Cellular pleomorphism in papillary tumors of the pineal region

Papillary tumor of the pineal region (PTPR) is a recently recognized entity. We present the pathologic findings of two cases of PTPR as examples, and discuss the presence of cellular pleomorphism in these tumors. Patient 1 is a 48-year-old man with a pineal region mass. The tumor had unique biphasic patterns, papillary/pseudopapillary areas, and increased mitotic activity. Juxtaposed areas had marked pleomorphism, including nuclear enlargement, smudgy chromatin, nuclear pseudoinclusions, and cytoplasmic vacuolation. Mitoses were absent in these areas. Immunohistochemical staining revealed strong S100 expression. CAM 5.2 and CK18 were strongly positive in a patchy fashion. MIB1 labeling indices were high in classic PTPR regions but very low in pleomorphic areas. Patient 2 was a 35-year-old male with a pineal region tumor characterized by papillary architecture and overall cellular monotony, rare mitoses, and pleomorphism as a more isolated finding, with associated nuclear enlargement and crowding. S100 and CAM 5.2 labeling were present, and MIB1 labeling index was very low throughout the tumor. We discuss the pathologic and phenotypic features of PTPR. Variable pleomorphism may be present, reflected in size variation and nuclear hyperchromasia, but was not accompanied by increased proliferative activity in these cases, suggesting a degenerative phenomenon.     

Successful treatment of neoadjuvant therapy for papillary tumor of the pineal region

We report a boy who in 1994, at the age of 11, presented with headache and vomiting. The fi nal diagnosis was papillary tumor of the pineal region (PTPR). Magnetic resonance imaging (MRI) revealed a heterogeneous mass. Hydrocephalus was addressed by immediate ventricle drainage; subsequently, we attempted tumor removal. As the intraoperative diagnosis of the hemorrhagic tumor was primitive neuroectodermal tumor (PNET), we did not proceed to total removal. After the delivery of radiotherapy (50.4 Gy) and one course of Nimustine hydrochloride (ACNU) chemotherapy, the residual tumor was completely resected. The diagnosis at that time (1994) was papillary pineocytoma. He was followed on an outpatient basis for 15 years and remained free of recurrence. This type of tumor was later proposed to represent a new distinct tumor subtype, papillary tumor of the pineal region (PTPR). Our data indicate that our patient’s tumor should be included in this category.     

Clinicopathological features from long-term observation of a papillary tumor of the pineal region (PTPR): a case report

Papillary tumor of the pineal region (PTPR) was recently added to the 2007 WHO classification of tumors of the central nervous system as a rare pineal tumor. We present a case of a 17-year-old man who developed a 3-cm pineal tumor that was incompletely excised following two operations. The pathological findings presented were extensive epithelial papillary structures surrounding vessels mimicking “perivascular pseudo-rosettes,” leading to a diagnosis of “papillary ependymoma.” Subsequently, the residual tumor recurred on three separate occasions. Immunohistochemical studies showed the tumor was positive for cytokeratin 18 (CK 18), microtubule-associated protein (MAP 2), neuron-specific enolase (NSE), neuronal nuclei (NeuN), and transthyretin, consistent with mature neuronal differentiation. Given these findings, the diagnosis of PTPR was made. The patient’s survival time of 218 months is the longest reported to date for this tumor.     

Pineal parenchymal tumor of intermediate differentiation with papillary features: a continuum of primary pineal tumors?

Pineal parenchymal tumors comprise a rare group of primary neoplasms of the pineal gland. We describe a case involving a 29-year-old woman who presented with signs and symptoms of hydrocephalus secondary to a pineal region tumor obstructing the third ventricle. Surgical resection was performed and pathological analysis revealed a novel diagnosis consistent with a pineal parenchymal tumor of intermediate differentiation (PPTID) with transition to a papillary tumor of the pineal region (PTPR). To our knowledge, this particular pineal region tumor pathology has not yet been reported in the literature and highlights the continuum with which primary pineal tumors exist. We provide a review of the existing literature on pineal region tumors, specifically PTPR and PPTID, and offer insight into the management of these rare neoplasms.     

