Clinically Discordant Indolent Lymphomas: A Subset of Indolent NHLs with a Less Favorable Prognosis and Propensity to Transform

Abstract INTRODUCTION: The typical presentation of patients with low grade lymphoma consists of disseminated lymphadenopathy, absence of constitutional symptoms, normal LDH, low Ki-67 and PET scan with low SUVs (i.e. <14). We have identified a subset of atypical cases who present with one or more clinically aggressive features. We have named these cases clinically discordant indolent histologies (CDIH). The goal of this study is to identify these cases with CDIH in order to determine if their prognosis and clinical behavior are different from those with the typical low grade NHL presentation. METHODS: We defined CDIH as any follicular grade 1-2, grade 3-A or small lymphocytic lymphoma (SLL) who meet at least one or more of the following conditions: constitutional symptoms, unexplained LDH elevation, PET SUV >14, Ki67 >30%, unusual areas of involvement for indolent NHL (bone, pleura, CNS, soft tissue, lung), necrotic areas seen in CT scan or discrete space occupying lesions in liver or spleen. We analyzed their failure free survival (FFS), overall survival (OS), rate of transformation to a high grade histology and correlation with FLIPI-2 prognostic score. RESULTS: A total of 97 cases (86 follicular, 11 SLL) with a median follow up of 56 months were identified from our data base. Of these 97 cases, 46 met the criteria for CDIH. Figure 1 shows the FFS of cases with CDIH as contrasted with 51 without CDIH. As is evident from Figure 1, those with CDIH not only had a higher relapse rate but also showed a trend for earlier relapses (within 3 years), reminiscent of high grade NHLs. Figure 2 depicts the OS of CDIH cases which is significantly inferior. We also analyzed the risk of transformation. The rate of transformation of CDIH was 5/46 (11%) in contrast to 0/51 with non CDIH (p=.02). All episodes of transformation occurred early, between 6 to 35 months from diagnosis. In order to determine if there was an underlying lymphoma of high grade histology at diagnosis, 8 cases with CDIH underwent a second biopsy of a site suspected of harboring an aggressive NHL because of findings such as SUV of ≥14. None of the 8 cases showed evidence of a high grade NHL in the second biopsy. In nearly all (94/97=97%) treatment included rituximab in combination with chemo and 80% of these were given maintenance. Management consisted of: Treatment A (n=55)-non-doxorubicin regimens, mostly fludara or bendamustine based; Treatment B (n=19)-R-CHOP; Treatment C (n=23)-R-CHOP x 6 followed by fludara based regimen (FND) x 4. The latter was used primarily for CDIH. Of the 46 cases of CDIH, 31 were treated with a doxorubicin-rituximab combination (either Treatment B or C). Their OS at 8 years was 98 % vs 62% for those who received a non- doxorubicin regimen (Treatment A), p=0.014. Of 40 cases without CDIH who received Treatment A, only 1 has relapsed. FLIPI-2 prognostic score correlated poorly with CDIH: of 23 with high risk score, 12 had CDIH and of 7 with low risk, 3 were CDIH. CONCLUSIONS: 1-Cases with CDIH have less favorable OS, FFS, and higher rate of transformation to a higher grade histology. 2-In spite of the fact that CDIH histologically is identical to an indolent NHL, it functionally behaves as an aggressive NHL with frequent early relapses. 3-FLIPI-2 prognostic score correlates poorly with CDIH. This is not surprising since FLIPI-2 score doesn't include B symptoms and LDH. 4-Confirmatory biopsies to rule out co-existing high grade NHL at diagnosis are not useful or recommended. 5-Those without CDIH do very well when treated with a non-doxorubicin regimen such as a fludarabine-rituximab containing combination while CDIH cases appear to fare better when treated with a doxorubicin-rituximab containing regimen. These conclusions have to be interpreted in light of the retrospective nature of the study. Disclosures No relevant conflicts of interest to declare.

