Proliferation Rate Ki-67 Research Articles

Colorectal cancer molecular subtypes by immunohistochemistry in a patient cohort from Nigeria.

e15145 Background: Colorectal cancer (CRC) classificationusesclinico-pathological characteristics. However, patients with similar histologic features and tumor stages have different clinical outcomes and drug responses. Studies of CRCmolecular heterogeneity have used genome-wide gene-expression data to classifypatients into four consensus molecular subtypes (CMS), but the complexity of analysis has limited its use in practice. Methods: With IRB approval, tissue microarray (TMA) blocks were constructed, IHC was performed and semi-quantitative scores completed. For the MMR proteins, MLH1 (Pierce), MSH2 (LifeTechnologies), MSH6 (Novex), PMS2 (Pierce) antibodies were used. Three markers were selected from transcriptomic analysis for IHC: CDX2 (LifeTechnologies), HTR2B (LifeTechnologies), and ZEB1 (eBioscience). Ki-67 (DAKO) proliferation rate was used as anequivalent marker for β-catenin activation.The CMS1 subtype was first separated using MSI/MSS status. A panel of CDX2, HTR2B, and ZEB1was then used to distinguish between CMS4 and CMS2/CMS3 subtypes, while Ki-67 was used to separate CMS2 from CMS3 subtype. Results: Of the total evaluable 75 CRC cases(mean age 44.8 years (SD = 16.1), 38% were <40 years old, and 60% were males. Of tumors with data on tumor grade (n=66), 62% were well differentiated. 59 patients (79%) had MSS, and the remaining16(21%) had MSI (i.e. CMS1). 22 (29%) patients with increased ZEB1 and lower CDX2 expression were classified as CMS4. 37 (49%) displayed increased CDX2 and lower ZEB1 expression and were classified as CMS2 (n=24) or CMS3 (n=13). HTR2B was universally expressed, but a higher median HTR2B score of 3 was observed in CMS4 cases compared to 1 for other subtypes (p=0.0001). The CMS4 subtype was significantly more likely to occur among young patients (p<0.001): in patients < 40 years, 70% of patients were CMS4 subtype, while in patients > 40, 7% were CMS4 subtype. Of the left-sided cancers, only 5% were CMS1 subtype, while CMS1 composed 75% of right-sided cancers (p<0.001). Conclusions: Using TMAs and a panel of antibodies, we show an association of a poorer prognostic subtype (CMS4) with younger age at diagnosis. IHC-based classification and screening could be a cost effective prognostic and predictive tool for Nigerian reference laboratories.

Chondroid atypical spitzoid melanocytic tumor

Chondroid stromal change is very rare in melanocytic nevi. We present a severely atypical symmetrical Spitz tumor on the right arm of a 24-years-old man. It showed maturation and occasional mitotic figures. The melanocytes were intermingled with cartilaginous stroma. The Ki67 proliferative rate was 5%. It was weakly positive for p16 and negative for BRAF/V600E. BAP1 expression was preserved. PCR for Myriad myPath® Melanoma test was also negative.

Abstract P4-02-09: Clinical and histopathologic characteristics of breast cancer in very young patients

