Primary Myelodysplastic Syndromes: The Mayo Clinic Experience With 1000 Patients.

OBJECTIVES: To share our 25 years of experience with patients with primary myelodysplastic syndromes (MDS) and to describe the natural history of the disease including presenting clinical and laboratory characteristics and long-term disease outcomes. PATIENTS AND METHODS: One thousand consecutive patients with primary MDS evaluated at Mayo Clinic between January 1, 1989, and May 1, 2014, were considered. The Revised International Prognostic Scoring System and other risk models were applied for risk stratification. Separate analyses were conducted for patients diagnosed before 2005 (n=531) and after 2005 (n=469). RESULTS: Eighty-five percent of patients were older than 60 years (median age, 72 years), with 69% being men. The median follow-up period was 27 months (range, 0-300 months), during which time 808 (81%) deaths and 129 (13%) leukemic transformations were documented. Median survival and leukemic transformation rates were similar in patients diagnosed before or after 2005, despite the significantly higher use of hypomethylating agents in the latter group: 33 months vs 28 months (P=.46) and 13% vs 10% (P=.92), respectively. Revised International Prognostic Scoring System risk distribution was similar in patients diagnosed before or after 2005 (P=.23): 17% were categorized as very low, 36% low, 21% intermediate, 15% high, and 11% very high risk, with a median survival of 72, 43, 24, 18, and 7 months, respectively (P<.001). We found Revised International Prognostic Scoring System cytogenetic risk categorization to be suboptimal in its performance, whereas contemporary prognostic models were broadly similar in their performance. CONCLUSION: The poor outcome in patients with MDS does not appear to have improved over time. Current risk stratification systems for MDS are not substantially different from each other. There is a dire need for drugs that are truly disease modifying and risk models that incorporate prognostically relevant mutations.

IgM multiple myeloma: pathologic evaluation of a rare entity.

OBJECTIVES: To delineate the pathology of immunoglobulin M-producing multiple myeloma (IgM MM). METHODS: Clinicopathologic data were reviewed for 15 cases meeting World Health Organization criteria for MM and having a serum IgM paraprotein. Immunohistochemistry was performed on diagnostic bone marrow specimens for common B-cell and plasma cell markers. RESULTS: Of the 15 IgM MM bone marrows reviewed, 6 (40%) had lymphoplasmacytoid cytology, and 12 (80%) expressed CD19, CD20, and/or CD45. Cyclin D1 expression was common (11 cases, 73%) and usually associated with t(11;14). No cases expressed CD5 or had an associated CD5-positive B-cell population. CD117 was positive in 20% of cases. CONCLUSIONS: The frequent B-cell-associated antigen expression by IgM MM distinguishes it from other MM types, causing significant pathologic overlap with lymphoplasmacytic lymphoma (LPL). However, IgM MM is usually distinguished from LPL by aberrant cyclin D1 expression or t(11;14). Therefore, assessing for these abnormalities is recommended when evaluating bone marrow involvement by IgM-associated lymphoplasmacytoid disorders.

Evaluation of revised IPSS cytogenetic risk stratification and prognostic impact of monosomal karyotype in 783 patients with primary myelodysplastic syndromes.

Cytogenetic classification by the revised international prognostic scoring system (IPSS-R) and the prognostic value of monosomal karyotype (MK) were assessed in 783 patients with primary myelodysplastic syndromes (MDS). At 22 months median follow-up, 562 (72%) deaths were recorded. Percentages of patients with IPSS-R "very good," "good," "intermediate," "poor," and "very poor" cytogenetic categories was 5, 63, 18, 4, and 10%, respectively. The corresponding median survivals were 21, 40, 24, 18, and 6.5 months and the inter-group differences (good vs. very good/intermediate/poor vs. very poor; P < 0.01) or similarities (very good vs. intermediate vs. poor; P = 0.79) were not significantly modified in multivariable analysis. Results were similar when analysis was restricted to 602 patients managed by supportive care. MK adversely affected survival in both poor and very poor karyotype groups (P < 0.01). In conclusion, we were unable to confirm the prognostic superiority of IPSS-R-very good karyotype or prognostically distinguish between very good, intermediate and poor karyotypes. Furthermore, we show additional prognostic information from MK in poor/very poor karyotype.

Spliceosome mutations involving SRSF2, SF3B1, and U2AF35 in chronic myelomonocytic leukemia: prevalence, clinical correlates, and prognostic relevance.