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Immunocytochemical expression of Ki-67/p16 in normal, atypical, and neoplastic cells in urine cytology using BD SurePath™ as preparation method

CytoJournal ◽

10.4103/cytojournal.cytojournal_9_19 ◽

2019 ◽

Vol 16 ◽

pp. 26 ◽

Cited By ~ 1

Author(s):

Kirsten Margrethe Østbye ◽

Mette Kristin Pedersen ◽

Torill Sauer

Keyword(s):

Urine Cytology ◽

Low Grade ◽

High Grade ◽

Ki 67 ◽

Additional Information ◽

Additional Marker ◽

Dual Positivity ◽

Normal Controls ◽

Dual Staining

Objective: The objective of this study was to investigate the expression of Ki-67/p16 in urothelial cells in cytological material. Materials and Methods: There were 142 urines including normal controls, anonymous rest urine, controls after treatment for urothelial carcinoma (UC) and newly diagnosed UC. Immunocytochemistry for ki-67/p16 dual staining kit was performed on all specimens. Results: Eight high-grade UC and six anonymous specimens showed dual positivity. None of the low-grade UC or the control specimens after treated UC showed dual staining. Fifteen of 84 (17.8%) symptomatic cases were negative for both markers, and 59/84 (70.2%) showed positivity for both but not dual staining. Twenty-seven of 84 cases were positive for either Ki-67 (n = 22) or p16 (n = 5). Normal controls and benign specimens were negative for p16. Conclusions: Co-expression of p16/Ki-67 in the same cells was found in 16.6% of the cases. All were high grade, and co-expression seems to have limited practical impact as an additional marker in urine cytology. Any positivity for p16 alone strongly indicates malignancy. Negative p16 accompanied by a positive Ki-67 rate at 5% or more could be considered as an additional marker for further clinical follow-up. Both markers, co-expressed and separate, can give additional information in follow-up patients after treatment for UC.

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High-Grade Progression Confers Poor Survival in Pancreatic Neuroendocrine Tumors

Neuroendocrinology ◽

10.1159/000504392 ◽

2019 ◽

Vol 110 (11-12) ◽

pp. 891-898 ◽

Cited By ~ 5

Author(s):

Johan Botling ◽

Angela Lamarca ◽

Duska Bajic ◽

Olov Norlén ◽

Vincent Lönngren ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Tumor Grade ◽

University Hospital ◽

High Grade ◽

Pancreatic Neuroendocrine Tumors ◽

Ki 67 ◽

Grade 3 ◽

Over Time ◽

Grade Progression

Introduction: Little is known about how pancreatic neuroendocrine tumors (PanNETs) evolve over time and if changes toward a more aggressive biology correlate with prognosis. The purpose of this study was to characterize changes in PanNET differentiation and proliferation over time and to correlate findings to overall survival (OS). Patients and Methods: In this retrospective cohort study, we screened 475 PanNET patients treated at Uppsala University Hospital, Sweden. Sporadic patients with baseline and follow-up tumor samples were included. Pathology reports and available tissue sections were reevaluated with regard to tumor histopathology and Ki-67 index. Results: Forty-six patients with 106 tumor samples (56 available for pathology reevaluation) were included. Median Ki-67 index at diagnosis was 7% (range 1–38%), grade 1 n = 8, grade 2 n = 36, and grade 3 n = 2. The median change in Ki-67 index (absolute value; follow-up – baseline) was +14% (range –11 to +80%). Increase in tumor grade occurred in 28 patients (63.6%), the majority from grade 1/2 to grade 3 (n = 24, 54.5%). The patients with a high-grade progression had a median OS of 50.2 months compared to 115.1 months in patients without such progression (hazard ratio 3.89, 95% CI 1.91–7.94, p < 0.001). Conclusions: A longitudinal increase in Ki-67 index and increase in tumor grade were observed in a majority of PanNETs included in this study. We propose that increase in Ki-67 index and high-grade progression should be investigated further as important biomarkers in PanNET.

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Exploration of Novel Prognostic Markers in Grade 3 Neuroendocrine Neoplasia

Cancers ◽

10.3390/cancers13164232 ◽

2021 ◽

Vol 13 (16) ◽

pp. 4232

Author(s):

Rebecca Abdelmalak ◽

Mark P. Lythgoe ◽

Joanne Evans ◽

Michael Flynn ◽

Justin Waters ◽

...

