Epigenetic inactivation of the miR-34a in hematological malignancies.

miR-34a is a transcriptional target of p53 and implicated in carcinogenesis. We studied the role of miR-34a methylation in a panel of hematological malignancies including acute leukemia [acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL)], chronic leukemia [chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML)], multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL). The methylation status of miR-34a promoter was studied in 12 cell lines and 188 diagnostic samples by methylation-specific polymerase chain reaction. miR-34a promoter was unmethylated in normal controls but methylated in 75% lymphoma and 37% myeloma cell lines. Hypomethylating treatment led to re-expression of pri-miR-34a transcript in lymphoma cells with homozygous miR-34a methylation. In primary samples at diagnosis, miR-34a methylation was detected in 4% CLL, 5.5% MM samples and 18.8% of NHL at diagnosis but none of ALL, AML and CML (P = 0.011). In MM patients with paired samples, miR-34a methylation status remained unchanged at progression. Amongst lymphoid malignancies, miR-34a was preferentially methylated in NHL (P = 0.018), in particular natural killer (NK)/T-cell lymphoma. In conclusion, amongst hematological malignancies, miR-34a methylation is preferentially hypermethylated in NHL, in particular NK/T-cell lymphoma, in a tumor-specific manner, therefore the role of miR-34a in lymphomagenesis warrants further study.

Frequent epigenetic inactivation of Rb1 in addition to p15 and p16 in mantle cell and follicular lymphoma.

Dysregulation of cell cycle control is an important mechanism in carcinogenesis. Gene promoter hypermethylation is an alternative mechanism of gene inactivation. We analyzed the methylation status of the tumor suppressor components of the INK4/Rb pathway in mantle cell lymphoma and follicular lymphoma by methylation-specific polymerase chain reaction for p15, p16, p18, and Rb1 in 23 mantle cell lymphoma and 30 follicular lymphoma cases and lymphoma cell lines. The methylation-specific polymerase chain reaction results showed that in mantle cell lymphoma, frequent p16 (82%) but infrequent p15 (8.7%) or Rb1 (17.4%) hypermethylation occurred, with p16 and Rb1 hypermethylation being mutually exclusive (P=.01). In follicular lymphoma, frequent hypermethylation of p15 (36.7%), p16 (56.7%), and Rb1 (43.3%) occurred, with p15 and Rb1 hypermethylation being mutually exclusive (P=.05). Concurrent methylation of p15 and p16 occurred in 26.7% of patients with follicular lymphoma and 8.7% of patients with mantle cell lymphoma. Compared with mantle cell lymphoma, there was more frequent p15 (P=.025) hypermethylation but comparable Rb1 (P=.07) and p16 (P=.07) hypermethylation in follicular lymphoma. In a patient with follicular lymphoma with sequential biopsies, Rb1 was unmethylated and expressed at diagnosis but became methylated and down-regulated at relapse. Moreover, methylation analysis of these 4 genes in an additional 8 patients with grade I follicular lymphoma showed that Rb, but not the other genes, was preferentially methylated in grade II (P=.03). In summary, most patients with mantle cell lymphoma and follicular lymphoma had epigenetic aberrations targeting the INK4/Rb pathway. There is more frequent p16 hypermethylation in mantle cell lymphoma and p15 or Rb1 hypermethylation in follicular lymphoma. The role of Rb methylation in disease or histologic transformation in follicular lymphoma warrants further study.

Management of herniated retroperitoneal adipose tissue during endoscopic extraperitoneal inguinal hernioplasty.

