shorter OS (P = 0.015). Multivariate Cox regression analysis showed that MCM5 was an independent prognostic indicator (P = 0.035, HR = 1.586, 95%CI: 1.032-2.437). We reported for the first time that higher MCM5 LIs could be an independent adverse prognostic biomarker for SCC patients.

Low Merlin expression and high Survivin labeling index are indicators for poor prognosis in patients with malignant pleural mesothelioma

IntroductionAlterations of the tumor suppressor Neurofibromatosis type II (NF2) have been reported in about 40% of Malignant pleural mesothelioma (MPM) patients. NF2 (Merlin) deficiency leads to alterations of the Hippo pathway; resulting in activation of the oncogenic Yes Associated Protein-1 (YAP1). Our aim was to investigate the association between these alterations and clinical outcomes. Material and methodsTissue microarrays composed of MPM tumors derived from 2 independent MPM cohorts were employed for this study. Immunohistochemical expression of Merlin, YAP1 and its target genes, Survivin and connective tissue growth factor (CTGF) were assessed in nuclear and cytoplasmic fractions. Cohort 1 was comprised of 145 patients intended to be treated with chemotherapy (CTX) followed by extrapleural pneumonectomy (EPP), thus both pre- and post-CTX tissues were available. Cohort 2 was comprised of 59 patients treated with EPP followed by intraoperative hyperthermic cisplatin and/or adjuvant CTX and/or radiotherapy. Marker expression was quantified by means of labeling index (%) for nuclear Survivin and by H-score for the other markers. The dichotomized marker expression was tested for the association with overall survival (OS) and freedom from recurrence (FFR). ResultsKaplan–Meier survival curves revealed a significant association between low cytoplasmic Merlin expression in pre-induction CTX tissues of cohort 1 with shorter FFR (p = 0.02) and OS (p = 0.03). The same tendency was observed in the chemotherapy naïve tissues obtained during EPP of cohort 2. Low nuclear Merlin expression in post-CTX tissues (available from cohort 1 only) was associated with shorter FFR (p = 0.04) and OS (p = 0.05). High nuclear Survivin labeling indices in both pre- and post-CTX tissues of cohort 1 was associated with shorter FFR (p = 0.02). In cohort 2, this was associated with both FFR and OS (p = 0.046 and p = 0.002, respectively). In multivariate analysis, low expression of cytoplasmic Merlin remained an independent prognosticator for shorter FFR of cohort 1 [hazard ratio (HR) = 0.5, 95% confidence interval (CI) = 0.3–0.9, p = 0.001] and OS [HR = 0.5, 95% CI = 0.3–1, p = 0.04]. High Survivin labeling index was an independent prognostic factor for shorter FFR in patients from cohort 1 [HR = 3.4, 95% CI = 1.7–6.8, p = 0.006] and shorter OS in patients from cohort 2 [HR = 2.35, 95% CI = 1.27–4.33, p = 0.006]. ConclusionsOur findings uncover the significance of Merlin protein expression and Survivin labeling index as prognosticators for poor clinical outcome in two independent MPM cohorts. If confirmed, these markers may be used to identify subgroups of patients benefitting from additional treatment.

Downregulation of sFRP-2 by epigenetic silencing activates the β-catenin/Wnt signaling pathway in esophageal basaloid squamous cell carcinoma

Basaloid squamous cell carcinoma (BSCC) of the esophagus is a rare variant of typical squamous cell carcinoma (SCC) associated with poor survival. A characteristic feature is nuclear accumulation of β-catenin, without a mutation of the gene. We studied the methylation status of Wnt antagonist genes, such as secreted frizzled-related protein (sFRP) gene family members, Wnt inhibitory factor-1 (WIF-1), Dickkopf-1 (Dkk-1), and human Dapper protein-1 (HDPR-1), and alterations of the APC, Axin1, and Axin2 genes in 30 cases of esophageal BSCC. β-catenin and sFRP (sFRP-1, sFRP-2, sFRP-4, sFRP-5) protein expression was examined by immunohistochemistry. APC, Axin1, and Axin2 gene mutations were detected in 3, 2, and 2 cases, respectively, and 6 cases (20%) harbored at least 1 alteration in these genes. Methylation of the sFRP-2 promoter region was observed in all cases, and methylation was frequent in sFRP-1 and sFRP-5, but infrequent in Dkk-1, WIF-1, sFRP-4, and HDPR-1. sFRP-2 expression was almost completely absent in 25 cases (83%), consistent with the methylation status. Nuclear accumulation of β-catenin was observed in all cases. sFRP-5 expression was associated with a low nuclear β-catenin labeling index. These results show that sFRP-2 is a target gene of hypermethylation in esophageal BSCC and suggest that sFRP-2 might contribute to BSCC tumorigenesis through the Wnt/β-catenin signaling pathway.

