Revised WHO Classification Research Articles

Histopathologie des Nierenzellkarzinoms

By integrating genetic data into the traditional histology and immunohistochemistry-based classification system, the revised WHO classification of malignant tumors (2004) defined additional renal cell carcinoma subtypes, thereby enabling the application of additional diagnostic procedures.

Accuracy and applicability of the revised WHO classification (2009) of dengue

Accuracy and applicability of the revised WHO classification (2009) of dengue

Absence of KIAA1549-BRAF fusion in rosette-forming glioneuronal tumors of the fourth ventricle (RGNT)

Rosette-forming glioneuronal tumors (RGNT) of the fourth ventricle are rare mixed glioneuronal tumors included in the revised WHO classification of central nervous system tumors, showing partial histological similarities to pilocytic astrocytomas. To evaluate potential similarities at the molecular level between these tumors, we analysed a series of 10 RGNT for the presence of KIAA1549-BRAF fusions using interphase fluorescence in situ hybridisation. However, we found no cases showing KIAA1549-BRAF gene fusion or BRAF (V600E) mutation. Our data support the hypothesis that RGNT may represent a distinct entity among the glioneuronal tumors of the central nervous system, with molecular features different from pilocytic astrocytomas.

BCR-ABL1 -Negative Chronic Myeloid Neoplasms: An Update on Management Techniques

Recent discoveries concerning mutations associated with chronic myeloproliferative neoplasms have modified our understanding of the biology of these incurable diseases and guided us to the development of inhibitors active on the constitutively activated JAK-STAT pathway. Concurrently, numerous studies dealt with clinical issues; it led to a revised WHO classification; clarified the role of mutated JAK2 and leukocytosis in the pathogenesis of cardiovascular events; allowed the development of risk prognostic scores and tools for monitoring response to therapy; and resulted in completion of Phase III trials with JAK2 inhibitor in myelofibrosis. All these results hold the promise of improving patient prognostication and therapeutic approach, with the aim of efficiently preventing disease-associated complications and, hopefully, to improve the dismal survival associated with myelofibrosis. This review discusses how to manage, according to current clinical practice, the steps of diagnosis, prognostication and therapeutic choices in myeloproliferative neoplasm patients.

Clinicopathological Features and Outcomes of T- and NK-Cell Lymphomas in European Russia

With the introduction of the revised World Health Organization Classification of Tumors of Hematopoietic and Lymphoid Tissues in 2001, many patients had to be re-evaluated for the correct diagnosis of T- and NK-cell lymphomas. Because some T-cell malignancies are associated with poor outcome, it is important to identify subsets of patients that may benefit from novel or more intensive therapies. The purpose of this study was to determine, for the first time, the relative frequencies, pathological features and outcomes of patients with T- and NK-cell lymphomas in a predominantly Russian Slavic population. We identified 291 patients with a diagnosis of T- and NK-cell malignancies treated at our Center between 2000-2008. In applying the revised WHO classification, we confirmed the diagnosis and had complete clinical follow up and pathological information on 264 cases that were included in the analysis. We found some differences in frequency of several subsets as compared with previously published reports, including younger age of onset and relatively higher incidence of T-LGL in our patients. We also confirm that intensive treatment regimens of advanced stage PTCL and ALK—ALCL led to considerable improvement in response rates, but not in the overall survival.

JAK2 Mutations in Chronic Myeloproliferative Neoplasm; Towards the Application of Personalized Treatments for Saudi Patients

