Identification of High-risk Cryptic CRLF2 Rearrangements in B-Cell Acute Lymphoblastic Leukemia Utilizing an FGFR3/IGH Dual-Color Dual-Fusion DNA Probe Set.

B-cell acute lymphoblastic leukemia (B-ALL) is the most common childhood malignancy with gene rearrangements involving the IGH locus occurring in ∼5% of cases. Fluorescence in situ hybridization (FISH) probes targeting the IGH locus are not included in the standard children's oncology group (COG) fluorescence in situ hybridization panel. At our institute, we incorporated the use of FGFR3/IGH dual-color dual-fusion DNA probes for confirmation of aneuploidy 4 and 14 in diagnostic B-ALL specimens. Subsequently we have identified 4 B-ALL cases with cryptic CRLF2-IGH translocations that would otherwise have gone undetected. Detection of genetic alterations in B-ALL, such as CRLF2 rearrangements, may enhance patient risk stratification and therapy options in pediatric B-ALL.

Proliferation centers in bone marrows involved by chronic lymphocytic leukemia/small lymphocytic lymphoma: a clinicopathologic analysis.

OBJECTIVES: Proliferation centers (PCs) are a characteristic finding in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) lymph nodes, and their presence and extent in this site are not currently felt to be related to clinical course. In contrast, detailed clinicopathologic analyses of bone marrow (BM) PCs have not been previously reported. METHODS: The PCs in 88 CLL/SLL BMs from 45 patients (pts) were graded (0-4) and were correlated with other morphologic, immunophenotypic, cytogenetic, and laboratory features. RESULTS: Proliferation centers were present in 69 BMs (78%) from 32 pts (71%) and were distinct/prominent (grades 2-4) in 21 pts (47%), with the latter more commonly found in follow-up BMs (1/7 diagnostic BMs vs 49/81 follow-up BMs; P=.04). When present, PCs were most commonly graded as distinct nodules easily visible on ×10. No relationships were identified between PCs and any complete blood count parameter, serum lactate dehydrogenase or IgG levels, degree or pattern of BM involvement, blood morphology, CD38 and FMC7 expression by flow cytometry, or fluorescence in situ hybridization results, when the first encountered BM was considered for each patient. CONCLUSIONS: This represents the first detailed analysis of PCs in CLL/SLL BMs. In our tertiary center, PCs were seen frequently, in approximately three-fourths of cases. There were no statistical associations identified between PCs and cytogenetic, immunophenotypic, or other laboratory and morphologic findings.

Clinicopathologic analysis of the impact of CD23 expression in plasma cell myeloma with t(11;14)(q13;q32).

A recent study has shown that 10% of plasma cell myelomas (PCMs) express CD23 and that expression is associated with abnormalities of chromosome 11, mainly t(11;14)(q13;q32); however, only 40% of t(11;14)(+) PCMs express CD23. Because these results were generated in a limited patient cohort and because the clinical relevance of CD23 expression in PCMs with t(11;14)(q13;q32) has not been fully characterized, we addressed this question in a large series of patients with t(11;14)(+) PCM. Forty-two bone marrow biopsies from patients with t(11;14)(+) PCM were evaluated for CD23 expression by immunohistochemistry. CD23 expression was correlated with laboratory and clinical data and outcome after autologous stem cell transplantation, including event-free survival and overall survival (OS). Plasma cell myelomas with t(11;14)(q13;q32) were frequently CD20(+) (46.4%) and CD56(-) (53.8%) and had a nonhyperdiploid karyotype (97.6%) with frequent 13q deletion (33.3%). Of 42 cases, 19 (45.2%) expressed CD23. CD23(+) PCMs were more likely to present with platelet counts less than 150 × 10(3)/µL (100% vs 50%, P = .006). There were no significant differences in other laboratory or presenting clinical data. The median event-free survival in patients treated with autologous stem cell transplantation (n = 29) was similar regardless of CD23 status, whereas the median OS (all patients) was longer in CD23(-) than in CD23(+) PCMs: not reached vs 3365 days (P = .08). Our findings suggest that patients with t(11;14)(+)/CD23(+) PCM present with lower platelet counts and may have a shorter OS than those with t(11;14)(+)/CD23(-) PCM.