Abstract Background: While breast cancer risk increases with age, about 7% of breast cancer cases in the US are diagnosed in women <40 years of age. Evidence suggests that young breast cancer patients tend to have more aggressive disease subtypes, less favorable tumor biomarker profiles, higher risk of relapse, and poorer survival. However, there is no universally accepted definition of "young patients," and most studies have focused on premenopausal women or those <40 years of age, with some studies using age <35. To date, very little is known on the clinical and histopathologic characteristics of breast cancer in very young women, namely those ≤30 years of age. In this study, we describe such features in a cohort of very young women treated for breast cancer at our academic institution. Methods: Our patient population consisted of all cases of invasive breast carcinoma at Northwestern Memorial Hospital in women <40 years of age at surgery between January 1, 2009, and December 31, 2015. Very young was defined as having an age ≤30. Histopathologic features including tumor size, grade, histologic type, presence of lymphovascular invasion (LVI), lymph node status, tumor markers (ER, PR, HER2) and Ki-67 proliferation rate were recorded. Cases in which specific histopathologic features could not be determined from available materials were excluded from the corresponding analysis. The use of neoadjuvant chemotherapy, type of surgery, and the use of prophylactic surgery on the contralateral side were also recorded and analyzed. Results: A total of 301 invasive breast carcinoma cases were identified (age range 18-39). 40 cases of very young (age ≤30) women with breast cancer (13%) were identified. Nearly all very young patients were diagnosed with tumors of ductal histology (39/40, 98%). Just under half of these patients (19/40, 48%) had a T1 (<2 cm), 16/40 (40%) had a T2 (2-5 cm), and 2/40 (5%) had a T3 (>5 cm) tumor at the time of surgery. The majority of these carcinomas were grade 3 (25/39, 64%), 14/39 (36%) were grade 2, and none were grade 1 tumors. Over half of the tumors were highly proliferative with a high Ki-67 count of >20% (17/31, 55%). ER was expressed in 34/40 (85%), PR in 25/40 (63%) and HER2 in 9/40 (23%). LVI was present in half of the cases (20/40, 50%), and positive lymph nodes were identified in over a third (15/40, 38%) of the cases. Neoadjuvant chemotherapy was used in 9/40 (23%). Three patients (8%) had no residual carcinoma at the time of surgery post chemotherapy. Most of these very young patients chose a mastectomy (28/40, 70%), and 19/40 (48%) also underwent a prophylactic mastectomy on the contralateral side. Conclusions: Our study is one of the largest to date to describe the characteristics of breast carcinomas in very young women (age ≤30). Poor pathologic features such as high tumor grade, high proliferation rate, and presence of LVI were seen in half or more of these very young patients. A high rate of positive lymph nodes was also seen. Mastectomy, often with contralateral prophylactic surgery, was the procedure of choice. Further studies evaluating the molecular characteristics of these tumors and the prevalence of underlying genetic mutations are under way in this unique population of very young breast cancer patients. Citation Format: Finkelman BS, Blanco LZ, Siziopikou KP. Clinical and histopathologic characteristics of breast cancer in very young patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-02-09.

Precursor Lesions of the Vocal Cord: a Study on the Diagnostic Role of Histomorphology, Histometry and Ki-67 Proliferation.

The precise typing of precursor lesions of squamous cell carcinoma of vocal cord is of vital importance since it determines the line of therapy and prognosis. The aim of the present study is to evaluate the possible value of the types of dyskeratosis, histometry and cell proliferation rate in discriminating these lesions. The present retrospective study was based on 145 patients, classified according to the updated 2017 WHO system and included: Low-grade dysplasia (24 cases), high -grade dysplasia (53 cases), carcinoma insitu (33 cases) and microinvasive carcinomas (35 cases). Cell proliferation was assessed by immunoreactivity to Ki-67. For histometry and quantitation of Ki-67 proliferation rate, an image analysis system was used (Leica LAS, Wetzlar, Germany). Epithelial pearls (cell nests) were commonly observed in microinvasive carcinoma (82.9%) than high-grade dysplasia (5.9%). The median epithelial thickness, as well as, proliferation rate showed a significant increase according to the grade of the lesion. It is concluded that dyskeratosis pattern, histometry and Ki-67proliferation rate are valuable parameters to characterize precursor lesions. The presence of epithelial pearls, thickness > 450μm and Ki-67 > 40% denote high risk lesions that require adequate excision and/or radiotherapy.

Toward a Risk-Tailored Therapeutic Policy in Mantle Cell Lymphoma.

Mantle cell lymphoma (MCL) prognosis is strictly related to the characteristics of the disease, which can range from very indolent cases to highly aggressive and refractory ones. Here we will review the current knowledge on MCL biomarkers. Biomarker-informed diagnosis is essential for differentiating MCL from other mature B cell tumors. Diagnosis of MCL relies on the identification of the t(11;14) translocation by FISH or the consequently aberrant expression of cyclin D1 by immunohistochemistry. For the few cases staining negative for cyclin D1, SOX11 may help to define the diagnosis. Prognostic biomarkers have been proposed to stratify MCL patients, including baseline clinical aspects (leukemic non-nodal presentation, in situ presentation, Mantle cell International Prognostic Index-MIPI), pathological aspects (blastoid morphology, Ki-67 proliferation index, SOX11 expression), genetic aspects (immunoglobulin gene mutation status, TP53 deletion or mutation, CDKN2A deletion), and depth of response after treatment (PET imaging, molecular minimal residual disease). Such tools are increasingly used as a guide for therapeutic decisions. Watchful waiting approach is recommended for patients harboring favorable clinico-biological features, such as leukemic non-nodal presentation, low MIPI score, non-blastoid disease, low Ki-67 proliferation rate, mutated immunoglobulin genes, and the lack of SOX11 expression. For patients in need of frontline therapy, the decision of whether to undertake intensive regimens is based upon patient's age and comorbidities. Central nervous system prophylaxis is recommended for cases showing blastoid morphology. The duration of remission is tightly correlated to the depth of response. With the aim of achieving a longer duration of remission and survival, younger patients may pursue more intensive regimens incorporating high-dose cytarabine, followed by myeloablative consolidation chemotherapy, autologous stem cell transplantation, and rituximab maintenance. Older patients could, on the other hand, benefit from lower intensity immunochemotherapy followed or not by a maintenance therapy depending on which frontline regimen is used. Despite the identification of several potential useful biomarkers that may inform the treatment decisions and the design of clinical trials, the treatment choice remains nowadays determined by the patient age and fitness rather than by the individual patient characteristics. Tailoring therapy toward a risk-adapted strategy to accommodate the wide spectrum of disease is an urgent challenge, and clinical trials may explore the feasibility of a biomarker-defined therapeutic policy.