Comparative analysis of [3H]-thymidine labelling index and monoclonal antibody Ki-67 in non-Hodgkin's lymphomas

The relation between the [³H]-thymidine labelling index (3H-Thy LI), which evaluates the S-phase cells, and the monoclonal antibody Ki-67 (MoAb Ki-67), which recognizes a nuclear antigen expressed during the cell cycle, was defined in 35 non-Hodgkin's lymphomas (NHL). Significantly higher median values of [³H]-Thy LI and Ki-67-positive cells were observed for high-grade than for low-grade malignancy tumours according to the Kiel classification, but with wide and overlapping values for the two morphologic subgroups. A significant correlation was observed between [³H]-Thy LI and Ki-67-positive cells (P < 0.0001; r = 0.62). However, the ratio between the two cell kinetic variables on individual tumours was not constant. It sharply increased with decreasing [³H]-Thy LI values and was much higher in low-grade NHL than in high-grade NHL. Follow-up studies are needed to establish the role of the tumour growth fraction as evaluated by MoAb Ki-67 as a prognostic indicator in NHL.     

Complete regression of papillary tumor of the pineal region after radiation therapy: case report and review of the literature

Papillary tumor of the pineal region (PTPR) is a rare neuroepithelial tumor that arises in the pineal region. The optimal treatment for PTPR remains controversial, as no definitive treatment strategy exists for this lesion. It is not clear whether aggressive surgical removal is superior to biopsy followed by radiotherapy. The majority of cases in the literature have undergone attempted gross total resection with a supracerebellar-infratentorial or a transcallosal-transventricular approach. In this report, we describe a case of PTPR in a 23 year-old male that presented as a third ventricular mass causing obstructive hydrocephalus. An endoscopic third ventriculostomy was performed followed by an endoscopic biopsy. Postoperative radiotherapy resulted in complete regression of the tumor with no evidence of tumor recurrence at 25 months. This case highlights a minimally invasive strategy for a rare neoplasm that resulted in a favorable response to radiation therapy, thereby avoiding the risks of aggressive surgical removal. We also review the radiographic and histopathologic features of PTPR and discuss various options of treatment reported in the literature.     

Determination of proliferative activities in human brain tumor specimens: a comparison of three methods

Summary Proliferative activities were determined in 72 human brain tumors, including 20 metastatic carcinomas, 41 gliomas, 8 meningiomas and 3 hematological tumors. Immunocytochemical techniques included labeling with monoclonal antibody (mAb) to bromodeoxyuridine (BrdU) which identifies S phase cells after previous in vitro BrdU incubation and paraffin embedding of fixed tissue specimens, and with mAb Ki-67 which reacts, in frozen sections, with a nuclear antigen expressed by all proliferating cells. BrdU labeling index (LI), Ki-67 LI and mitotic index (MI) correlated well with histological malignancy. Among the three proliferation indices, Ki-67 LI and BrdU LI were highly significantly correlated. With the exception of hematological malignancies, hyperbaric oxygenation of in vitro BrdU labeling did not significantly increase BrdU LI or depth of BrdU penetration into tissue. This study indicates that in vitro BrdU labeling is a useful alternative to Ki-67 immunolabeling of human brain tumor specimens. By such determination of tumor proliferation, it might be possible to design a more adequate postoperative therapy tailored to patients individually.     

Topoisomerase II alpha expression and the Ki-67 labeling index correlate with prognostic factors in estrogen receptor-positive and human epidermal growth factor type-2-negative breast cancer

Background

Topoisomerase II alpha (Topo IIa) is involved in DNA replication and is a molecular target for anthracycline-based chemotherapy. The Ki-67 labeling index (LI) is an evaluation of tumor cell proliferation. The objective of this study was to evaluate relationships among Topo IIa expression, the Ki-67 LI, and prognostic factors in estrogen receptor (ER)-positive, human epidermal growth factor type-2 (HER2)-negative breast cancer.