SRSF2, SF3B1, and U2AF35 (U2AF1) are the three most frequent genes involved with spliceosome mutations in myeloid malignancies. SF3B1 mutations are most frequent (~80%) in myelodysplastic syndromes (MDS) with ring sideroblasts (RS) but lack prognostic relevance. SRSF2 mutations are associated with shortened overall (OS) and leukemia-free survival (LFS) in both MDS and myelofibrosis. In this study of 226 patients with chronic myelomonocytic leukemia (CMML), mutational frequencies were 40% for SRSF2 (all affecting P95), 6% for SF3B1 (primarily K700E) and 9% for U2AF35 (mostly S34F and Q157P/R). These mutations were mutually exclusive and 54% of the patients displayed at least one mutation. The three mutation groups were phenotypically similar, with the exception of higher RS% (P < 0.0001) in patients with SF3B1 mutations. At a median follow-up of 15 months, 176 (78%) deaths and 32 (14%) leukemic transformations were documented. OS (median survivals of 17, 16, 17, and 20 months; P = 0.48) and LFS (leukemic transformation rates of 17, 13, 15, and 5%; P = 0.63) were similar among patients with none of the three mutations, SRSF2, SF3B1, or U2AF35 mutations, respectively. We conclude that SRSF2 is the most frequently mutated spliceosome gene in CMML but neither it nor SF3B1 or U2AF35 mutations are prognostically relevant.

Prognostic irrelevance of ring sideroblast percentage in World Health Organization-defined myelodysplastic syndromes without excess blasts.

The presence of ≥ 15% bone marrow (BM) ring sideroblasts (RS) and < 5% blasts is required for a diagnosis of refractory anemia with ring sideroblasts. We examined the phenotypic and prognostic relevance of this "15%" RS threshold in 200 patients with myelodysplastic syndromes (MDS) without excess blasts and with ≥ 1% RS. The impact of RS% was assessed both as a continuous and categorical variable: < 5% (n = 56), 5%-14% (n = 32), 15%-50% (n = 79), and > 50% (n = 33). RS% correlated (P < .05) directly with age, platelet count, transfusion dependency, BM cellularity, and mutant SF3B1 and inversely with hemoglobin level, multilineage dysplasia, and high-risk karyotype; but did not correlate with IDH mutations. At a median follow-up of 33 months, 156 (73%) deaths and 24 (12%) leukemic transformations were documented. Neither univariate nor multivariable analysis showed significant effect for RS% on overall or leukemia-free survival, suggesting the limited prognostic value of quantifying BM RS in MDS.

SF3B1 mutations are prevalent in myelodysplastic syndromes with ring sideroblasts but do not hold independent prognostic value.

SF3B1 mutations were recently reported in myelodysplastic syndromes (MDSs), especially in the presence of ring sideroblasts (RSs). We sought to define the interaction between SF3B1 mutations, morphology, karyotype, and prognosis in MDS with more than or equal to 15% RS (MDS-RS). We studied 107 patients with MDS-RS, including 48 with refractory anemia with RS (RARS), 43 with refractory cytopenia with multilineage dysplasia (RCMD)-RS, 11 with refractory anemia with excess blasts-1 (RAEB1)-RS, and 5 with RAEB2-RS. SF3B1 mutations were detected in 53 (∼ 50%) patients: 35 RARS (73%), 16 RCMD-RS (37%), and 2 RAEB1-RS (18%). In univariate analysis, the presence of SF3B1 mutations was associated with better overall (P < .01) and leukemia-free (P < .01) survival; however, in both instances, significance was completely accounted for by World Health Organization morphologic risk categorization. In other words, when RARS and RCMD-RS were analyzed separately, there was no additional prognostic value from the presence or absence of SF3B1 mutations.

The significance of isolated Y chromosome loss in bone marrow metaphase cells from males over age 50 years.

To further investigate the potential clinical significance of Y chromosome loss as the sole bone marrow karyotype change, we studied 161 Mayo Clinic male patients with 75% or more metaphase cells with Y loss, and correlated the percent Y loss with age and hematopathologic review. In patients with a lymphoproliferative or plasma cell disorder, the negligible proportion of bone marrow involvement cannot account for the observed high proportion of -Y cells. In males with myeloid disease, Y loss appears to often represent the abnormal myeloid clone, which may also harbor acquired genetic changes that are not observed by conventional cytogenetic analysis.

Predictive value of blood and bone marrow flow cytometry in B-cell lymphoma classification: comparative analysis of flow cytometry and tissue biopsy in 252 patients.