Anaplastic thyroid carcinoma: an epidemiologic, histologic, immunohistochemical, and molecular single-institution study

Anaplastic thyroid carcinoma (ATC) is a highly aggressive form of thyroid cancer. A single-institution thyroid cancer cohort of ATC was identified within the last 10 years at our institution. Retrospective analysis revealed that the frequency of ATC was 0.5% (11/2106 thyroid carcinomas). The average age at diagnosis of ATC was 74 years, and the female-to-male ratio was 1.2:1. ATC presented as a rapidly enlarging neck mass involving predominantly the left thyroid lobe (7/11; 64%). Cervical adenopathy was present in 7 (64%) of 11 cases. Fifty-five percent (6/11) of patients had distant metastases at the time of diagnosis. Histologically, ATC closely simulated a large variety of soft tissue sarcomas; osteoclast-like giant cell-rich tumors; squamous cell, spindle cell, and small cell carcinomas; and anaplastic/large cell lymphomas. Four tumors (4/11; 36%) showed heterologous elements, including rhabdoid and chondroid differentiation. Immunohistochemical studies showed that all ATCs lost TTF-1 and thyroglobulin expression, whereas PAX-8 expression was identified in 36% (4/11) of tumors. Intense and extensive nuclear staining of p53 (>50%) and high Ki-67 proliferative rate (>30%) were seen in all ATCs (11/11; 100%). Next-generation sequencing revealed recurrent BRAF V600E and TP53 gene mutations. Individual examples of a BRAF G469A mutation in ATC with follicular carcinoma component, EGFR, PTEN, PIK3CA, and FGFR3 mutations, were also identified, whereas 1 case of ATC showed wild-type sequencing with no identifiable alterations.

Histomorphometric evaluation of the Ki-67 proliferation rate and CD34 microvascular and D2-40 lymphovascular densities drives the pulmonary typical carcinoid outcome

Ki-67 has shown promise as a prognostic factor in pulmonary carcinoids. In this study, we sought to validate the importance of Ki-67 and study the relationships between Ki-67 and other stromal biomarkers of vascular density. We examined Ki-67, CD34, and D2-40 in tumor tissues from 128 patients with surgically excised typical carcinoid of the lung. We used immunohistochemistry and morphometry to evaluate the amount of tumor staining for cellular proliferation (Ki-67), microvascular density (CD34-MVD), and D2-40 lymphovascular density. The main outcome was overall survival, considered as life expectancy until death from metastasis. Specimens from patients with central tumors showed high CD34-MVD (P = .01), which was also significantly associated with a compromised surgical margin, lymph node metastasis, and clinical stage Ib. Equally significant was high D2-40 lymphovascular density in central specimens with a compromised surgical margin and lymph node metastasis. A high Ki-67 proliferation rate was significantly associated with tumors from patients with clinical stage IIb, IIIa, and IV disease. Multivariate Cox model analysis demonstrated that tumor location and stage, surgical margin, tumor size, and N stage were significantly related to survival time (P < .05). Quantitative staining of the tumor for Ki-67 and CD34-MVD served as prognostic factors (P < .05), which were more relevant than the surgical and pathological stage. Ki-67 greater than 5% and CD34-MVD greater than 7% staining comprise a subset of patients with higher death hazard; this outcome may harbor evidence for further prospective studies of target therapy after surgical resection.

Abstract 5011: Patient-derived organotypic cancer spheroids (PDOCS) as predictive models for the treatment of cancer in a clinically meaningful time frame