Materials and methods

Seventy-one patients were diagnosed with ER-positive, HER2-negative breast cancer between July 2003 and December 2004. Formalin-fixed, paraffin-embedded tumor specimens were stained for Topo IIa expression and Ki-67 LI. We investigated the correlation of the level of Topo IIa expression and the Ki-67 LI with clinical factors such as age, tumor size, progesterone receptor status, nodal status, nuclear grade, and lymphovascular invasion (LVI).

Results

Statistically significant differences were observed between Topo IIa overexpression, nuclear grade (p?=?0.036), and LVI (p?=?0.029). Topo IIa overexpression was statistically correlated with the Ki-67 LI (p?p?=?0.01). Survival analysis revealed the significant prognostic value of Ki-67 LI in patients with ER-positive, HER2-negative breast cancer (p?=?0.003).

Conclusions

Ki-67 LI is a strong prognostic factor in ER-positive HER2-negative breast cancer. Topo IIa overexpression was significantly correlated with the Ki-67 LI, nuclear grade, and LVI. These findings suggest use of Topo IIa expression as a proliferation marker and a prognostic factor in ER-positive, HER2-negative breast cancer.     

Bevacizumab is Effective for Recurrent Papillary Tumor of the Pineal Region: First Report

Papillary tumor of the pineal region (PTPR) is a rare brain tumor that probably arises from ependymal cells. There are no known systemic treatments for PTPR once it is refractory to surgery and radiation. We present the first case of a durable radiographic and clinical response of a PTPR to bevacizumab, an antibody against vascular endothelial growth factor, despite multiple prior treatments. Bevacizumab may be an effective treatment for PTPR.Key words: Pineal tumor, Bevacizumab, Angiogenesis     

Histopathologic validation of 3′-deoxy-3′-F-fluorothymidine PET for detecting tumor repopulation during fractionated radiotherapy of human FaDu squamous cell carcinoma in nude miceF-FLT PET repopulation -->

Background and purpose

FaDu human squamous cell carcinoma (FaDu-hSCC) demonstrates accelerated tumor repopulation during fractionated irradiation with pathological validation (Ki-67 and BrdUrd makers) in a xenograft model system. However, these and other functional assays must be performed ex vivo and post hoc. We propose a novel, in vivo, real-time assay utilizing ¹⁸F-FLT PET.

Material and methods

Nude mice with FaDu-hSCC were irradiated with 12 or 18 fractions of 1.8 Gy ([Dm] = 3.0 Gy), either daily or every second day. ¹⁸F-FLT micro-PET scans were performed at different time points, FLT parameters (SUVmax, SUVmean, and T/NT) were measured. Tumor sections were stained for Ki-67 and BrdUrd, a labeling index (LI) was calculated. Imaging-pathology correlation was determined by comparing FLT parameters and immunohistochemical results.

Results

Measured SUVmax, SUVmean and T/NT decreased significantly after daily irradiation with 12 fractions in 12 days (P < 0.05) and 18 fractions in 18 days (P < 0.05). In contrast, these parameters increased in mice treated with 12 fractions in 24 days (P > 0.05) and 18 fractions in 36 days (P > 0.05), suggesting accelerated repopulation. Similarly, Ki-67 and BrdUrd LIs demonstrated significant decreases with daily irradiation (P < 0.05), and increases with every-second-day irradiation (P > 0.05). ¹⁸F-FLT parameters correlated strongly with proliferation markers (r²: 0.679–0.879, P < 0.001).

Conclusions

¹⁸F-FLT parameters were in good agreement with Ki-67 and BrdUrd Li. These results may support a potential role for ¹⁸F-FLT PET in real-time detection of tumor repopulation during fractionated radiotherapy.     

