Elizabeth L. Courville

Isolated asymptomatic ileitis does not progress to overt crohn disease on long-term follow-up despite features of chronicity in ileal biopsies

Isolated ileal abnormalities may be detected during routine colonoscopy performed for polyp screening or surveillance. The significance of these abnormalities in asymptomatic patients without a prior diagnosis of inflammatory bowel disease is unknown. A critical clinical issue is whether isolated ileitis in asymptomatic patients is a manifestation of early Crohn disease (CD). We examined clinical, endoscopic, and pathologic data from 29 patients with isolated ileitis and no prior history of inflammatory bowel disease, and no colonic or upper gastrointestinal involvement. Only patients with at least 2 years of follow-up (range: 2.2 to 12.6 y) were included. Fifteen of 29 patients had colonoscopy for gastrointestinal symptoms whereas the remaining 14 were asymptomatic (screening colonoscopy). Seven of 15 (47%) of patients categorized as chronic active ileitis and 3 of 14 (21%) of those classified as focal active ileitis, on blinded histopathologic review, had a clinical diagnosis of CD at last follow-up. One or more features of chronicity were present in 11 of 14 (79%) of asymptomatic ileitis patients but none developed any manifestations of CD on long-term follow-up. In contrast, 8 of 10 (80%) of symptomatic patients with features of chronicity in ileal biopsies progressed to a diagnosis of CD, as did 2 of 5 (40%) symptomatic patients with focal active ileitis. Thus, the presence of symptoms seems to be the best predictor of likelihood of progression to CD in patients with isolated ileitis (P<0.001). Isolated ileitis detected in asymptomatic patients undergoing polyp screening or surveillance does not evolve into CD on follow-up, despite endoscopic and histologic overlap with findings typically seen in CD.

Clinicopathologic analysis of acute myeloid leukemia arising from chronic myelomonocytic leukemia

Acute myeloid leukemia arising from chronic myelomonocytic leukemia is currently classified as acute myeloid leukemia with myelodysplasia-related changes, a high-risk subtype. However, the specific features of these cases have not been well described. We studied 38 patients with chronic myelomonocytic leukemia who progressed to acute myeloid leukemia. We compared the clinicopathologic and genetic features of these cases with 180 patients with de novo acute myeloid leukemia and 34 patients with acute myeloid leukemia following myelodysplastic syndromes. We also examined features associated with progression from chronic myelomonocytic leukemia to acute myeloid leukemia by comparing the progressed chronic myelomonocytic leukemia cases with a cohort of chronic myelomonocytic leukemia cases that did not transform to acute myeloid leukemia. Higher white blood cell count, marrow cellularity, karyotype risk score, and Revised International Prognostic Scoring System score were associated with more rapid progression from chronic myelomonocytic leukemia to acute myeloid leukemia. Patients with acute myeloid leukemia ex chronic myelomonocytic leukemia were older (P<0.01) and less likely to receive aggressive treatment (P=0.02) than de novo acute myeloid leukemia patients. Most cases showed monocytic differentiation and fell into the intermediate acute myeloid leukemia karyotype risk group; 55% had normal karyotype and 17% had NPM1 mutation. Median overall survival was 6 months, which was inferior to de novo acute myeloid leukemia (17 months, P=0.002) but similar to post myelodysplastic syndrome acute myeloid leukemia. On multivariate analysis of all acute myeloid leukemia patients, only age and karyotype were independent prognostic variables for overall survival. Our findings indicate that acute myeloid leukemia following chronic myelomonocytic leukemia displays aggressive behavior and support placement of these cases within the category of acute myeloid leukemia with myelodysplasia-related changes. The poor prognosis of these patients may be related to an older population and lack of favorable-prognosis karyotypes that characterize many de novo acute myeloid leukemia cases.

Diverse clinicopathologic features in human herpesvirus 8-associated lymphomas lead to diagnostic problems.

OBJECTIVES Human herpesvirus 8 (HHV8)-associated lymphomas are uncommon, mainly affect men infected with the human immunodeficiency virus (HIV), and usually have a poor prognosis. We sought to characterize the HHV8+ lymphomas seen at our institution since the mid-1990s. METHODS We identified 15 patients with HHV8-associated lymphomas and evaluated their clinical and pathologic features. RESULTS Diagnoses included primary effusion lymphoma (PEL) (n = 2), extracavitary PEL (n = 8), intravascular large B-cell lymphoma (n = 1), HHV8+ plasmablastic microlymphoma (n = 3), and germinotropic lymphoproliferative disorder (GLD) (n = 1). The case of GLD progressed to a high-grade HHV8+ Epstein-Barr virus-positive lymphoma, an evolution that has not been previously reported. Four patients were HIV-(three from an HHV8-endemic area). Potentially misleading pathologic features in our series of extracavitary PEL included classic Hodgkin lymphoma-like features, lymph node sinus involvement, and T-cell antigen expression. CONCLUSIONS HHV8-associated lymphomas can be clinically and pathologically heterogeneous, with features that may lead to misdiagnosis as other types of lymphoma.