The chronic myeloproliferative neoplasms (CMPN) are a group of clonal hematopoietic stem cell disorders in which large numbers of red blood cells, white blood cells, or platelets grow and spread excess in the bone marrow and the pe- ripheral blood. Cytogenetic analysis of the t (9:22) and molecular detection of BCR/ABL is the main diagnostic criteria in Philadelphia positive CMPN (CML). The identification of non-receptor tyrosine kinase JAK2 mutations (exon 14 JAK2 V617F and exon 12) have significantly contributed to our understanding of the molecular mechanisms in the pathogenesis of Philadelphia negative CMPN such as polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) patients. According to the revised WHO classification, JAK2 mutation is considered as a major diagnostic and clonal marker in Philadelphia negative CMPN which will play a major role in designing personal- ized treatments for the disease. JAK2 V617F mutation frequency is unknown in Saudi Arabia. Therefore, investigation of the JAK2 V617F mutation was carried out in DNA samples from 78 peripheral blood specimens corresponding to patients with polycythemia vera (PV) (n = 11), Chronic myeloid leukemia (CML) (n = 45), essential thrombocythemia (ET) (n = 10), idiopathic myelofibrosis (MF) (n = 12). We used polymerase chain reaction and direct DNA sequencing to detect the JAK2 mutation. Overall, the incidence of the JAK2 V617F mutation was 91% in PV, 40% in ET, and 25% in MF. This approach proved to be reliable and more sensitive in detecting the mutation. Two essential findings arose from our study. First, this technique could be carried out with DNA samples, even partially degraded, from routinely processed BM or peripheral blood specimens. Second, after correlation with morphological features, it turned out that the characteristics of the megakaryocytes were more specific than the mutational status of JAK2 in characterizing ET and PMF. Concerning PV, as expected, the incidence of the JAK2 mutation was higher, but the morphological criteria were misleading in some cases, strongly suggesting that the combination of both morphology and molecular data would enable the characterization of virtually all cases. JAK2 V617F mutation frequency along with accurate morphological characterization is very reliable tool in diagnosing and classifying CMPN in Saudi patients.

AML with Recurrent Genetic Abnormalities and AML with Myelodysplasia-Related Changes Account for Three-Quarters of Previously Untreated Pediatric AML-the Results of a Nation-Wide Central Review in Japan-

Abstract 4899 [Background]The WHO classification has been widely accepted among physicians who are engaged in treating pediatric AML patients. In 2008, the revised WHO classification has expanded the two categories in AML; AML with recurrent genetic abnormalities and AML with myelodysplasia-related changes. The epidemiology and prognostic significance of these refined categories remains to be explored in children. [Methods]JPLSG AML-05 is a nationwide clinical trial for children with de novo AML, excluding acute promyelocytic leukemia and myeloid leukemia with Down syndrome, which was conducted between November 2006 and December 2010 in Japan. A central review of diagnosis based on the WHO classification was prospectively performed on each case soon after morphological, cytogenetical and immunological data were submitted to data center. Regarding the cases with discrepant results among these parameters, further diagnostic tests including FISH and chimera gene analyses were underwent to confirm the diagnoses. [Results]Four hundred and eighty four patients were enrolled in the study. Thirty patients did not meet the criteria of AML. We could not collected suitable data for diagnosis in 6 patients. Regarding the rest 448 patients, diagnoses based on the WHO classification 2001 and 2008 were determined. According to the 2001 version, 227 (50.6%) had AML with recurrent genetic abnormalities:124 (27.7%) of AML with t(8;21)(q22;q22);(AML1/ETO ), 32 (7.1%) of AML with inv(16)(p13q22); (CBFβ/MYH11), 38 (8.5%) of AML with t(9;11)(p22;q23), and 33 (7.4%) of AML with the other11q23 (MLL) abnormalities, 36 (8.0%) had AML with multilineage dysplasia, and 185 (41.3%) had AML, not otherwise categorized. According to 2008 version, 235 (52.5%) had AML with recurrent genetic abnormalities: 124 (27.7%) of t(8;21)(q22;q22);(AML1/ETO ), 32 (7.1%) of AML with inv(16)(p13q22); (CBFβ/MYH11), 38 (8.5%) of AML with t(9;11)(p22;q23), 33 (7.4%) of AML with the other11q23 (MLL) abnormalities,4 of AML with t(6;9)(p23;q34);DEK-NUP214,2 of AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2);RPN1-EVI13, and 2 of AML with t(1;22)(p13;q13);RBM15-MKL, 88 (19.6.7%) had AML with myelodysplasia-related changes (29 from morphological features of myelodysplasia and 59 from myelodysplasia-related cytogenetic abnormalities), 119 (26.6%) had AML, not otherwise categorized and 7(1.6%) had mixed phenotype acute leukemia (6 of T/myeloid and 1 of B/myeloid). [Discussion]Our comprehensive approach for diagnosis was a useful modality for precise diagnosis of uncertain cases, which might have been assigned to the category of AML, with not otherwise categorized, previously. As a result, the present study shows an increased prevalence of AML with recurrent genetic abnormalities or AML with myeloid dysplasia-related changes among pediatric patients with previously untreated AML. Analysis of the AML-05 trial will elucidate the prognostic impact of these categories. Disclosures:No relevant conflicts of interest to declare.