Keyword(s):

Risk Stratification ◽

Prognostic Markers ◽

Prognostic Score ◽

Multivariable Analysis ◽

Glasgow Prognostic Score ◽

Prognostic Scores ◽

High Grade ◽

Ki 67 ◽

Lymphocyte Ratio ◽

Grade 3

Background: High-grade neuroendocrine tumours and carcinomas (NET/NECs) behave aggressively, typically presenting at an advanced stage. Prognosis is poor, with median survival between 5 and 34 months. The mainstay of treatment is palliative systemic therapy. However, therapy carries a risk of toxicity, which can reduce quality of life. Therefore, accurate prognostic scores for risk stratification of patients with high-grade NET/NECs are needed to help guide patient management to decide whether active treatment is likely to improve overall survival (OS). We aimed to compare the prognostic ability of published prognostic scores to predict OS in a cohort of patients with high-grade NET/NECs of any primary site. Methods: Treatment, biochemical and clinicopathological data were collected retrospectively from 77 patients with high-grade NET/NECs across three hospitals between 2016 and 2020. Variables including performance status (PS), Ki-67, age at diagnosis, previous treatment and presence of liver metastases were recorded. Pre-treatment neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio, modified Glasgow prognostic score (mGPS), and gastrointestinal neuroendocrine carcinoma (GI-NEC) score were derived. Univariable and multivariable survival analyses were used to assess prognostic ability. Results: The median age of the cohort was 63 years (range: 31–85); 53% of subjects were female. Grade 3 NETs (G3-NETs) were identified in 32 patients and NECs in 45 patients. The median OS was 13.45 months (range: 0.87–65.37) with no difference observed between G3-NETs and NECs. Univariable analysis revealed that NLR (n = 72, p = 0.049), mGPS (n = 56, p = 0.003), GI-NEC score (n = 27, p = 0.0007) and Ki-67 (n = 66, p = 0.007) were significantly associated with OS. Multivariable analysis confirmed that elevated mGPS (p = 0.046), GI-NEC score (p = 0.036), and Ki-67 (p = 0.02) were independently prognostic for reduced OS across the entire cohort. mGPS was identified as an independent prognostic factor in G3-NETs. Independent predictors of OS in NECs were PS and Ki-67. Conclusions: mGPS, PS and Ki-67 are independent prognostic markers in high-grade NET/NEC patients. Our study supports the use of these prognostic scores for risk stratification of patients with high grade cancers and as useful tools to guide treatment decisions.

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Oral Abstract

10.1055/s-0039-1685335 ◽

2016 ◽

Author(s):

Dharma Ram

Keyword(s):

Survival Data ◽

Eligible Patient ◽

Stage Iv ◽

Endometrial Stromal Sarcoma ◽

Uterine Sarcoma ◽

Low Grade ◽

Uterine Leiomyosarcoma ◽

High Grade ◽

Lost To Follow Up

Introduction: Uterine sarcoma accounts for nearly 3% of all uterine malignancies. They have 4 major pathology includes endometrial stromal sarcoma high grade, ESS low grade, uterine leiomyosarcoma (uLMS) and undifferentiated uterine sarcoma (UUS). Recent WHO classification 2014, recognizes low grade ESS and high grade ESS as distinct entity. They differ from endometrial carcinoma in their aggressive nature and poor prognosis. We review our database and found total 44 eligible patient treated at our institute. Materials and Methods: Its retrospective analysis of computer based database of our institute from January 2009 to December 2015. We analyzed demographic, pathological, treatment and survival data. Results: Total 44 patient treated for uterine sarcoma at our institute. Among these 16 were operated at our institute during study period. Here we reporting results of operated patients at our institute. The histological diagnosis LMS (5/16), ESS-L (4/16), MMMT (3/16), UUS (3/16) and ESS-H (1/16). Stage distribution was stage I, (6/16) stage II, (5/16) stage III, (3/16) stage IV, (0/16) and unknown stage (2/16). Two patients underwent completion surgery for outside myomectomy. The adjuvant treatment was CT in 3/16, CT with RT in 7/16, HT in 4/16 and one lost to follow up with one was put on observation. Median follow up is 30 month with 14 patients alive and one lost to follow up. At last follow up 4 patients alive with metastatic disease and 10 patients alive with no evidence of disease. Conclusion: Uterine sarcoma are uncommon disease with

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Validation of a clinicopathological score for the prediction of post-surgical evolution of pituitary adenoma: retrospective analysis on 566 patients from a tertiary care centre

Acta Endocrinologica ◽

10.1530/eje-18-0749 ◽

2019 ◽

Vol 180 (2) ◽

pp. 127-134 ◽

Cited By ~ 19

Author(s):

S Asioli ◽

A Righi ◽

M Iommi ◽

C Baldovini ◽

F Ambrosi ◽

...