Neuroradiological follow-up of the growth of papillary tumor of the pineal region: a case report

Papillary tumor of the pineal region (PTPR) is a recently described distinct clinicopathological entity. The purpose of this case report is to increase the knowledge of its neuroradiological findings and natural history by describing the long-term clinical and neuroradiological follow-up of a PTPR occurring in a 56-year-old Italian male patient. At magnetic resonance imaging (MRI) obtained at diagnosis, the lesion showed a subtle high signal intensity on T1-weighted imaging. Twenty-nine months later, MRI showed clearcut enlargement of the lesion, which had only a small area of high signal intensity on T1-weighted images, and a minimum apparent diffusion coefficient of 0.854 × 10⁻³ mm²/s. Treatment included surgery followed by irradiation. Three-month MRI follow-up did not show disease relapse.     

Sarcoidosis of the pineal gland: an unusual presentation of neurosarcoidosis

Introduction Sarcoidosis is an inflammatory disease characterized by noncaseating granulomas that is rarely found as primary CNS pathology. We report an unusual case of sarcoidosis involving the pineal gland with radiographic, histopathology, and clinical data. Case report A 45-year-old man without evidence of systemic sarcoidosis presented with a history of gradual onset of blurry vision and diplopia that progressed over 3 months. MR imaging demonstrated an enhancing mass in the pineal region. A suboccipital craniotomy was performed with resection of the mass through a supra-cerebellar infratentorial approach. Histopathologic analysis did not reveal a pineoblastoma but instead revealed noncaseating granulomas within the pineal gland. Extensive hematologic laboratory examinations, cerebral spinal fluid studies, and cultures for infection were all negative. This mass lesion was diagnosed as solitary neurosarcoidosis of the pineal gland, without dissemination. The patient was treated with steroids and at 4-year follow-up is asymptomatic with an unremarkable MRI scan. Conclusion This is an unusual case of pineal sarcoidosis mimicking a tumor with associated MRI, CT and histopathologic findings reported together. Although rare, sarcoidosis of the pineal gland should not be excluded from a comprehensive differential diagnosis of an enhancing pineal region mass.     

Prognostic value of proliferation assay in the luminal, HER2-positive, and triple-negative biologic classes of breast cancer

Introduction

Although the prognostic significance of proliferation in early invasive breast cancer has been recognized for a long time, recent gene-expression profiling studies have reemphasized its biologic and prognostic value and the potential application of its assessment in routine practice, particularly to define prognostic subgroups of luminal/hormone receptor-positive (HR⁺) tumors. This study aimed to assess the prognostic value of a proliferation assay by using Ki-67 immunohistochemistry as compared with mitotic count scores.

Method

Proliferation was assessed by using Ki-67 labeling index (Ki-67LI) and mitotic scores in a large (n = 1,550) and well-characterized series of clinically annotated primary operable invasive breast cancer with long-term follow-up. Tumors were phenotyped based on their IHC profiles into luminal/HR⁺, HER2⁺, and triple-negative (TN) classes. We used a split-sample development and validation approach to determine the optimal Ki-67LI cut-offs.

Results

The optimal cut-points of Ki-67LI were 10% and 50% for the luminal class. Both Ki7LI and MS were able to split luminal tumors into subgroups with significantly variable outcomes, independent of other variables. Neither mitotic count scores nor Ki-67LI was associated with outcome in the HER2⁺ or the TN classes.

Conclusions

Assessment of proliferation by using Ki-67LI and MS can distinguish subgroups of patients within luminal/hormone receptor-positive breast cancer significantly different in clinical outcomes. Overall, both Ki-67 LI and mitotic-count scores showed comparable results. The method described could provide a cost-effective method for prognostic subclassification of luminal/hormone receptor-positive breast cancer in routine clinical practice.     