Analysis of KIAA1549-BRAF fusion status in a case of rosette-forming glioneuronal tumor of the fourth ventricle (RGNT)

Rosette-forming glioneuronal tumors (RGNT) of the fourth ventricle are rare mixed glio-neuronal tumors included in the revised WHO classification of CNS tumors and show histopathological features similar to pilocytic astrocytomas. To evaluate at molecular level potential affinities between these tumors, we investigated a case of RGNT, arising in the cerebellum of a young patient, for the presence of transcriptional products originating from the KIAA1549-BRAF fusion. However, the analysis did not show any fusion. Further studies in larger RGNT case series are needed in order to demonstrate the possible presence of KIAA1549-BRAF fusion and better delineate its relationship with pilocytic astrocytomas.

Hyalinizing spindle cell tumor with giant rosettes

Low-grade fibromyxoid sarcomas are uncommon deep-seated soft tissue neoplasms that exhibit a deceptively benign appearance microscopically. The finding of a linear or whorled array of spindled cells with few or no mitoses in a characteristic myxoid stroma can pose diagnostic dilemmas. Recurrences are common, and late metastases have been recorded. A closely related tumor, the so-called hyalinizing spindle cell tumor with giant collagen rosettes (HSCTGR), has also been described, with both the neoplasms having a similar cytogenetic abnormality and clinical behavior. Because of the similarities, both lesions are considered to be a single entity within the spectrum of low-grade sarcomas. Two cases of HSCTGR occuring in the lower limb are described in this report.

Refractory cytopenia with unilineage dysplasia: analysis of prognostic factors and survival in 126 patients

According to the revised WHO classification of 2008, dysplasia in ≥10% of one bone marrow lineage and one cytopenia constitutes the low-risk category of unilineage cytopenia and unilineage dysplasia (UCUD). We retrospectively reclassified, according to WHO, low-risk MDS from our database and found 126 subjects with these features at diagnosis: 79 patients were categorized as refractory anemia (RA), 23 patients as refractory neutropenia (RN), and 24 as refractory thrombocytopenia (RT). We did not find differences between the three subgroups as regards sex, median age, and cytogenetic aberrations. Lower PMN count (0.8 × 109/L) was observed in the RN category, as well as lower platelet count in the RT category (51 × 109/L). Moreover, we found a lower rate of patients requiring RBC transfusions, during the disease course, in the RT category (45.8%) as compared to RA (62%) and RN (69%) groups (p = 0.05); a lower incidence of infections at diagnosis in the RT category (20.8%) compared to RA (32%) and RN (43%) categories (p = 0.03); and a higher incidence of hemorrhagic symptoms at diagnosis in the RT category (41.6%) and RN category (26%) as compared to the RA group (5%) (p = 0.001). Application of different scoring systems (Bournemouth and Spanish scores, WPSS) revealed a low OS in high-risk patients within the RT category, compared to RA and RN categories, although unlikely to reflect the consequences of low OS found in the former category. Statistically significant differences were also evidenced in the incidence of acute myeloid leukemia (AML) evolution and overall survival: 7/79 (8%) patients with the RA category evolved to AML in a median time of 89 months, whereas 4/23 (17%) of the RN category and 1/24 (4%) of the RT category experienced disease progression, in a median time of 33.8 and 12.8 months, respectively (p = 0.03). The RT category had a lower overall survival (15.9 months) as compared to RA (48.2 months) and RN (35.9 months) categories (p < 0.001). In conclusion, in our study, application of the revised 2008 WHO classification confirmed the importance of separating patients with unilineage dysplasia for prognostic disease assessment; from our results it seems that the RT category has a worse outcome.

Classification of Childhood Bone Marrow Failure Syndrome Based On Revised WHO Classification.