OBJECTIVE: To study the effectiveness of peripheral blood (PB) and bone marrow flow cytometric immunophenotyping (FCIP) in predicting the histologic B-cell lymphoma type. PATIENTS AND METHODS: We studied the FCIP results and tissue histopathology from 252 patients with B-cell lymphoma seen at Mayo Clinic's site in Rochester, MN, between January 1, 1997, and January 1, 2004, who had positive results on PB, bone marrow, or body fluid FCIP and a corresponding diagnostic tissue biopsy specimen. RESULTS: Most of the B-cell lymphomas studied were low grade, with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma being most common. Flow cytometric immunophenotyping histogram analysis was more informative than tabulated percentage antigen positivity; surface immunoglobulin and CD20 staining intensity, CD5 and CD23 positivity, CD10 positivity, and the coexpression of CD11c/CD22 and CD103 were the most pertinent markers. Using these FCIP parameters and strict immunophenotypic definitions for CLL, mantle cell lymphoma (MCL), and hairy cell leukemia, we obtained greater than 95% specificity for each diagnosis. However, we encountered the following exceptions to standard paradigms of B-cell lymphoma-associated FCIP: (1) CD5 expression by disorders distinct from CLL and MCL, (2) lack of uniform CD5 positivity in some CLL and MCL cases, (3) absence of CD10 in approximately 50% of follicular lymphomas, and (4) expression of CD103 by occasional marginal zone lymphomas. CONCLUSION: Stringent interpretation of PB and bone marrow FCIP results enables identification of certain B-cell lymphoma types. However, the observed exceptions to accepted immunophenotypic paradigms highlight the occasional phenotypic overlap among diseases and emphasize that a systematic approach to FCIP interpretations is key to providing clinically useful diagnostic information.

Isolated trisomy 15: a clonal chromosome abnormality in bone marrow with doubtful hematologic significance.

We identified 18 patients with an isolated bone marrow clonal chromosomal abnormality, trisomy 15 (with or without -Y), who did not have any morphologic or clinical features of hematologic disease at initial examination. All but 1 patient was older than 65 years. Fourteen patients had underlying nonhematologic, chronic diseases. Four patients had histories of hematologic malignancies. Eleven of the patients also had a -Y. All but 1 case had a marrow cellularity of less than 50%. Extensive morphologic review of the specimens showed no features of myelodysplastic syndrome (MDS). Clinical follow-up was available for all patients and ranged from 1 month to 16.3 years (median, 4.0 years). No subsequent clinical or hematologic manifestations of MDS were identified in any of these patients. Clonal trisomy 15 in isolation or in combination with -Y is an uncommon cytogenetic finding that does not seem to be associated with definitive morphologic or clinical features of MDS or any other malignant process.

Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma.

BACKGROUND: Smoldering (asymptomatic) multiple myeloma is an asymptomatic plasma-cell proliferative disorder associated with a high risk of progression to symptomatic multiple myeloma or amyloidosis. Prognostic factors for the progression and outcome of this disease are unclear. METHODS: We searched a computerized database and reviewed the medical records of all patients at Mayo Clinic who fulfilled the criteria of the International Myeloma Working Group for the diagnosis of smoldering multiple myeloma between 1970 and 1995. Bone marrow aspirate and biopsy specimens were studied, and patients were followed throughout the course of disease. RESULTS: During the 26-year period, 276 patients fulfilled the criteria for smoldering multiple myeloma. During 2131 cumulative person-years of follow-up, symptomatic multiple myeloma or amyloidosis developed in 163 persons (59%). The overall risk of progression was 10% per year for the first 5 years, approximately 3% per year for the next 5 years, and 1% per year for the last 10 years; the cumulative probability of progression was 73% at 15 years. At diagnosis, significant risk factors for progression included the serum level and type of monoclonal protein, the presence of urinary light chain, the extent and pattern of bone marrow involvement, and the reduction in uninvolved immunoglobulins. The proportion of plasma cells in the bone marrow and the serum monoclonal protein level were combined to create a risk-stratification model with three distinct prognostic groups. CONCLUSIONS: The risk of progression from smoldering multiple myeloma to symptomatic disease is related to the proportion of bone marrow plasma cells and the serum monoclonal protein level at diagnosis.

An unusual case of leukemic mantle cell lymphoma with a blastoid component showing loss of CD5 and aberrant expression of CD10.