Abstract Background: Standard two-dimensional cell cultures do not retain the key characteristics of the human cancers from which they are derived and treatment effects are not always able to be replicated in vivo, making the development of alternative culturing systems paramount. Specifically, commercially available cell lines do not fully represent the mutation profiles seen in human cancers. Here we investigate the feasibility of three-dimensional PDOCS to more accurately represent the cancers from which they are derived and to predict treatment sensitivity in a clinically meaningful time frame. Methods: Surgical resection, core needle biopsies, paracentesis or thoracentesis samples from patients with various types of cancer were obtained under an approved IRB protocol, digested and spheroid cultures grown suspended in Matrigel. PDOCS were grown for up to two weeks and passaged at least once prior to treatment. PDOCS were imaged using brightfield imaging (4X) prior to treatment with vehicle or 5-fluorouracil (5-FU; 1, 10, or 100 µM) and/or radiation (2 or 5 Gy). After 2 days of treatment, the 5-FU was removed and the cultures were allowed to grow for an additional 2 days. PDOCS were re-imaged and the relative change in diameter was calculated using ImageJ software and compared to untreated controls. Optical metabolic imaging (OMI) was performed with a multiphoton microscope to probe the fluorescence lifetime and optical redox ratio of metabolic co-enzymes NAD(P)H and FAD. Single-cell analysis of each image was completed using Cell Profiler software to parse resistant cell populations in each PDOCS sample tested. DNA for mutation profile analysis was isolated and sequenced using a QIAseq targeted panel. Results: PDOCS were successfully isolated from a variety of cancers including colorectal (CRC), pancreas, lung, neuroendocrine, liver, breast, and ovarian. Key phenotypic characteristics of the tumors were retained in PDOCS cultured including crypt-like structures, mucin production and Ki67 proliferation rates. Cancer hot spot sequencing was performed comparing PDOCS and the tumors from which they were derived. Over 90% of the nonsynonymous mutations were identical, except in the setting of microsatellite instability. All driver mutations were identical (i.e., APC, KRAS, PIK3CA, TP53). Differential sensitivity to chemoradiation was observed among 4 different colorectal PDOCS treated with 5-FU and radiation (Median % PDOCS diameter change vs control: Patient A 17.1, p=0.64; Patient B -3.05, p=0.02; Patient C -19.4, p=2x10-5; Patient D -31.3, p=0.002). Similar response data were determined using OMI; however, single-cell analyses identified potentially resistant cell populations. Conclusions: PDOCS retain key characteristics of the cancers from which they are derived and can be utilized for treatment sensitivity testing in a clinically meaningful time frame. Citation Format: Cheri A. Pasch, Peter F. Favreau, Alex E. Yueh, Kwang P. Nickel, Christopher P. Babiarz, Philip B. Emmerich, Rosabella T. Pitera, Susan N. Payne, Demetra P. Korkos, Joseph T. Sharick, Carley M. Sprackling, Linda Clipson, Kristina A. Matkowskyj, Michael A. Newton, Melissa C. Skala, Michael F. Bassetti, Randall J. Kimple, Dustin A. Deming. Patient-derived organotypic cancer spheroids (PDOCS) as predictive models for the treatment of cancer in a clinically meaningful time frame [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5011.

Clinical and histologic characteristics of breast cancers in women with previous pathologic diagnosis of benign breast disease in Spain.

Women with a benign breast disease (BBD) have an increased risk of subsequent breast carcinoma. Information is scarce regarding the characteristics of breast carcinomas diagnosed after a BBD. Our aim was to point out the differences in clinical and histologic characteristics of breast carcinomas diagnosed in women with and without a previous pathologic diagnosis of BBD in the context of population-based mammography screening. Retrospective cohort study of all women aged 50-69years who were screened at least once in a population-based screening program in Spain, between 1994 and 2011 and followed up until December 2012. The mean follow-up was 6.1years. We analyzed 6645 breast carcinomas, of whom 238 had a previous pathologic diagnosis of BBD. Information on clinical and histologic characteristics was collected from pathology reports. Logistic regression was used to estimate the odds ratio (OR) and 95% confidence intervals (95%CI) of occurrence of selected histologic characteristics of breast carcinomas in women with and without a previous BBD. Women with a previous BBD had a higher proportion of ductal carcinoma insitu (DCIS) compared with women without a BBD (22.1% and 13.6%, respectively). Among those diagnosed with an invasive breast carcinoma, women with previous BBD were more likely to be diagnosed with carcinomas sized >2cm (OR=1.46; 95%CI=1.03-2.08), metastatic positive (OR=2.66; 95%CI=1.21-5.86), and with a high Ki-67 proliferation rate (OR=1.93; 95%CI=1.24-2.99). No differences were found across histologic subtypes of BBD. Screening participants with a previous pathologic diagnosis of BBD had a higher proportion of DCIS. However, invasive carcinomas detected in women with a BBD were associated with clinical and histologic characteristics conferring a worst prognosis.

Fine-needle aspiration–based grading of pancreatic neuroendocrine neoplasms using Ki-67: is accurate WHO grading possible on cytologic material?