Inheritance of a Balanced t(12;20)(q24.33;p12.2) and Unbalanced der(13)t(7;13)(p21.3;q33.2) from a Maternally Derived Double Balanced Translocation Carrier.

We report a 4-month-old male proband with a history of prominent forehead, hypertelorism, ear abnormalities, micrognathia, hypospadias, and multiple cardiac abnormalities. Initial microarray analysis detected a concurrent 7p21.3-p22.3 duplication and 13q33.2-q34 deletion indicating an unbalanced rearrangement. However, subsequent conventional cytogenetic studies only revealed what appeared to be a balanced t(12;20)(q24.33;p12.2). Fluorescence in situ hybridization (FISH) using chromosome-specific subtelomere probes confirmed the presence of an unbalanced der(13)t(7;13)(p21.3;q33.2) and balanced t(12;20)(q24.33;p12.2), both of maternal origin. In addition to our unique clinical findings, this case highlights the benefits and limitations of both conventional cytogenetic studies and microarray analysis and how FISH complements each methodology.

Mosaic Trisomy 9p in a Patient with Mild Dysmorphic Features and Normal Intelligence.

To the Editor: Partial and whole duplications of the short arm of chromosome 9 have been commonly reported in the literature with characteristic phenotypic features and intellectual disabilities. The clinical features of 9p duplications are broad and can include growth retardation, developmental delay, intellectual disability, microbrachycephaly, deep set eyes, hypertelorism, downslanting palpebral fissures, prominent nasal root, bulbous nasal tip, low-set ears, short fingers and toes with hypoplastic nails, and delayed bone age (Bonaglia et al., 2002; Zou et al., 2009; Guilherme et al., 2014).

Recurrent giant cranial desmoid tumor in a 3-year-old boy with familial adenomatous polyposis requiring bifrontoparietal cranioplasty: case report.

Desmoid tumors, also known as aggressive fibromatosis, are locally infiltrating musculoaponeurotic neoplasms arising in connective tissues. Desmoid tumors may be associated with familial adenomatous polyposis (FAP), a genetic disorder that presents with hundreds to thousands of precancerous colorectal polyps. The authors report the case of an 18-month-old boy who underwent resection of a right temporal desmoid tumor (initially diagnosed as cranial fasciitis) and developed a bilateral frontoparietal calvarial desmoid tumor 2 years later. The patient underwent gross-total resection of the tumor that required a large cranioplasty. He was subsequently diagnosed with FAP. The patient has been without tumor recurrence for 9 years afterwards and has not required revision of his cranioplasty. This is the first report describing a recurrent cranial desmoid tumor in a pediatric patient with FAP. The authors believe, however, that some of the cases previously reported as cranial fasciitis are likely desmoid tumors pathobiologically and genetically.

Mantle cell lymphoma in lymph nodes with metastatic small cell carcinoma of lung: a diagnostic and treatment dilemma.

We report a rare case of small cell carcinoma (SCC) of lung, metastatic to ipsilateral hilar and peribronchial lymph nodes with synchronous mantle cell lymphoma (MCL), in a 58-year-old female. She was treated with Cisplatin, Etoposide, and Rituximab, and remained in complete remission for approximately two and a half years following the initial diagnosis. To the best of our knowledge, synchronous SCC and MCL or SCC metastatic to lymph nodes involved by MCL has not been previously reported. In this case, the features of MCL were very inconspicuous in the lymph nodes with extensive metastases of SCC. The presence of MCL was confirmed by immunohistochemistry and fluorescence in situ hybridization (FISH). The co-existence of lymphoma and metastatic carcinoma in the same lymph node, as seen in this case, highlights the significance of analyzing subtle lymphoid architectural changes, and applying ancillary studies such as immunohistochemistry and molecular analysis in suspicious cases. The management of synchronous SCC and MCL requires consideration of their respective biologic behavior, and cumulative toxicity of treatment regimens of both tumors. In such cases an optimum treatment strategy should be adopted to cover both malignancies with minimal toxic effect.