BACKGROUND: Herniation of retroperitoneal adipose tissue into the inguinal canal, traditionally called cord lipoma, is frequently encountered during endoscopic totally extraperitoneal inguinal hernioplasty (TEP). Failure to recognize and manage the cord lipoma accounted for 30%-50% of recurrent hernia after TEP. The present study was undertaken to evaluate the incidence, risk factors, and management of herniated retroperitoneal adipose tissue during TEP. METHODS: Between December 2002 and November 2005 all patients who underwent TEP were prospectively evaluated for the presence of cord lipoma. Clinical outcomes of patients who were treated for their cord lipoma were compared with those without cord lipoma. Risk factors for the occurrence of cord lipoma were also examined. RESULTS: A total of 498 patients underwent unilateral (n = 386) or bilateral (n = 112) TEP. The overall incidence of cord lipoma was 26.5% (n = 132). A higher body weight, a higher body mass index, and a larger hernial defect were significantly associated with the presence of cord lipoma. Most of the cord lipoma cases (n = 119) were reduced to pelvic peritoneal reflection line after division of the feeding vessels from surrounding structures, while the rest (n = 13) were resected. Early postoperative outcomes, including pain score, morbidities, and other recovery variables, showed no significant difference between the two groups. No recurrence occurred in the present series. CONCLUSIONS: Herniation of retroperitoneal adipose tissue into the inguinal canal occurred in more than one-fifth of the patients with inguinal hernia. Awareness and appropriate treatment of the cord lipoma helped to reduce the risk of recurrence. During TEP, the internal inguinal ring and inguinal canal should always be cleared of any herniated adipose tissue by either reduction or resection. This clearing posed no adverse effects on postoperative outcome.

Primary large B-cell lymphoma of the ampulla of Vater.

Primary lymphoma of the ampulla of Vater is rare. The clinico-pathological and interesting endoscopic and radiological features of a patient with this disorder is presented.

Somatic mutations in the BRCA1 gene in Chinese sporadic breast and ovarian cancer.

Inherited mutations in the BRCA1 gene confer increased susceptibility to breast and ovarian cancer. Its role in sporadic carcinogenesis is not well defined. Somatic mutations in breast cancers have not been reported and to date there are only three reports of somatic mutations in sporadic ovarian cancers. To investigate the contribution of BRCA1 mutations to sporadic breast and ovarian cancer in the Chinese population, we analysed 62 samples from Chinese women using the protein truncation test. There were 40 cases of breast cancer under age 50 and 22 cases of ovarian cancer, all unselected for family history. There was no age selection for the ovarian cancers. We found two somatic BRCA1 mutations in exon 11, one in a breast cancer and the other in an ovarian cancer, both of which result in truncated proteins. Our results indicate that somatic BRCA1 mutations, like somatic mutations in the BRCA2 gene, though very rare, can be found in both breast and ovarian cancers and support a tumor suppressor function for BRCA1 in sporadic tumors.

Diagnostic cues for natural killer cell lymphoma: primary nodal presentation and the role of in situ hybridisation for Epstein-Barr virus encoded early small RNA in detecting occult bone marrow involvement.

Natural killer (NK) cell lymphomas are rare, and atypical features might lead to diagnostic pitfalls. This report describes an unusual patient in whom lymphoma occurred initially as isolated lymph node involvement, an exceptional presentation of an almost exclusively extranodal disease. Furthermore, during the terminal haemophagocytosis in the bone marrow, lymphoma cells lost the expression of the NK cell marker, CD56, making the histopathological diagnosis of bone marrow involvement difficult. This was resolved by in situ hybridisation for Epstein-Barr virus encoded small RNA, which detected occult bone marrow infiltration.

Inflammatory cell-rich gastrointestinal autonomic nerve tumor. An expansion of its histologic spectrum.

Gastrointestinal autonomic nerve (GAN) tumor is an uncommon neoplasm of the gastrointestinal tract. Its histologic appearance is similar to other gastrointestinal stromal tumors. Ultrastructural demonstration of neural differentiation is required for its definitive diagnosis. Recently, we encountered two examples of GAN tumor that occurred in the body of the stomach and the cervical esophagus; the latter site has never been reported previously. These tumors showed unequivocal evidence of neural differentiation ultrastructurally, confirming the diagnosis of GAN tumor. Histologically, they were composed of swirling fascicles of spindle cells as well as a minor component of epithelioid cells, similar to that described previously. In addition, a cuff of lymphoid cells was noted at the peripheral part of both tumors and a scattering of mature plasma cells, lymphocytes, and foam cells was intermingled with the tumor cells. Such histologic features have not been described hitherto and can potentially be misinterpreted as features of inflammatory pseudotumor, inflammatory fibrosarcoma, or follicular dendritic cell tumor. There is a lack of CD34 expression in both tumors, but it would be premature to draw any conclusions about the potential usefulness of this observation.

Mucosa-associated lymphoid tissue (MALT) lymphoma of the jejunum: an elusive cause of recurrent upper gastrointestinal bleeding.