Keyword(s):

Pituitary Adenomas ◽

Proliferative Activity ◽

Disease Free Survival ◽

Low Grade ◽

High Grade ◽

Tumour Type ◽

Disease Evolution ◽

Free Survival ◽

Disease Free

Objective and design A clinicopathological score has been proposed by Trouillas et al. to predict the evolution of pituitary adenomas. Aim of our study was to perform an independent external validation of this score and identify other potential predictor of post-surgical outcome. Methods The study sample included 566 patients with pituitary adenomas, specifically 253 FSH/LH-secreting, 147 GH-secreting, 85 PRL-secreting, 72 ACTH-secreting and 9 TSH-secreting tumours with at least 3-year post-surgical follow-up. Results In 437 cases, pituitary adenomas were non-invasive, with low (grade 1a: 378 cases) or high (grade 1b: 59 cases) proliferative activity. In 129 cases, tumours were invasive, with low (grade 2a: 87 cases) or high (grade 2b: 42 cases) proliferative activity. During the follow-up (mean: 5.8 years), 60 patients developed disease recurrence or progression, with a total of 130 patients with pituitary disease at last follow-up. Univariate analysis demonstrated a significantly higher risk of disease persistence and recurrence/progression in patients with PRL-, ACTH- and FSH/LH-secreting tumours as compared to those with somatotroph tumours, and in those with high proliferative activity (grade 1b and 2b) or >1 cm diameter. Multivariate analysis confirmed tumour type and grade to be independent predictors of disease-free-survival. Tumour invasion, Ki-67 and tumour type were the only independent prognostic factors of disease-free survival. Conclusions Our data confirmed the validity of Trouillas’ score, being tumour type and grade independent predictors of disease evolution. Therefore, we recommend to always consider both features, together with tumour histological subtype, in the clinical setting to early identify patients at higher risk of recurrence.

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Study the activity of P53 & Bcl-2 genes in the biopsies of inflamed colon from patients of ulcerative colitis

Journal of Biotechnology Research Center ◽

10.24126/jobrc.2010.4.1.90 ◽

2010 ◽

Vol 4 (1) ◽

pp. 34-43

Author(s):

Zainab M. T. Jafer ◽

Esmail K. Shubber

Keyword(s):

Ulcerative Colitis ◽

Intermediate Stage ◽

Hybridization Technique ◽

Low Grade ◽

High Grade ◽

Colonic Tissue ◽

Grade 3 ◽

Apoptosis Gene ◽

Tumor Gene

The study has been done on 36 samples of biopsies which drawn from patients suffered from ulcerative colitis, the samples were taken from female & male of different ages. The goal was to observe the gene expression of the suppresser tumor gene P53, & the suppresser apoptosis gene Bcl-2, by using in situ hybridization technique. The results showed that there were relationships between both genes (P53 & Bcl-2) in patients suffered from ulcerative colitis compared with healthy individuals. The suppresser gene P53 gave 63% in the high grade(3) , 29 % in the intermediate stage (2) & 8% in the low grade (1) .While for the suppresser apoptosis gene Bcl-2 , the results showed increasing in the activity of this gene , which gave 66% in the high grade(3) , 27% in the intermediate stage (2) , & 7% in the low grade (1) . These results indicate accumulated mutations in the gene P53 & increase in the activity of gene Bcl-2 in inflamed colonic tissue of chronic ulcerative colitis. This gave an indication of early detection for diagnostic, therapeutic and monitoring purposes.

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Redefining Stage I Endometrial Cancer: Incorporating Histology, a Binary Grading System, Myometrial Invasion, and Lymph Node Assessment

International Journal of Gynecological Cancer ◽

10.1097/igc.0b013e3182a5055e ◽

2013 ◽

Vol 23 (9) ◽

pp. 1620-1628 ◽

Cited By ~ 14

Author(s):

Joyce N. Barlin ◽

Robert A. Soslow ◽

Megan Lutz ◽

Qin C. Zhou ◽

Caryn M. St. Clair ◽

...

Keyword(s):