Abstract 4212The WHO classification revised in 2008 proposes the term, “refractory cytopenia of childhood (RCC)” for children with myelodysplastic syndrome (MDS) and a low blast count. This condition is characterized by persistent cytopenia with < 5% blasts in the bone marrow and < 2% blasts in the peripheral blood. Dysplastic changes must be recognized in more than two cell lineages, or exceed 10% in a single cell line on bone marrow aspirate smears. To differentiate between RCC and aplastic anemia (AA) is challenging, especially when the bone marrow is hypoplastic and chromosomal abnormalities are undetectable. Aplastic anemia can progress to MDS and some patients with RCC respond to immunosuppressive therapy, suggesting that the two conditions have an overlapping pathophysiology. The spectrum of RCC ranges from mild cytopenia to cytogenetic abnormalities of monosomy 7, which carries an increased risk for disease progression. However, few studies have attempted to differentiate the two diseases. To compare the clinical and biological features of AA and RCC, we retrospectively reviewed bone marrow smears from 140 patients registered for the childhood AA-97 study. The smears were classified as AA (no morphologically dysplastic changes in any hematopoietic cell lineages), AA-RCC borderline (< 10% dysplastic changes only in erythroid lineage) and RCC groups. Disease severity was classified as non-severe (n = 32), severe (n = 43) and very severe (n = 65). Aplastic anemia was idiopathic in 116 patients and associated with hepatitis in 24. Two patients had chromosomal abnormalities at presentation. The AA, AA-RCC borderline and RCC groups comprised 96 (67%), 20 (16%) and 24 (17%) patients, respectively. Bone marrow smears in the RCC group frequently presented megaloblastoid changes in cells of erythroid lineage and the pseudo-Pelger-Huet anomaly in those of myeloid lineage. Dysplastic changes in the megakaryocytic lineage were rare. The median ages were 9, 9 and 11 years in the AA, AA-RCC borderline and RCC groups, respectively. The AA group included most of the patients with hepatitis-associated AA and those with very severe AA. On the other hand, 6 (9%), 7 (16%) and 11 (35%) patients in the RCC group had very severe, severe and with non-severe disease, respectively. Four patients in the AA group developed new chromosomal abnormalities: trisomy 8 (n = 2) and monosomy 7 (n = 2). Two patients with monosomy 7 progressed to acute myeloid leukemia (AML). Three patients in the RCC group developed new chromosome abnormalities; 2 had trisomy 8 and 1 had ? X. None of the patients in the RCC group developed MDS or AML. The response rates for immunosuppressive therapy with cyclosporine and antithymocyte globulin were 55%, 50% and 67% in the AA, AA-RCC borderline and RCC groups, respectively. To determine whether the two diseases are truly different entities, response rates to immunosuppressive therapy, the frequency of clonal evolution and the genetic background should be prospectively compared between AA and RCC in a larger patient cohort. Disclosures:No relevant conflicts of interest to declare.

Prodromal myeloproliferative neoplasms: The 2008 WHO classification

The concept of prodromal chronic myeloproliferative neoplasms has been endorsed by the WHO classification implicating a stepwise evolution of disease. Histology of the bone marrow (BM) and borderline to mildly expressed clinical features play a pivotal role for diagnosing prefibrotic-early primary myelofibrosis. By lowering the platelet count for essential thrombocythemia and regarding BM morphology, early manifestations are tackled. Pre-polycythemic stages of polycythemia vera with a low hemoglobin level at onset are diagnosed by positive JAK2V617F mutation status, a low erythropoietin value, and characteristic BM features. The revised WHO classification incorporates hematological, morphological, and molecular-genetic parameters to generate a consensus-based working diagnosis.