Characteristically, mantle cell lymphoma (MCL) expresses surface immunoglobulin (sIg), CD19, CD20, and CD5 and lacks CD10 and CD23. Rare CD5-MCL variants have been described. This report describes a case of leukemic MCL with morphologically and immunophenotypically distinct classic MCL and blastoid-variant MCL (BV-MCL) components. The classic MCL had typical morphologic features and immunophenotype (kappa sIg light chain-restricted and CD5+; CD10- and CD23-). The BV-MCL had larger nuclei and open chromatin; these cells also were kappa sIg light chain-restricted; however, they were CD10+ and CD5-. Fluorescence in situ hybridization studies demonstrated cyclin D1-immunoglobulin heavy chain gene fusion in both components; the bone marrow biopsy cellularity was replaced by CD10+ and cyclin D1+ and CD5-BV-MCL. This case illustrates the phenotypic heterogeneity of MCL and underscores the need for histopathologic correlation and, in some instances, ancillary genetic studies to accurately classify B-cell lymphomas.

Despite apparent morphologic and immunophenotypic heterogeneity, Waldenstrom's macroglobulinemia is consistently composed of cells along a morphologic continuum of small lymphocytes, plasmacytoid lymphocytes, and plasma cells.

We studied the clinical, morphologic, and immunophenotypic features of 26 Waldenstrom's macroglobulinemia (WM) cases, each with an IgM spike of >or=3.0 g/dL. The neoplastic cells were consistently composed of a spectrum of small lymphocytes, plasmacytoid lymphocytes, and plasma cells. Bone marrow (BM) involvement ranged from 10% to 90%, showed four histologic patterns (nodular [75%], interstitial [75%], paratrabecular [42%], and diffuse [4%]), two histologic subtypes (lymphoplasmacytic [87%] and lymphoplasmacytoid [13%]), and several cytologic variants (monocytoid [n = 2], signet-ring cell [n = 2], and hairy cell leukemia-like [n = 1]). By flow cytometry (FC), all cases expressed monoclonal surface immunoglobulin, CD19, and CD20. Most cases (58%) lacked expression of CD5, CD10, and CD23. However, variants such as CD5(+)CD10(-)CD23(-) (n = 3), CD5(+)CD10(-)CD23(+) (n = 1), and CD5(-)CD10(+)CD23(+/-) (n = 2) were seen. At last follow-up, 18 of 26 patients were alive (median survival, 94 months). Causes of death included WM (n = 1), large cell lymphoma (n = 1), acute myeloid leukemia (likely therapy-related [n =2]), and nonhematologic/unknown. When individual WM cases are compared, apparent morphologic diversity is suggested. However, every WM case is comprised of cells along a morphologic continuum from small lymphocytes to plasma cells, delineating a uniform, consistent pathology. As WM shows immunophenotypic heterogeneity, morphology must be the cornerstone of the diagnosis.

Clonal cytogenetic abnormalities in bone marrow specimens without clear morphologic evidence of dysplasia: a form fruste of myelodysplasia?

Cytogenetic abnormalities suggestive of a myeloid disorder are occasionally observed in the bone marrow (BM) cells of patients with morphologically and immunohistochemically unremarkable marrow aspirates and biopsies. Between 1994 and 2000, 55 such patients were seen at our institution (34 men; median age of 66 years). The indications for BM sampling included unexplained cytopenias (31 patients), staging or follow-up of a lymphoproliferative disorder or a plasma cell dyscrasia (18 patients), or another miscellaneous reason (6 patients). Specific cytogenetic abnormalities included a 20q deletion or monosomy 20 (10 patients), a chromosome 7 deletion (8 patients), +8 (5 patients), del(5q) or a 5q translocation (4 patients), and del(13q) (2 patients). Eleven patients had a complex karyotype. As of January 2002, 23 of the 55 patients were dead; median follow-up for living patients is 20 months. Of the 23 dead patients, 1 died of acute myelogenous leukemia (AML) and 6 of complications related to cytopenias. This study provides support for obtaining cytogenetic studies in patients with unexplained cytopenias if a morphologic explanation for the cytopenias is lacking. Continued follow-up of this heterogeneous cohort and further studies of similar patients will more clearly define the disease processes and prognosis for this constellation of laboratory findings.

Primary myelodysplastic syndrome with normal cytogenetics: utility of 'FISH panel testing' and M-FISH.

The myelodysplastic syndromes (MDS) are a clinically heterogeneous group of hematologic disorders. Cytogenetic analysis is crucial as it can provide both diagnostic and prognostic information. Herein, 32 cytogenetically normal patients with primary MDS were analyzed both by multiple FISH probes on interphase nuclei (FISH panel testing) and by M-FISH (metaphase nuclei). One patient had a chromosome 13q-arm deletion, while the remaining 31 patients had normal results. These findings confirm standard cytogenetics as an excellent technique in identifying the common chromosomal abnormalities associated with MDS and suggest limited utility for either a FISH panel test or M-FISH in primary MDS.