Ki-67 Labeling is Correlated with the Time to Recurrence in Primary Glioblastomas

The Ki-67 labeling index (LI) was shown in many cut-off studies to be significantly correlated to the postoperative survival probability in gliomas in univariate and multivariate analyses. However, a direct relationship of the Ki-67 LI and the growth fraction, respectively, to clinical growth parameters was not demonstrated in a single tumor type of this group until now.We compared the Ki-67 LI of 20 primary glioblastomas and their recurrent tumors with the time to reoperation for recurrence. Regression analyses showed (1) a high reproducibility of the LIs at the second versus the first operation corresponding to an inherent growth potential of a given individual tumor and (2) a strong inverse correlation of LI to time to recurrence (TR) (r = –0.92). Additionally to a lower LI (corresponding to a smaller growth fraction), a longer cycle time could be derived in slowly growing as compared to rapidly growing tumors.A direct relationship of the Ki-67 LI to a clinical time parameter (the TR) was obtained, and a predictive significance of individual LIs in glioblastomas could be defined.     

Analysis of immunohistochemical expression of p53 and the proliferation marker Ki-67 antigen in skull base chordomas: relationships between their expression and prognosis

The prognosis of chordomas is difficult to predict based solely on histological findings. The purpose of this study was to assess the immunohistochemical expression of the proliferation marker Ki-67 antigen and the expression of p53 in skull base chordomas and to relate their expressions to the outcome. We examined the expression of p53 and the MIB-1 labeling index (LI), assessed by Ki-67 expression, in 19 tumors (initial, n = 11; recurrent, n = 8) from 11 patients. The correlation among the MIB-1 LI, p53 expression, and the clinical outcome was analyzed. The mean MIB-1 LI and p53 expression at the initial surgery were 5.6 ± 4.6% and 9.0 ± 9.4%, respectively. At the time of recurrence, the mean MIB-1 LI and p53 expression were 10.2 ± 7.4% and 16.5 ± 12.0%. The correlation between the MIB-1 LI and p53 expression at the initial and recurrent surgeries was highly significant (r = 0.948; P < 0.0001). The change in p53 expression from the initial to the recurrent chordomas was significantly greater in patients who died of tumor-related causes than in the surviving patients. In the surviving patients, the values for MIB-1 LI and p53 expression in the recurrent tumors were significantly higher in the disease-ongoing group than in the disease-free group. Our results suggest that determination of the immunohistochemical expression of p53 and Ki-67 antigen is helpful to predict tumor recurrence and prognosis in skull base chordomas.     

Apoptotic and proliferation indexes in primary superficial bladder tumors

Whether apoptotic index [AI] and/or Ki-67 labeling index [Ki-67LI] add prognostic information in bladder cancer remains unclear. Mean AI and Ki-67 LI increased with grade and stage in 147 superficial bladder tumors. AI (>1.7%) correlated with tumor size, grade and proliferation. Ki-67 LI (>10%) correlated with higher grade and stage. Tumor size and Ki-67 LI were independent predictors of disease-free and progression-free survival, respectively. Tumor size, patient's age and tumor's recurrence predicted overall survival. We conclude that conventional clinical parameters and Ki-67 LI define risk groups of bladder tumors, while AI has limited value.     

Recurrences of meningiomas: predictive value of pathological features and hormonal and growth factors

Summary Objective Recurrence of apparently completely resected benign meningiomas is a rather frequent event, the mechanisms of which are still unclear. The aim of this study is to define the pathological features, proliferation indexes, growth factors and hormone receptor expression in predicting the meningioma recurrence. Methods Two groups of 50 completely resected benign WHO I meningiomas, with and without recurrence respectively, have been reviewed. Tumor location, consistency, vascularity, and histological types have been considered. Immunohistological studies include mitotic index (MI), Ki-67 LI, estrogen and progesterone receptors (ER and PR), Vascular Endothelial Growth Factor (VEGF), Epidermal Growth Factor (EGF), and Bcl-2. All these factors have been correlated with the recurrence. Results The tumor recurrence was not correlated with the patient age, tumor location, consistency, vascularity and histology. There was not difference in the histological pattern between local and diffuse recurrences. M.I. and Ki-67 LI were significantly correlated with the recurrence (P<0.0001). PR negativity had a strong predictive value of recurrence (P<0.0001), whereas the ER status was not relevant. VEGF and EGF-R were not correlated with the recurrence of meningiomas, whereas the Bcl-2 protein positivity showed a tendency to the significativity (P=0.0294). The negative association between Bcl-2 and PR is an interesting finding of our study. Conclusions Higher MI and Ki-67 LI and PR negativity are predictive factors of recurrence of benign (WHO I) completely resected meningiomas, particularly when Bcl-2 positivity is associated.     