Subependymal giant cell astrocytoma (SEGA): Is it an astrocytoma? Morphological, immunohistochemical and ultrastructural study

Subependymal giant-cell astrocytoma (SEGA) is a rare intra-ventricular low-grade tumor which frequently occurs as a manifestation of tuberous sclerosis complex. The histogenesis of SEGA is controversial and its astrocytic nature has been doubted. First studies suggested the astrocytic nature of SEGA while several recent reports demonstrate its glio-neuronal nature. In spite of this, in the recently revised WHO classification of the CNS tumors, SEGA has been still included in the group of astrocytomas. We studied nine tuberous sclerosis complex-associated SEGAs. Patients were 1-18 years old. Eight patients (89%) had a solitary lesion located in the lateral ventricle close to of the head of the caudate nucleus, the remaining patient (11%) had two tumors, one located close to the head of the left caudate nucleus and the other in the central part of the right lateral ventricle. Histologically, tumors were composed of three types of cells: spindle, gemistocytic and ganglion-like. Four tumors (44%) had a prominent vascularization and three (33%) showed an angiocentric pattern. Calcifications were observed in six cases (66%). By immunohistochemistry, the majority of the tumors were GFAP- (9; 100%), neurofilament- (8, 89%), neuron-specific enolase- (9, 100%), and synaptophysin- (8; 89%) positive. Ultrastructural studies were performed on four cases. In all four there were glial cell processes filled with intermediate filaments. In one case dense core putative neurosecretory granules were appreciable. Our results emphasize the glio-neuronal nature of SEGA. We suggest moving it into the group of mixed glio-neuronal tumors under the denomination of subependymal giant cell tumor.

Outline and direction of revised WHO classification

Outline and direction of revised WHO classification

Clinical Characterization of Acute Myeloid Leukemia with Myelodysplasia-Related Changes as Defined by the 2008 WHO Classification System.

Background: Although some studies have validated the 2001 WHO classification of acute myeloid leukemia (AML), including the importance of multilineage dysplasia, others have suggested that multilineage dysplasia correlates with unfavorable cytogenetics but has no independent impact on prognosis. In 2008, the revised WHO classification system has expanded this category into “AML with myelodysplasia-related changes” (AML-MRC) that now includes 1) AML arising from myelodysplastic syndrome (MDS), 2) AML with MDS-related cytogenetic abnormalities, and 3) AML with multilineage dysplasia. An individual case may fall into this category by meeting any of the criteria. The goal of the current study is to clinically characterize this newly defined AML-MRC subgroup.Methods: One-hundred consecutive AML patients diagnosed at Stanford University Hospital between 2005 and 2007 with adequate material for mutation analysis were studied. Cases were classified using the 2008 WHO criteria. Diagnostic cytogenetic findings were reviewed and patients were stratified into risk groups using Southwest Oncology Group criteria. Available flow cytometry immunophenotyping results were reviewed and all samples were tested for NPM, FLT3 (ITD and D835) and CEBPA mutations. Clinical parameters including hemogram data at time of diagnosis were reviewed. Clinical follow-up including overall survival (OS), progression free survival (PFS) and complete remission (CR) rates were retrospectively determined. Kaplan-Meier methods and univariate and multivariate Cox proportional hazards regression analysis were used to compare the clinical data.Results: The cases included 57 males and 43 females with a median age of 56 (range 17–81). Cytogenetic risk-group stratification resulted in 9 patients with favorable, 65 with intermediate and 19 with unfavorable risk status. Using the 2008 WHO criteria, there were 48 AML-MRC, 40 AML not otherwise specified (AML-NOS), 9 AML with either t(8;21), inv(16) or t(15;17), and 3 therapy related AMLs. Overall, 26 patients had a NPM1 mutation (16 of which were FLT3 mutated), 25 had FLT3-ITD, 8 had FLT3-D835 and 9 had a CEBPA mutation (3 of which were FLT3 mutated). Compared to AML-NOS, patients with AML-MRC were significantly older (59 vs 51 years, p=0.014) and presented with lower hemoglobin (9 vs 11.2 g/dL, p=0.044), lower platelets (47 vs 54 K/uL, p=0.059), unfavorable cytogenetics (14/46 vs 3/36, p=0.014) and exhibited a decreased frequency of CEBPA mutation (0/46 vs 7/40, p=0.001) as compared to AML-NOS. Based on the flow cytometry immunophenotyping, the blasts from patients with AML-MRC more frequently expressed CD14 compared to AML-NOS (10/46 vs 4/36, p=0.048). Clinical outcome data showed that patients with AML-MRC had a significantly worse OS, PFS and CR compared to AML-NOS (Figure, all p<0.0001). Even after excluding the 14 patients with unfavorable cytogenetics from the AML-MRC group, the remaining patients with AML-MRC (defined solely by the presence of multilineage dysplasia) had worse outcomes compared to all AML-NOS patients (OS, p=0.013; PFS, p=0.012; CR, p=0.0076). Among 65 patients with intermediate risk cytogenetics, the outcome difference between the AML-MRC and AML-NOS groups remained significant (OS, p=0.0292; PFS, p=0.0232), also indicating prognostic significance of multilineage dysplasia. Within the AML-MRC group, univariate analysis showed that low platelets (<20,000/mm3), FLT3-D835 mutation and MDS-related cytogenetics correlated with OS (p=0.0456, p=0.0265, p=0.002 respectively) and PFS (p=0.0478, p=0.0626, p=0.001). A multivariate Cox proportional hazard analysis, performed on the entire group, identified unfavorable cytogenetic risk group, advanced age (> 60), FLT3-ITD and AML-MRC status as significant predictors of worse OS with the following respective hazard ratios: 2.82 (95% CI, 1.52–5.26), 2.11 (1.01–4.42), 1.98 (1.01–3.90), 1.92 (1.01–3.65).Conclusion: The newly defined WHO category of AML-MRC exhibits a significantly worse clinical outcome compared to AML-NOS and is predictive of worse overall survival in the multivariate analysis of AML patients, independent of age or cytogenetic risk group. These findings support the clinical, morphologic and cytogenetic criteria for this 2008 WHO AML category. [Display omitted]