Endometrial Cancer ◽

Myometrial Invasion ◽

Staging System ◽

Stage I ◽

Low Grade ◽

List Type ◽

High Grade ◽

High Grade Carcinoma ◽

Concordance Probability ◽

Grade 3

ObjectiveWe propose a new staging system for stage I endometrial cancer and compare its performance to the 1988 and 2009 International Federation of Gynecology and Obstetrics (FIGO) systems.MethodsWe analyzed patients with 1988 FIGO stage I endometrial cancer from January 1993 to August 2011. Low-grade carcinoma consisted of endometrioid grade 1 to grade 2 lesions. High-grade carcinoma consisted of endometrioid grade 3 or nonendometrioid carcinomas (serous, clear cell, and carcinosarcoma). The proposed system is as follows:IA. Low-grade carcinoma with less than half myometrial invasionIA1: Negative nodesIA2: No nodes removedIB. High-grade carcinoma with no myometrial invasionIB1: Negative nodesIB2: No nodes removedIC. Low-grade carcinoma with half or greater myometrial invasionIC1: Negative nodesIC2: No nodes removedID. High-grade carcinoma with any myometrial invasionID1: Negative nodesID2: No nodes removedResultsData from 1843 patients were analyzed. When patients were restaged with our proposed system, the 5-year overall survival significantly differed (P < 0.001): IA1, 96.7%; IA2, 92.2%; IB1, 92.2%; IB2, 76.4%; IC1, 83.9%; IC2, 78.6%; ID1, 81.1%; and ID2, 68.8%. The bootstrap-corrected concordance probability estimate for the proposed system was 0.627 (95% confidence interval, 0.590–0.664) and was superior to the concordance probability estimate of 0.530 (95% confidence interval, 0.516–0.544) for the 2009 FIGO system.ConclusionsBy incorporating histological subtype, grade, myometrial invasion, and whether lymph nodes were removed, our proposed system for stage I endometrial cancer has a superior predictive ability over the 2009 FIGO staging system and provides a novel binary grading system (low-grade including endometrioid grade 1–2 lesions; high-grade carcinoma consisting of endometrioid grade 3 carcinomas and nonendometrioid carcinomas).

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Endoscopic Surveillance Practice for Barrett's Oesophagus in Scotland and Early Experience in Implementing Local Guidelines

Scottish Medical Journal ◽

10.1177/003693300304800205 ◽

2003 ◽

Vol 48 (2) ◽

pp. 43-45 ◽

Cited By ~ 2

Author(s):

E F Shen ◽

S Gladstone ◽

G Milne ◽

S Paterson-Brown ◽

I D Penman

Keyword(s):

Early Experience ◽

High Grade Dysplasia ◽

Low Grade ◽

High Grade ◽

Wide Variability ◽

Low Grade Dysplasia ◽

Surveillance Practice ◽

Four Quadrant ◽

The Impact

Management of columnar lined oesophagus (CLO; Barrett s oesophagus) is controversial. We prospectively audited surveillance practices in Scotland and prospectively assessed the impact of introducing local guidelines for Barrett s surveillance in Edinburgh. Most respondents were gastroenterologists. The majority take random, not four quadrant, biopsies from the CLO. In Edinburgh during 2000, 80 patients underwent surveillance. The guideline protocol was not followed in 30 (37.5%) patients. Follow up of patients without dysplasia generally conformed to the guidelines. Follow up of patients with low grade dysplasia was highly variable while management of those with high grade dysplasia followed the guidelines. Overall we found a wide variability in the management and surveillance of CLO. Early experience suggests that implementation of guidelines is helpful but there is still variation in practice.

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Survivorship After Meniscal Allograft Transplantation According to Articular Cartilage Status

The American Journal of Sports Medicine ◽

10.1177/0363546516682235 ◽

2017 ◽

Vol 45 (5) ◽

pp. 1095-1101 ◽

Cited By ~ 27

Author(s):

Bum-Sik Lee ◽

Seong-Il Bin ◽

Jong-Min Kim ◽

Won-Kyeong Kim ◽

Jun Weon Choi

Keyword(s):