What do we know about the α/β for prostate cancer?

Since last decade, the debate on the parameter which reflects prostate cancer sensitivity to fractionation in a radiotherapy treatment, the α/β, has become extensive. Unlike most tumors, the low labeling indices (LI) and large potential doubling time that characterize the prostate tumor led some authors to consider that it may behave as a late responding tissue. So far, the existing studies with regard to this subject point to a low value of α/β, around 2.7 Gy, which may be considered as a therapeutic gain in relation to surrounding normal tissues by using fewer and larger fractions. The aim of this paper is to review several estimates that have been made in the last few years regarding the prostate cancer α/β both from clinical and experimental data, as well as the set of factors that have potentially influenced these evaluations.

Ancient Melanocytic Nevus: A Simulator of Malignant Melanoma

Ancient melanocytic nevus (AN) is an unusual but distinctive melanocytic neoplasm within the spectrum of simulators of malignant melanoma. This report describes 13 patients with AN where a long follow-up information was available. Histopathology is characterized by 2 populations of melanocytes, namely, one with large pleomorphic cells and the other with small melanocytes. A few mitotic figures may be present exceptionally. MIB-1 (Ki67) proliferation marker reveals an overall low nuclear labeling index. Additional important findings are stromal degenerative changes. AN must be especially differentiated from dermal melanoma arising in a nevus.

Chordoid glioma in suprasellar location with extension into the third ventricle: Smear preparation morphology of a rare tumor

We report a rare case of recurrent chordoid glioma in suprasellar region with extension into the third ventricle diagnosed peroperatively. On MRI, a brilliantly contrast enhancing lesion in the suprasellar region extending superiorly into the third ventricle and measuring 2.5 × 3 × 3.5 cm was identified. Patient had a previous history of subtotal removal of the tumor 8 months back and had received 56 Gy of postoperative radiotherapy. On smear preparation the tumor was composed of cells arranged in chords and rows in a myxoid background with sprinkling of lymphocytes. The individual cells were polygonal with moderate amount of faintly eosinophilic cytoplasm with cytoplasmic vacoules in few cells. The nuclei showed fine chromatin with small prominent nucleoli. Paraffin sections confirmed the diagnosis and on immunohistochemistry the tumor cells showed strong positivity for GFAP and focal weak positivity for EMA with low MIB-1 labeling index (<1%). To the best of our knowledge this is the first documented case of chordoid glioma described on crush cytology.

Multi-focal Myxopapillary Ependymoma in the Lumbar and Sacral Regions Requiring Cranio-spinal Radiation Therapy: A Case Report

Ependymomas are uncommon tumors that arise in the brain, spinal cord or cauda equina. Myxopapillary ependymomas is located exclusively in the conus medullaris or cauda equina, or film terminale region. In most myxopapillary ependymomas, the histological examination reveals low mitotic activity that is associated with a low MIB-1 labeling index (LI). The prognosis is generally favorable, when the appropriate treatment, including a total resection, is performed. The authors encountered a 39-year-old man with multifocal type of myxopapillary ependymomas compressing the cauda equina from the L2 to L3 level and L5-S1 level. A subtotal resection of the tumor was carried out. The histological examination revealed extremely high mitotic activity with a MIB-1 LI of 9.1%. Therefore, cranio-spinal radiation was added after surgery. The postoperative course was uneventful over the 3.5 year follow-up period.