Refractory Anemia with Ringed Sideroblasts Associated with Marked Thrombocytosis (RARS-t): A Clinicopathological Entity with Questionable Pathogenesis

Refractory anemia with ringed sideroblasts associated with marked thrombocytosis (RARS-t) is a clinicopathological entity with features of both myelodysplastic syndrome and myeloproliferative disorder. The cases of RARS-t reported in literature are few and do not confirm whether this disease represents a variant of Refractory anemia with ringed sideroblasts (RARS), a variant of Essential Thrombocythemia (ET), or the simultaneous occurrence of two separate disorders (RARS and ET). Because of this ambiguity, RARS-t has been assigned to MDS/MPD- Unclassifiable subcategory as a provisional entity in the WHO (2001) classification. Recent studies have demonstrated association of RARS-t with JAK2 V617F mutation in up to 67% of cases, suggesting its proximity to MPD. In a few studies, presence of JAK2 mutation was related with better prognosis. Based on this evidence, there are chances that this provisional entity may be clubbed with the group of MPD disorders in the revised WHO classification. We present here 4 cases of RARS-t diagnosed within a period of 1 year (2007–2008) at our institution. Clinicopathological features of these cases are mentioned in the attached table (Table-1). Two of these cases were not associated with anemia at the time of presentation, however could be diagnosed as RARS-t based on the presence of dyserythropoetic features and >15% ringed sideroblasts in marrow on iron stains. Other causes of reactive ring sideroblasts and thrombocytosis were ruled out in these cases. 2/4 cases were positive for JAK2 V617F mutation, however no correlation was found between the JAK2 positivity and the clinicopathological features including prognosis. All the 4 patients were given hydroxyurea and pyridoxine therapy. In contrast to other studies, one of our JAK2 positive cases had to be maintained on the transfusion support alone due to the multiple treatment failures. Our data adds to the literature supporting the association of RARS-t with JAK2 mutation. However, we do not agree with the notion that JAK2 positivity renders a better prognosis. Also, lack of any correlation of clinicopathological features in our cases with the JAK2 mutation drives us to think that it might be only a secondary association rather a primary pathogenesis event. Review of the literature reminds us that the pathogenetic events resulting in myelodysplastic component of this overlap syndrome have only been rarely addressed. In future, more studies focusing on the mutations responsible for genesis of ringed sideroblasts such as ALAS2, ABCB7, FECH and gene expression profiles of bone marrow progenitor cells are required for better understanding of this common but under reported entity.Table 1CaseAgeSexHb. (g/dL)Hct.MCV (fL)RS%Platelet (× 109/L)WBC (× 109/L)JAK2mutationOther cytogeneticsFibrosisOrganomegalyCase#184F12.938.994.6>15%7098.3Negativenormal karyotype1+ reticulinAbsentCase#285M10.328.3131>15%10727.2Negativenormal karyotype1+ reticulinAbsentCase#368M6.925101.3>15%6345.4Positivenormal karyotype1+ reticulinAbsentCase#463M13.741.578.7>15%127217.7Positivenormal karyotype1+reticulinAbsent