MALT lymphoma often involves the stomach but much less commonly the small bowel. We present clinico-pathologic and radiologic features of a patient with recurrent gastrointestinal bleeding due to MALT lymphoma of the jejunum. Because of the small bowel location, the source of bleeding has been elusive, resulting in delayed diagnosis. The diagnosis was based on the small B cell morphology, demonstration of lympho-epithelial lesions, and immunophenotypic profile.

Primary follicular lymphoma of the small intestine.

While nodal follicular lymphoma is prevalent in western countries, primary extranodal presentation is rare. We present the clinico-pathological and radiologic features of a patient with primary follicular lymphoma of the small intestine presenting with intestinal obstruction. This is followed by the discussion on the frequency and staging systems for primary gastrointestinal lymphomas, and the relevance of monoclonal anti-CD20 antibody therapy.

Primary granulocytic sarcoma of the mediastinum.

Primary granulocytic sarcoma (GS) is rare, and poses a diagnostic pitfall for both pathologists and oncologists. Previous literature showed that almost half of the patients with primary GS were misdiagnosed initially. We presented the clinico-pathological and radiological features of a patient with primary mediastinal GS, and discussed the differential diagnoses and clinical management.

Type II EATL (epitheliotropic intestinal T-cell lymphoma): a neoplasm of intra-epithelial T-cells with predominant CD8αα phenotype.

In this multicentre study, we examined 60 cases of Type II enteropathy-associated T-cell lymphoma (EATL) from the Asia-Pacific region by histological review, immunohistochemistry and molecular techniques. Patients were mostly adult males (median age: 58 years, male:female 2.6:1), presenting with abdominal pain (60%), intestinal perforation (40%) and weight loss (28%). None had a history of coeliac disease and the median survival was only 7 months. Histologically, these tumours could be divided into (i) central tumour zone comprising a monotonous population of neoplastic lymphocytes, (ii) peripheral zone featuring stunted villi and morphologically atypical lymphocytes showing epitheliotropism, and (iii) distant mucosa with normal villous architecture and cytologically normal intra-epithelial lymphocytes (IELs). Characterized by extensive nuclear expression of Megakaryocyte-associated tyrosine kinase (MATK) (87%) and usually a CD8(+)CD56(+) (88%) cytotoxic phenotype, there was frequent aberrant expression of CD20 (24%). T-cell receptor (TCR) expression was silent or not evaluable in 40% but of the remainder, there was predominant expression of TCRαß over TCRγδ (1.6:1). In keeping with the normal ratio of IEL subsets, CD8(+) cases showed predominant CD8αα homodimer expression (77%), regardless of TCR lineage. These tumours constitute a distinct entity from classical EATL, and the pathology may reflect tumour progression from IEL precursors, remnants of which are often seen in the distant mucosa.

Natural killer cell lymphoma shares strikingly similar molecular features with a group of non-hepatosplenic γδ T-cell lymphoma and is highly sensitive to a novel aurora kinase A inhibitor in vitro.

Natural killer (NK) cell lymphomas/leukemias are rare neoplasms with an aggressive clinical behavior. The majority of the cases belong to extranodal NK/T-cell lymphoma, nasal type (ENKTL) in the current WHO classification scheme. Gene-expression profiling (GEP) of 21 ENKTL and NK-cell lymphoma/leukemia patients, 17 NK- and T-cell lines and 5 indolent NK-cell large-granular-lymphocytic proliferation was performed and compared with 125 peripheral T-cell lymphoma (PTCL) patients previously studied. The molecular classifier derived for ENKTL patients was comprised of 84 transcripts with the majority of them contributed by the neoplastic NK cells. The classifier also identified a set of γδ-PTCLs both in the ENKTL cases as well as in cases initially classified as PTCL-not otherwise specified. These γδ-PTCLs expressed transcripts associated with the T-cell receptor (TCR)/CD3 complex, suggesting T cell rather than NK-cell lineage. They were very similar to NK-cell tumors by GEP, but were distinct from cytotoxic (αß)-PTCL and hepatosplenic T-cell lymphoma, indicating derivation from an ontogenically and functionally distinct subset of γδ T cells. They showed distinct expression of Vγ9, Vδ2 transcripts and were positive for TCRγ, but negative for TCRß by immunohistochemistry. Targeted inhibition of two oncogenic pathways (AURKA and NOTCH-1) by small-molecular inhibitors induced significant growth arrest in NK-cell lines, thus providing a rationale for clinical trials of these inhibitors in NK-cell malignancies.