The World Health Organization (WHO) has provided grading guidelines for pancreatic neuroendocrine neoplasms (PanNENs) based on mitotic count and Ki-67 proliferation index. Due to the desire to provide earlier tumor grading for clinical management decisions, some groups have proposed grading PanNENs at the time of fine needle aspiration (FNA) using Ki-67 proliferation rates. While a Ki-67 can be performed on FNA cell blocks, there are potential sampling limitations with this technique that may affect the reliability of the Ki-67 result. Forty-nine PanNENs with FNA cell blocks and corresponding resection material were evaluated by immunohistochemistry for expression of Ki-67. Ki-67 proliferation rate was calculated based on cell counts of >500 cells in the highest staining areas. Ki-67 scores from FNA cell blocks were correlated with Ki-67 scores from resection specimens. The FNA Ki-67 proliferation rates overall did not correlate well with the resection specimen. A linear regression analysis of the correlation between FNA %Ki-67 and resection %Ki-67 showed a slope of 3.2 and an R2=0.58. The average difference in Ki-67 proliferation rate between FNA and resection was 5.9%. Thirty-nine percent (19/49 cases) of PanNENs showed discordant grading between the FNA cell block and resection specimen. Almost all (18/19) discordant cases demonstrated a lower FNA-based grade as compared to the resection grade. FNA cell block grading using Ki-67 frequently led to under-grading of the tumor. This finding is consistent with concerns that FNA may not provide accurate grading due to the limited sampling of the tumor.

Endometrial Serous Carcinoma With Clear-Cell Change: Frequency and Immunohistochemical Analysis.

The diagnostic distinction between endometrial serous carcinoma (ESC) and endometrial clear-cell carcinoma (CCC) may occasionally be problematic, and one potentially contributing factor is the finding of clear cells in otherwise classic cases of ESC. This study aimed to define the frequency of this finding and comparatively assessed the immunophenotype of the clear cells. A review of 56 cases of ESC identified 8 (14.28%) with clear cells, representing 1% to 20% (median 7.5) of tumoral volume in these cases. In only 3 cases were clear cells discernible at low (×20) magnification. There was no significant difference in stage distribution or age between ESC patients with and without clear cells. The immunophenotypes of ESC-associated clear cells (group 1) were compared with foci of conventional ESC on another tissue block within the same case (group 2; n = 8) as well as a randomly selected cohort of CCC cases (group 3; n = 8). Groups 1 and 2 showed no significant differences regarding p53, ER, PR, Napsin-A, p504S, and hepatocyte nuclear factor 1β (HNF1β) expression, or regarding mitotic indices or Ki67 proliferation rate. In contrast, group 1 cases showed an immunophenotypic profile that was notably different from that of group 3 cases, with the former showing statistically significantly higher/more frequent expression of ER, PR, Ki67, and p53 and lower/less frequent expression of Napsin-A, p504S, and HNF1β. We conclude that clear-cell change is seen in 14% of ESCs and is discernible at low magnification in only 5%; these areas show an immunophenotype that is essentially identical to the associated background conventional ESC and are phenotypically dissimilar to CCC.

Composite Pheochromocytoma/Paraganglioma-Ganglioneuroma: A Clinicopathologic Study of Eight Cases with Analysis of Succinate Dehydrogenase.

Ganglioneuromas represent the most well-differentiated spectrum of neoplasia arising from the sympathetic nervous system, while neuroblastomas represent the most poorly differentiated counterpart, and ganglioneuroblastomas represent intermediate stages of differentiation. Small series of cases have documented the co-occurrence of ganglioneuroma with a pheochromocytoma (Pheo)/paraganglioma (PGL) component. We report the clinicopathologic features of eight such cases, diagnosed between 2003 and 2015 with a mean follow-up of 22months (1-47), which were evaluated for syndrome associations, SDHB expression, and clinical outcome. Mutations of the succinate dehydrogenase (SDH) complex subunits (A, B, C, D, and SDHAF2) have been implicated in predicting metastatic behavior and in identifying possible paraganglioma syndromes. The proliferative index was calculated by manual quantification of Ki-67-positive cells at selected hot-spots using ImageJ (NIH). In our series, composite Pheo/PGL-ganglioneuromas predominantly involved the adrenal gland (Pheo 7, PGL 1). The cases had an equal gender distribution (males 4, females 4), with a mean age at diagnosis of 67years (range 53 to 86years), an average size of 5.2cm (range 2 to 8.2cm), an average weight of 49.3g (7.8 to 144.7g, n=6), and the majority were functionally active (7 of 8, 88%). The mean Ki67 proliferation rate was 2% (range 0.3 to 3%), and all cases retained SDHB expression (8/8, 100%). No patient (0/8, 0%) developed metastatic disease on follow-up. One patient had a retroperitoneal composite PGL-ganglioneuroma in the setting of neurofibromatosis type 1. No recurrent disease or other associations were identified. In our study, composite Pheo/PGL-ganglioneuromas predominantly affected the adrenal gland in older patients, showed no loss of SDHB, and no disease recurrence was identified.