The Detection of Multilineage Dysplasia (MLD) Has No Influence on Prognosis in NPM1 Mutated Acute Myeloid Leukemia (AML) with Normal Karyotype

Acute myeloid leukemia with mutated nucleophosmin (AML NPM1mut) represents about one-third of all adult AML and shows distinctive biological and clinical features. For this reason, AML NPM1mut is planned to be included as a separate category in the revised WHO classification. A yet controversial issue, however, is whether AML NPM1mut with or without multilineage dysplasia (MLD) may differ biologically and clinically, as the presence of MLD might confer a negative prognostic impact. A further feature that was suggested to be typical for NPM1 mutated AML is “cup-like” morphology of blasts. We here analyzed 128 pts with AML NPM1mut and normal karyotype at first manifestation (59 females, 69 males; median age 60.5 years; 23.5–79.3 y). We investigated in parallel cytomorphology from bone marrow and/or peripheral blood, chromosome banding analysis, and molecular analyses. Presence of dysplasia was defined by dysplastic features in ≥50% of cells in the respective hematopoietic lineage as defined by the WHO. A 5% cut-off was taken for the presence of “cup-like” morphology of blasts. All cases were additionally analyzed for the FLT3-ITD, and in 122 pts for the FLT3-TKD. Statistical analysis was performed for overall survival (OS), and event-free survival (EFS) according to Kaplan-Meier using the 2-sided log-rank test. Cox regression analysis related OS and EFS with the analyzed parameters. We found a predominance of the FAB M1 (21.3% of all cases), M2 (33.9%), and M4 subtypes (28.3%). Cup-like morphology in ≥5% of all blasts was observed in 39 of 127 evaluable cases (31.3%) confirming previous observations of an association of the NPM1mut and this specific blast appearance. Molecular characterization detected NPM1 mutation subtype A (n=90/122; 73.8%), B (15/122; 12.3%), and D (7/122; 5.7%), which was in accordance to previous studies. In 56 cases (43.8%) there was a coincidence with an FLT3-ITD. Dysplasia of granulopoiesis was detected in 28/126 (22.2%), of erythropoiesis in 28/104 (26.9%), and of megakaryopoiesis in 57/87 (44.5%) cases in which the respective cell lineage could be analyzed. MLD (≥2 dysplastic hematopoietic lineages) was detected in 28 of 105 evaluable cases (21.9%). Clinical follow-up was available in 104 pts. (median follow-up 12,7 months). CR rate was 83.1% in 77 evaluable pts., and median EFS was 42.1 months in 104 evaluable pts (median OS not reached). An additional FLT3-ITD had a significantly inferior OS (p=0.003) and EFS (p=0.007), confirming the present series being representative. However, the presence of MLD was not significantly related to any endpoint such as CR rate, EFS, or OS. There was no association between MLD and the NPM1-subtype. Also, there was no significant correlation of MLD and the presence of a FLT3-ITD. In conclusion, the presence of MLD in AML NPM1mut with normal karyotype had no impact on CR rate and outcome, whereas coincidence of FLT3-ITD significantly worsened prognosis. These results give further evidence that AML with NPM1mut AML is a unique biological entity with clinical course mainly influenced by FLT3-ITD coincidence. These data do not support any additional prognostic influence of MLD in this AML subtype.