Identification of Luminal Subtypes of Breast Carcinoma Using Surrogate Immunohistochemical Markers and Ascertaining Their Prognostic Relevance

BackgroundTherapeutic decisions in breast carcinoma are being made on the basis of tumor cell proliferation using exorbitant genomic tests. The 2013 St Gallen meeting advocated surrogate definitions for classifying tumors into luminal subtypes on the basis of immunohistochemical (IHC) markers. We studied the classification of estrogen receptor (ER)-positive tumors using these definitions as well as different methods for Ki-67 labeling index (LI) estimation.Patients and MethodsA total of 541 ER⁺ invasive breast carcinoma cases from January 2012 to December 2012 were evaluated for Ki-67 LI by the average and hot spot methods. The IHC results of ER, PR, and human epidermal growth factor receptor 2 (HER2) were noted. HER2 IHC equivocal (2+) samples were subjected to HER2 fluorescence in-situ hybridization testing. Luminal subgroups created on the basis of the 2013 St Gallen meeting guidelines were correlated with clinicopathologic variables and disease-free survival.ResultsThe distribution of luminal subtypes was as follows: luminal A–like, 13.3%; luminal B–like (HER2⁻), 57.9%; and luminal B–like (HER2⁺), 28.8%. Approximately 6% of cases were recategorized into different subgroups when the average method was used instead of the hot spot method for Ki-67 LI assessment. Younger patients (≤ 50 years), grade 3 tumors, positive axillary nodes, recurrence, and distant metastasis had a positive statistical correlation with luminal B–like (HER2⁻) subtype. Patients with luminal B–like (HER2⁻) tumors had a shorter disease-free survival compared to patients with luminal A–like tumors.ConclusionKi-67 LI, irrespective of the method of assessment, along with PR, can be efficiently used to divide ER⁺ tumors into prognostic subgroups in Indian patients.     

Papillary tumor of the pineal region

Tumors of the pineal region are rare in adulthood, accounting for approximately 1% of intracranial neoplasms in this age range. Papillary tumor of the pineal region (PTPR) was first described by Jouvet et al. in 2003. In 2007, PTPR was included by the World Health Organization as a distinct entity in their new classification of central nervous system tumors. We report a case of PTPR, and undertake a literature review of this rare neuroepithelial neoplasm. Patients with PTPR need long-term follow up, and new cases should be well documented so that we can gain a better understanding of this neoplasm.     

Comparison of visual and automated assessment of Ki-67 proliferative activity and their impact on outcome in primary operable invasive ductal breast cancer

Background:

Immunohistochemistry of Ki-67 protein is widely used to assess tumour proliferation, and is an established prognostic factor in breast cancer. There is interest in automating the assessment of Ki-67 labelling index (LI) with possible benefits in handling increased workload, with improved accuracy and precision.

Patients and methods:

Visual and automated assessment of Ki-67 LI and survival were examined in patients with primary operable invasive ductal breast cancer. Tissue microarrays (n=379 patients) immunostained for Ki-67 were scored visually and automatically with the Slidepath Tissue IA system.

Results:

Visual and automated Ki-67 LI were in excellent agreement (ICCC=0.96, P<0.001). On univariate analysis, visual (P<0.001) and automated Ki67 LI (P<0.05) were associated with cancer-specific survival in patients with invasive ductal breast cancer overall and in patients who received endocrine therapy (Tamoxifen) (P<0.01 for visual and P<0.05 for automated scoring).

Conclusion:

Automated assessment of Ki-67 LI would appear to be comparable to visual Ki-67 LI. However, automated Ki-67 LI assessment was inferior in predicting cancer survival in patients with breast cancer, including patients who received Tamoxifen.