Histopathological prognostic factors of recurrence following definitive therapy for atypical and malignant meningiomas.

OBJECTIVE Patients with atypical and malignant (WHO Grade II and III) meningiomas have a worse prognosis than patients with benign (WHO Grade I) meningiomas. However, there is limited understanding of the pathological risk factors that affect long-term tumor control following combined treatment with surgery and radiation therapy. Here, the authors identify clinical and histopathological risk factors for the progression and/or recurrence (P/R) of high-grade meningiomas based on the largest series of patients with atypical and malignant meningiomas, as defined by the 2007 WHO classification. METHODS Patients diagnosed with WHO Grade II and III meningiomas between 2007 and 2014 per the WHO 2007 criteria and treated with both surgery and external beam radiation therapy were retrospectively reviewed for clinical and histopathological factors at the time of diagnosis and assessed for P/R outcomes at the last available follow-up. RESULTS A total of 76 patients met the inclusion criteria (66 Grade II meningiomas, 10 Grade III meningiomas). Median follow-up from the time of pathological diagnosis was 52.6 months. Three factors were found to predict P/R: Grade III histology, brain and/or bone invasion, and a Ki-67 proliferation rate at or above 3%. The crude P/R rate was 80% for patients with Grade III histology, 40% for those with brain and/or bone involvement (regardless of WHO tumor grade), and 20% for those with a proliferative index ≥ 3% (regardless of WHO tumor grade). The median proliferation index was significantly different between patients in whom treatment failed and those in whom it did not fail (11% and 1%, respectively). CONCLUSIONS In patients with atypical or malignant meningiomas, the presence of Grade III histology, brain and/or bone involvement, and a high mitotic index significantly predicted an increased risk of treatment failure despite combination therapy. These patients can be stratified into risk groups predicting P/R. Patients with high-risk features may benefit from more treatment and counseling than is typically offered currently.

CD5-negative mantle cell lymphoma shows a less aggressive outcome and variable SOX11 staining

Mantle cell lymphoma (MCL) is an uncommon B-cell lymphoma that prototypically expresses CD5, but a small subset is CD5 negative. The clinical significance of CD5 negativity is not yet well-elucidated. This case series aims to contribute to the understanding of CD5-negative MCL by looking at specific markers and outcome in our cases with long-term follow-up. Eight cases of CD5-negative MCL were identified in the case files at the Massachusetts General Hospital from 1978 to 2016. Clinicopathological characteristics were evaluated, including immunohistochemical stains for cyclin D1, SOX11, Ki67, and p53. Patients initially presented with involvement of lymph nodes and spleen (n = 4), sinonasal or oral mucosa (n = 2), orbital soft tissue (n = 1), and salivary gland (n = 1). On histology, the cases all showed classic MCL morphology, with a monotonous population of medium-sized cells with irregular nuclear contours. The cases were positive by immunohistochemistry for cyclinD1 (8/8 cases), essentially negative for p53 staining (8/8 cases), and mostly positive for SOX11 (5/8 cases). All cases had a low Ki67 proliferation rate (<5%). Long-term clinical follow-up on five cases showed that four patients had a clinical course complicated by multiple relapses to the skin, soft tissue, liver, and bone marrow. Seven cases with available follow-up showed an average survival of 121 months (SD 86 months), with no detectable survival difference between the SOX11 positive and negative cases. CD5-negative MCL is an uncommon subtype of MCL that overall appears to have a better prognosis and longer overall survival than classic MCL, despite SOX11 expression. The cases also show little p53 expression and a low Ki67 proliferation index.

Mantle Cell Lymphoma With MYC Rearrangement: A Report of 17 Patients.