Articular Cartilage ◽

Graft Survival ◽

Arthroscopic Surgery ◽

Survival Rates ◽

Low Grade ◽

High Grade ◽

Meniscal Allograft ◽

Chondral Damage ◽

Relative Indication

Background: Clinical outcomes after meniscal allograft transplantation (MAT) in arthritic knees are unclear, and objective estimates of graft survival according to the articular cartilage status have not been performed. Hypothesis: MAT should provide clinical benefits in knees with high-grade cartilage damage, but their graft survivorship should be inferior to that in knees with low-grade chondral degeneration after MAT. Study Design: Cohort study; Level of evidence, 3. Methods: The records of 222 consecutive patients who underwent primary MAT were reviewed to compare clinical outcomes and graft survivorship. The patients were grouped according to the degree and location of articular cartilage degeneration: low-grade chondral lesions (International Cartilage Repair Society [ICRS] grade ≤2) on both the femoral and tibial sides (ideal indication), high-grade lesions (ICRS grade 3 or 4) on either the femoral or tibial side (relative indication), and high-grade lesions on both sides (salvage indication). Kaplan-Meier survival analysis with the log-rank test was performed to compare the clinical survival rates and graft survival rates between the groups. A Lysholm score of <65 was considered a clinical failure, and graft failure was defined as a meniscal tear or meniscectomy of greater than one-third of the allograft, objectively evaluated by magnetic resonance imaging (MRI) and second-look arthroscopic surgery. Results: The mean (±SD) Lysholm score significantly improved from 63.1 ± 15.1 preoperatively to 85.1 ± 14.3 at the latest follow-up of a mean 44.6 ± 19.7 months ( P < .001). However, the postoperative scores were not significantly different between the 3 groups (85.7 ± 14.2 for ideal indication, 84.7 ± 17.0 for relative indication, and 84.7 ± 14.2 for salvage indication; P = .877). On MRI at the latest follow-up of a mean 23.0 ± 19.9 months and second-look arthroscopic surgery of a mean 19.3 ± 20.7 months, there were 25 (11.3%) failed MAT procedures (4 medial, 21 lateral); of these, 5 lateral MAT procedures (2.3%) went on to allograft removal. Clinical survival rates were not significantly different between the groups ( P = .256). However, on objective evaluation, the estimated cumulative graft survival rate at 5 years in the salvage indication group (62.2% [95% CI, 41.6-82.8]) was significantly lower than that in the other 2 groups (ideal indication: 93.8% [95% CI, 88.5-99.1]; relative indication: 90.9% [95% CI, 81.1-100.0]) ( P = .006). Conclusion: Our findings showed that MAT was an effective symptomatic treatment in knees with advanced bipolar chondral lesions. However, better graft survival can be expected when articular cartilage is intact or if chondral damage is limited to a unipolar lesion. MAT should be considered before the progression of chondral damage to a bipolar lesion for better graft survivorship and should be performed cautiously in arthritic knees.

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Increased proteasome degradation of cyclin-dependent kinase inhibitor p27 is associated with a decreased overall survival in mantle cell lymphoma

Blood ◽

10.1182/blood.v95.2.619 ◽

2000 ◽

Vol 95 (2) ◽

pp. 619-626 ◽

Cited By ~ 156

Author(s):

Roberto Chiarle ◽

Leo M. Budel ◽

Jeffrey Skolnik ◽

Glauco Frizzera ◽

Marco Chilosi ◽

...

Keyword(s):

Overall Survival ◽

Protein Degradation ◽

Mantle Cell Lymphoma ◽

Molecular Mechanisms ◽

Kinase Inhibitor ◽

Cell Lymphoma ◽

Low Grade ◽

High Grade ◽

Ki 67 ◽

Mantle Cell

Mantle cell lymphoma (MCL) is an aggressive neoplasm characterized by the deregulated expression of cyclin D1 by t(11;14). The molecular mechanisms responsible for MCL's clinical behavior remain unclear. The authors have investigated the expression of p53, E2F-1, and the CDK inhibitors p27 and p21 in 110 MCLs, relating their expression to proliferative activity (Ki-67). For comparison, they have similarly analyzed low-grade (12 MALT, 16 CLL/SLL) and high-grade (19 DLCL) lymphomas. p53 was detected more frequently in large-cell MCL (l-MCL; 5 of 7) than in classical MCL (s-MCL; 13 of 103) and DLCL (8 of 19). In MCL and DLCL, the percentage of E2F-1+ nuclei was high, correlating with high Ki-67 expression. Most MCLs (91 of 112) and DLCLs (12 of 19) showed a loss of p27; MALT and CLL/SLL, however, were p27 positive. Reverse transcription–polymerase chain reaction and in vitro protein degradation assays demonstrated that MCLs have normal p27 mRNA expression but increased p27 protein degradation activity via the proteasome pathway. Correlation of MCL p53 and p27 expression with clinical data showed an association between reduced overall survival rates and the overexpression of p53 (P = .001), the loss of p27 (P = .002), or both. Loss of p27 identified patients with a worse clinical outcome among p53 negative cases (P = .002). These findings demonstrated that MCL has a distinct cell cycle protein expression similar to that of high-grade lymphoma. The loss of p27 and the overexpression of p53 in MCL are prognostic markers that identify patients at high risk. The demonstration that low levels of p27 in MCL result from enhanced proteasome-mediated degradation should encourage additional clinical trials. (Blood. 2000;95:619-626)

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