Monosomal karyotype at the time of diagnosis or transplantation predicts outcomes of allogeneic hematopoietic cell transplantation in myelodysplastic syndrome.

Various cytogenetic risk scoring systems may determine prognosis for patients with myelodysplastic syndromes (MDS). We evaluated 4 different risk scoring systems in predicting outcome after allogeneic hematopoietic cell transplantation (alloHCT). We classified 124 patients with MDS using the International Prognostic Scoring System (IPSS), the revised International Prognostic Scoring System (R-IPSS), Armands transplantation-specific cytogenetic grouping, and monosomal karyotype (MK) both at the time of diagnosis and at alloHCT. After adjusting for other important factors, MK at diagnosis (compared with no MK) was associated with poor 3-year disease-free survival (DFS) (27% [95% confidence interval, 12% to 42%] versus 39% [95% confidence interval, 28% to 50%], P = .02) and overall survival (OS) (29% [95% confidence interval, 14% to 44%] versus 47% [95% confidence interval, 36% to 59%], P = .02). OS but not DFS was affected by MK at alloHCT. MK frequency was uncommon in low-score R-IPPS and IPSS. Although IPSS and R-IPSS discriminated good/very good groups from poor/very poor groups, patients with intermediate-risk scores had the worst outcomes and, therefore, these scores did not show a progressive linear discriminating trend. Cytogenetic risk score change between diagnosis and alloHCT was uncommon and did not influence OS. MK cytogenetics in MDS are associated with poor survival, suggesting the need for alternative or intensified approaches to their treatment.

Use of sorafenib for post-transplant relapse in FLT3/ITD-positive acute myelogenous leukemia: maturation induction and cytotoxic effect

Internal tandem duplication (ITD) mutation of the FLT3 receptor tyrosine kinase ( FLT3/ITD ) is one of the most common gene mutations in patients with acute myeloid leukemia (AML) and is a notoriously poor prognostic factor. The ligand-independent constitutive activation of the FLT3 kinase and its

Double- and triple-hit lymphomas can present with features suggestive of immaturity, including TdT expression, and create diagnostic challenges

Abstract Double- and triple-hit lymphomas (DHL/THL) are aggressive B-cell neoplasms characterized by translocation of MYC with concurrent BCL2 and/or BCL6 translocation. In this retrospective study from one institution, we report clinicopathologic features of 13 cases (9 DHL/4 THL). The median age was 59 years (range 30–74) and patients included eight females and five males. Presentation included enlarging lymphadenopathy/masses (11 patients) and abnormal peripheral blood findings (2 patients). Features which raised the differential of an immature neoplasm included terminal deoxynucleotidyl transferase positivity (four cases, two THL/two DHL); dim CD45 expression (seven cases), lack of CD20 (two cases), or lack of surface immunoglobulin light chain (three cases) by flow cytometry; and blastoid morphology (two cases). We conclude that expression of TdT in a B-cell lymphoma with mature features or expression of surface light chain in a case otherwise suggestive of B-lymphoblastic leukemia/lymphoma should prompt an expedited evaluation for DHL/THL.

EBV-negative monomorphic B-cell post-transplant lymphoproliferative disorders are pathologically distinct from EBV-positive cases and frequently contain TP53 mutations

Monomorphic post-transplant lymphoproliferative disorder commonly resembles diffuse large B-cell lymphoma or Burkitt lymphoma, and most are Epstein–Barr virus (EBV) positive. We retrospectively identified 32 cases of monomorphic post-transplant lymphoproliferative disorder from two institutions and evaluated EBV in situ hybridization; TP53 mutation status; p53, CD30, myc, and BCL2 expression by immunohistochemistry; proliferation index by Ki67; and germinal center vs non-germinal center immunophenotype by Hans criteria. Post-transplant lymphoproliferative disorder arose after hematopoietic stem cell transplant in five and solid organ transplant in 27 patients, a median of 4 and 96 months after transplant, respectively (overall median latency 71 months, range 2–295). The most common morphology was diffuse large B-cell lymphoma (28 cases), with three cases of Burkitt lymphoma, and one case of plasmablastic lymphoma. Ten cases (31%) were EBV negative. Of those with the morphology of diffuse large B-cell lymphoma, the EBV-negative cases were more frequently TP53-mutated (P<0.001), p53 positive by immunohistochemistry (P<0.001), CD30 negative (P<0.01), and of germinal center immunophenotype (P=0.01) compared with EBV-positive cases. No statistically significant difference in overall survival was identified based on EBV, TP53 mutation status, germinal center vs non-germinal center immunophenotype, or other immunohistochemical parameters evaluated. Patients who died of post-transplant lymphoproliferative disorder were older with a longer latency from time of transplant to diagnosis (P<0.05). Our study demonstrates that diffuse large B-cell lymphoma-related immunohistochemical prognostic markers have limited relevance in the post-transplant setting and underscores differences between EBV-positive and EBV-negative post-transplant lymphoproliferative disorder in terms of immunophenotype and TP53 mutation frequency, supporting an alternative pathogenesis for EBV-negative post-transplant lymphoproliferative disorder.