MYC rearrangement in mantle cell lymphoma (MCL) is rare, and its clinicopathologic significance is not well defined. We report 17 cases of MCL with 8q24/MYC rearrangement, detected at the time of initial diagnosis of MCL in 10 patients and subsequently during the clinical course in 7 patients. There were 12 men and 5 women with a median age of 61 years (range, 49 to 81 y). Fourteen patients had lymphadenopathy (Ann Arbor stage III/IV), and 3 patients presented with a leukemic pattern without lymphadenopathy. Thirteen of 14 patients with available karyotyping data had a complex karyotype. In 8 cases the partner chromosome locus was an IG locus: t(8;14) (n=7) and t(8;22) (n=1). When MYC rearrangement was detected, most patients had a high-risk MCL international prognostic index, and the lymphoma cells had histologically aggressive features. Immunophenotypic analysis showed that the lymphoma cells were positive for cyclin D1 (n=16/16), Myc (9/11), and P53 (n=9/9). The Ki-67 proliferation rate was high (≥60%) in 10/11 cases. All patients received chemotherapy. The median follow-up time was 23 months. Clinical follow-up was available for 14 patients and treatment response in 13 patients. Eleven of 13 patients had refractory or relapsed disease, and 11 patients died. In conclusion, MCL with MYC rearrangement is characterized by advanced-stage disease, aggressive morphologic features, a high proliferation rate, p53 expression, a complex karyotype, and a poor prognosis. We believe these neoplasms fit within the overall concept of double-hit lymphoma, and the designation double-hit MCL may be helpful. We also believe that MYC rearrangement in MCL conveys important prognostic information that should be incorporated into the pathology report.

Diagnostic Significance of Cellular Neuroglial Tissue in Ovarian Immature Teratoma.

BackgroundImmature teratoma (IT) is a tumor containing immature neuroectodermal tissue, primarily in the form of neuroepithelial tubules. However, the diagnosis of tumors containing only cellular neuroglial tissue (CNT) without distinct neuroepithelial tubules is often difficult, since the histological characteristics of immature neuroectodermal tissues remain unclear. Here, we examined the significance of CNT and tried to define immature neuroectodermal tissues by comparing the histological features of neuroglial tissues between mature teratoma (MT) and IT.MethodsThe histological features of neuroglial tissue, including the cellularity, border between the neuroglial and adjacent tissues, cellular composition, mitotic index, Ki-67 proliferation rate, presence or absence of tissue necrosis, vascularity, and endothelial hyperplasia, were compared between 91 MT and 35 IT cases.ResultsCNTs with a cellularity grade of ≥ 2 were observed in 96% of IT cases and 4% of MT cases (p < .001); however, CNT with a cellularity grade of 3 in MT cases was confined to the histologically distinct granular layer of mature cerebellar tissue. Moreover, CNT in IT exhibited significantly higher rates of Ki-67 proliferation, mitoses, and necrosis than those in MT (p < .001). Furthermore, an infiltrative border of neuroglial tissue and glomeruloid endothelial hyperplasia were significantly more frequent in IT cases than in MT cases (p < .001).ConclusionsOur results suggest that if CNT with a cellularity grade of ≥ 2 is not a component of cerebellar tissue, such cases should be diagnosed as IT containing immature neuroectodermal tissue, particularly if they exhibit an infiltrative border, mitoses, necrosis, and increased Ki-67 proliferation.

Renal Leiomyoma and Leiomyosarcoma: A Study of 57 Cases.

Primary renal leiomyomas and leiomyosarcomas are rare, and there is a paucity of data regarding the pathologic features and outcomes of patients with these tumors. The objective of this study was to review a large series of renal smooth muscle tumors, in order to more fully elucidate their natural histories. Fifty-seven renal smooth muscle tumors were reviewed for various histopathologic features, and leiomyosarcomas were graded using the French Federation of Cancer Centers (FNCLCC) system. Tumor cores in tissue microarrays were evaluated for smooth muscle actin, desmin, h-caldesmon, calponin, myogenin, cytokeratin (OSCAR), CD117, Ki67, estrogen receptor (ER), progesterone receptor (PR), and Wilms tumor 1 (WT1). Leiomyomas were selected on the basis of preexisting diagnostic criteria, which included a lack of cytologic atypia, necrosis, and mitotic activity (0 to 1 mitoses/10 hpf). These were found to have a strong predilection for women, tended to arise from the renal capsule, were small (mean size, 4.2 cm), and had a low Ki67 proliferative rate (mean 1.4%). In addition, they uniformly expressed all smooth muscle markers and were ER/PR/WT1 positive in nearly all cases. In 10 patients with clinical follow-up, none had a tumor recurrence. In contrast, leiomyosarcomas had an equal sex distribution, were larger (mean size, 9.8 cm), had significantly higher mitotic activity (mean 8.6 mitoses/10 hpf), with most being FNCLCC grade 2. Leiomyosarcomas expressed at least 1 muscle marker, higher Ki67 proliferative activity (mean 20.4%) than leiomyomas, and most were ER/PR/WT1 negative. Tumor recurrence occurred in 65% of patients, and 35% of patients died of disease. This study therefore validates existing criteria to distinguish between leiomyomas and leiomyosarcomas.