Malignant gastrointestinal neuroectodermal tumor: clinicopathologic, immunohistochemical, ultrastructural, and molecular analysis of 16 cases with a reappraisal of clear cell sarcoma-like tumors of the gastrointestinal tract.

The clinical, histologic, immunophenotypic, ultrastructural, and molecular features of a distinctive gastrointestinal tumor are described. Sixteen patients, 8 women and 8 men aged 17 to 77 years (mean age, 42 y; 63% less than 40 y) presented with abdominal pain, intestinal obstruction, and an abdominal mass. Mean tumor size was 5.2 cm (range, 2.4 to 15.0 cm). The tumors arose in the small bowel (10), stomach (4), and colon (2) and were histologically characterized by a sheet-like or nested population of epithelioid or oval-to-spindle cells with small nucleoli and scattered mitoses. Five cases showed focal clearing of the cytoplasm. Scattered osteoclast-type multinucleated giant cells were present in 8 cases. The tumor cells were positive for S-100 protein, SOX10, and vimentin in 100% of cases, for CD56 in 70%, for synaptophysin in 56%, for NB84 in 50%, for NSE in 45%, and for neurofilament protein in 14% of cases. All cases tested were negative for specific melanocytic, gastrointestinal stromal tumors, epithelial, and myoid markers. Ultrastructural examination of 5 cases showed features of primitive neuroectodermal cells with clear secretory vesicles, dense-core granules, occasional gap junctions, and no evidence of melanogenesis. EWSR1 gene rearrangement was assessed by fluorescence in situ hybridization in 14 cases. Twelve cases (86%) showed split EWSR1 signal consistent with a chromosomal translocation involving EWSR1. One case showed extra intact signals, indicating that the nuclei possessed either extra copies of the EWSR1 gene or chromosome 22 polysomy. Only 1 case showed no involvement of the EWSR1 gene. Six cases demonstrated rearrangement of the partner fusion gene ATF1 (46%), and 3 showed rearrangement of CREB1 (23%); 2 cases lacked rearrangement of either partner gene. Clinical follow-up was available in 12 patients and ranged from 1.5 to 106 months. Six patients died of their tumors (mean survival, 32 mo; 83% less than 24 mo). At last follow-up, 4 patients were alive with regional, lymph node, and liver metastases, and 2 patients were alive with no evidence of disease. The tumor described here is an aggressive form of neuroectodermal tumor that should be separated from other primitive epithelioid and spindle cell tumors of the gastrointestinal tract. The distinctive ultrastructural features and absence of melanocytic differentiation serve to separate them from soft tissue clear cell sarcomas involving the gastrointestinal tract. The designation "malignant gastrointestinal neuroectodermal tumor" is proposed for this tumor type.

Follicular lymphoma transformation to dual translocated Burkitt-like lymphoma: improved disease control associated with radiation therapy.

Dual translocated (or "dual hit") lymphomas are highly aggressive B cell neoplasms associated with an extremely poor prognosis. The optimal treatment for these lymphomas remains undefined. We present two cases of follicular lymphoma with transformation to Burkitt-like lymphoma. In both cases dual translocations involving both the bcl-2 and c-myc loci were present. Each patient underwent intensive induction immunochemotherapy followed by autologous stem cell transplantation and radiation therapy. The first patient received post-transplant mediastinal radiation and developed recurrence in multiple areas outside of the radiation field. The second patient received total body irradiation as part of the conditioning regimen, and is without recurrence 18 months after transplant, and 24 months after diagnosis of the dual translocated lymphoma. We review dual translocation B cell lymphoma in the setting of transformation from follicular lymphoma, and suggest a potential role for total body irradiation in the management of this highly aggressive non-Hodgkin lymphoma.