Bosutinib, a Lyn/Btk inhibiting tyrosine kinase inhibitor, is ineffective in advanced systemic mastocytosis

vival (P 5 0.08). Our goal is to improve the nationwide survival of myeloma patients. We have established a national registry of all myeloma patients to identify areas of intervention. A population-based survey showed no difference in causes of death among patients ineligible for HDT, who died within 30 days from diagnosis as compared to patients who died between 31 and 180 days. Patients who died within 30 days had higher LDH levels and lower levels of plasma albumin as compared to those patients who died within 31– 180 days, and may reflect patients with high tumor burden and a high degree of stress caused by severe infection, impaired kidney, and liver function. When compared with patients who died later than 180 days of diagnosis, WHO performance status was worse in patients with early death. A clinician will not find these results surprising. However, our data may imply that elderly patients with multiple myeloma are diagnosed with delay and a nationwide focus is now on accelerated diagnosis to clarify whether individuals presenting with an M-protein in blood or urine or with myeloma associated symptoms are suffering from myeloma. Furthermore, our survey showed that among patients with early deaths the most common causes of deaths were infections, cardiovascular failure, and renal failure. Standard induction treatment for patients ineligible for HDT now includes adjustment of chemotherapy dose according to co-morbidity and a proteasome inhibitor. Clinicians use several approaches to avoid life-threatening infections among the elderly such as granulocyte colony-stimulating factor (G-CSF) in patients with neutropenia and supportive treatment with immunoglobulins. To provide the patients with the best antibiotic treatment in future we are now conducting a nationwide prospective study on prophylactic antibiotic treatment.

Green Neutrophilic Inclusions are Frequently Associated With Liver Injury and May Portend Short-Term Mortality in Critically Ill Patients

Background: Few studies have described an association among acute liver disease, high short-term mortality, and blue-green refractile neutrophilic inclusions on blood smears. Objective: To describe our experience with 13 patients and compare our data to those from other cases reported in the literature regarding the interplay of acute liver disease, high short-term mortality, and blue-green refractile neutrophilic inclusions on blood smears. Methods: We performed a retrospective review of blood smears, patient medical information, and outcomes for our 13 studied patients. Results: The patients in our series had lower short-term mortality than the patients whose cases were reported in the literature (P = .04), and inclusions were identified in 2 patients who were not critically ill. In 3 patients without liver enzyme elevation, elevated lactate dehydrogenase (LDH) levels were present. Conclusions: Blue-green refractile inclusions are associated with tissue or liver injury; consequently, liver enzyme and LDH testing should be considered when these inclusions are present. These inclusions are more common in critically ill patients but can be observed in patients who are not acutely ill, and the prognosis may not be as dire as previously reported. Greater awareness of these inclusions and their implications will strengthen our understanding of their etiology and diagnostic significance.

Routine evaluation of adult tonsillectomy specimens: Toward establishing a new standard of care

Tonsil excision is a common surgery for both children and adults. Prior studies have consistently shown that the rate of malignancy in tonsil specimens is low and that the possibility of true, occult malignancy is remote. Practice trends accept triage of pediatric tonsillectomies for exemption or gross exam only. However, for adults, despite a low malignancy rate, routine histological evaluation of tonsillectomy specimens is standard of care at most health care facilities. The authors performed a retrospective review of all tonsil specimens received in their department over 45 months with categorization of pathological diagnosis and surgical indication. Of 1746 adult tonsillectomy specimens removed during this time, there were no incidental/occult malignancies. These data indicate that gross examination of adult tonsillectomy specimens excised for chronic tonsillitis or sleep apnea is sound practice, and this, taken together with other published data, provides a basis for consensus-derived practice guidelines.