Atypical type II silent corticotrophic adenoma developing into Cushing's disease upon second recurrence

Herein, we report the case of a 73-year old male patient who presented with two recurrences of a pituitary adenoma within a period of 15 years. During the first operation 15 years ago, a clinically non-functioning pituitary macroadenoma was removed. 11 years later, the first recurrence of the tumor was reoperated. Throughout the early course of the disease, he suffered from secondary adrenal insufficiency and required replacement therapy with hydrocortisone. Currently, he presented with the second recurrence and clinical examination revealed signs of Cushing's disease. This was clearly confirmed by endocrinological evaluation. A retrospective analysis of all histological specimens showed an adenoma exhibiting chromophobia, ACTH-positivity and features of atypia with elevated p53 and Ki67 expression as well as nuclear polymorphism. According to the revised WHO classification it was classified as atypical type II silent corticotroph adenoma at the time of the first and second surgery. The specimen removed during the recent surgery displayed the same histological features and was classified as corticotroph adenoma. The combination of an atypical type II adenoma and the switch in the hormone status to an endocrinologically active adenoma makes this case exceedingly rare.

Atypical Type II Silent Corticotrophic Adenoma Developing into Cushing's Disease upon Second Recurrence

Herein, we report the case of a 73-year old male patient who presented with two recurrences of a pituitary adenoma within a period of 15 years. The first tumor resection 15 years ago revealed a non-functioning pituitary macroadenoma. 11 years later, the first recurrence of the tumor was reoperated. Throughout the early course of the disease, he suffered from secondary adrenal insufficiency and required replacement therapy with hydrocortisone. Currently, he presented with the second recurrence and clinical examination revealed signs of Cushing's disease. This was clearly confirmed by endocrinological evaluation. A retrospective analysis of all histological and immunohistochemical slides rendered an adenoma exhibiting chromophobia, ACTH-positivity and features of atypia such as elevated p53 and Ki67 expression as well as nuclear polymorphism. According to the revised WHO classification it was classified as atypical type II silent corticotroph adenoma at the time of the first and second surgery. The specimen removed during the recent surgery displayed the same histological features and was classified as corticotroph adenoma. The combination of an atypical type II adenoma and the switch in the hormone status to an endocrinologically active adenoma makes this case exceedingly rare.

The natural history of bronchioloalveolar carcinoma (BAC) using the 1999 revised who classification

BAC is a histological subtype of non-small cell lung cancer (NSCLC) that is known to have a distinct presentation and natural history. The 1999 WHO classification of BAC is more restrictive by excluding stromal, vascular and pleural invasion. Our purpose was to investigate the natural history, demographics and survival outcomes for a cohort of patients registered with BAC prior to 1999. Our intent was to determine if a more restrictive cohort of BAC resulted in a survival advantage. Additionally, our intent was to hypothesize subsets that may have maximal benefit from epidermal growth factor (EGFR) inhibitors, which have documented activity in BAC. The records from the Tumor Registry of ScottsWhite Hospital were retrospectively reviewed for all BAC cases from 1986–1998. There were 100 cases eligible for review. Demographic data and information on clinical presentation was collected through both chart reviews and tumor registry abstracts. All cases were pathologically reevaluated using the revised WHO system. Kaplan-Meier product-limit survival curves were computed and compared for the true BAC (classic) and adenocarcinoma with BAC features (non-classic) groups. Gender, smoking history, presenting complaint, type of surgery, stage and treatment modalities were compared for both subgroups. Of the entire group 55% were male, 78% were smokers and the presenting complaint in 71% of the cohort was an asymptomatic chest x-ray. There were no significant differences between the classic and non-classic groups for these factors. The cumulative survival curves for the classic and non-classic designation were not significantly different (p = 0.44) with a median survival for the classic group of 4.6 years versus 3.2 years for the non-classic group. Among the 100 cases 30% were reclassified as true BAC and 33% of these were mucinous. Of the group 23% were stage IV at presentation and, of note, chemotherapy was used in 6% of the patients. Radiation therapy was used as part of primary treatment in 13% of the patients. The literature on the natural history of BAC needs to be reevaluated given the revised WHO classification. Our data does not discriminate clinical outcomes for classic BAC and adenocarcinoma with BAC features. Our data supports a trend toward under treatment in a group of patients with a median survival of 3.5 years. There was a non-significant trend toward an improved survival for classic mucinous (6.3 years) versus classic non-mucinous (4.0 years) BAC. This finding supports data that non-mucinous BAC has higher expression of EGFR