F45 - The power of traditional prognostic factor and immunohistochemical (IHC) surrogate molecular subtypes of breast cancer (BC) in predicting neoadjuvant chemotherapy response: results of a retrospective study

Background: Neoadjuvant chemotherapy (NAC) improves surgical outcomes in local advanced BC when mastectomy is technically impossible and in early cases of operable BC desiring breast conservative surgery. Many clinical trials established the prognostic significance of pathological complete response (pCR) after NAC. In this study we assessed both traditional prognostic factor (histological grade (G), ER/PR status, Ki-67 rate, HER2 overexpression) as well as the surrogate intrinsic subtypes BC reclassification regarding their power to predict neoadjuvant chemotherapy benefit. Patients and methods: We reviewed data of 58 patients with BC at Stage II and III that received in a single oncology unit NAC with Anthracyclines and Taxanes +\- Trastuzumab according HER2 overexpression between 2010 and 2015. pCR was defined as no evidence of residual invasive cancer (or very few scattered tumor cells) in primary tumor and lymph nodes. Interactions between pCR and single HIC prognostic factors (ER/PR receptors, HER2 status, Ki-67) and each surrogate molecular subtype (Luminal A-like, Luminal B-like HER2-, Luminal B-like HER2 + , HER2-enriched, Triple Negative) of BC were analyzed. Results: In our retrospective study, eighteen (31%) out the 58 patients achieved pCR. Higher rate of pCR was observed in patients with ER and PR negative BC (p = 0.01 and p = 0.005, respectively) with high ki-67 proliferation rate (p= 0.01), and HER2+ overexpressed (p = 0.01) BC tumors. The multivariate analysis indicated that HER2 overexpression was the most important predictive factor to pCR (HR 8.239 p = 0.01). As regard IHC surrogate intrinsic subtypes reclassification, Triple Negative tumors (33%), Luminal-B HER2+ (27.8%) and HER2 enriched (22%) BCs show much higher rates of pCR. Conclusions: Our findings may influence clinical practice. In fact, in patients who received NAC for locally advanced BC, traditional prognostic factors as ER, PR, Ki-67, and HER2 overexpression appeared to be also predictive biomarkers of chemotherapy efficacy. The highest rate of pCR was observed in Triple Negative tumors. Patients who received NCT combined with Trastuzumab exhibited a higher pCR rate than those who received other regimens.

Clinical and Pathologic Correlation of Increased MYC Gene Copy Number in Diffuse Large B-Cell Lymphoma.

Only a few studies have investigated the presence of increased MYC gene copy number (ICN) as a prognostic indicator in patients with diffuse large B-cell lymphoma (DLBCL), and the results have been variable. We compared overall survival in patients with ICN to MYC-negative patients and investigated the prognostic significance of increased MYC gene copy number. Two groups, those with MYC ICN (n= 33) and those with no MYC aberrations (n= 43), identified by fluorescence in-situ hybridization DNA probes for the MYC region at 8q24, were compared for survival (1-9 years), MYC immunohistochemical (IHC) protein expression, and treatment protocol. Comparison of cases of DLBCL with MYC ICN to those with no MYC aberration demonstrated no significant difference in survival (P= .58). Additionally, no difference in survival was found between patients with increased MYC protein expression (IHC MYC≥ 40%) compared to those with IHC MYC< 40% (P= .5). Comparison of Ki-67 proliferation rates, stratified into low and high groups, did not achieve statistical significance (P= .67). Patients with MYC ICN showed a slightly increased MYC protein expression (P > .05). Importantly, the majority of patients in both groups (79% of patients with ICN and 81% of patients with no MYC aberrations) were treated with rituximab-based therapies. No significant difference in survival was found between patients with DLBCL with MYC ICN and patients with no MYC aberrations (P= .58).

An alternate red and white colour-changing rectal carcinoid tumour

A 56-year-old female presented with a 3-month history of iarrhoea and abdominal pain. Colonoscopy examination found a ass (approximately 0.5 × 0.6 × 0.3 cm) in the rectum 5 cm from he anus. The overlying mucosa regularly alternated colour from hite (Fig. 1) to red (Fig. 2) approximately every 10 s. Endoscopic ltrasonography revealed its origin in the submucosa, and rectal arcinoid tumour was suspected. However, an ulcerative lesion was ound in the transverse colon, and was pathologically diagnosed as denocarcinoma. The patient underwent transanal local excision or rectal neoplasm and laparoscopic radical resection of transverse olonic carcinoma in the Department of Surgery. Immunohistohemical results of rectal neoplasm were positive for Syn, CD56, gA, CK and Ki-67 proliferation rate of 2%; thus, rectal carcinoid umour was confirmed. Postoperative course was unremarkable, nd the patient was discharged 3 weeks postoperatively.