Michael E. Kallen

Triple Hit Lymphoma: Rare Cases With Less Dire Than Usual Prognosis

Triple hit lymphomas are a subset of so-called double hit non-Hodgkin lymphomas exhibiting simultaneous gene translocations/disruption of MYC, BCL2, and BCL6; however, their overlapping morphologic features and complex genetic rearrangements can render classification and prognostication vexing. Clinically triple hit lymphomas are thought to demonstrate aggressive behavior, similar to or worse than that of double hit lymphomas. Only rare reports of long term survivors exist and raise the possibility that unidentified morphologic, immunologic, or cytogenetic differences may impart a less adverse prognosis than current literature and opinion may suggest. Here we report 3 such cases with less aggressive behavior. Cases such as these may prove useful in comparing outcomes, and underlying mechanisms of tumor progression, in aggressive non-Hodgkin lymphomas.

Type II bare lymphocyte syndrome: role of peripheral blood flow cytometry and utility of stem cell transplant in treatment.

Major histocompatibility complex class II (MHCII) deficiency is a rare autosomal recessive immunodeficiency disorder characterized by lack of expression of MHCII molecules, causing defective CD4+ lymphocyte function and an impaired immune response. Clinical manifestations include susceptibility to severe bacterial, viral, and fungal infections which can lead to failure to thrive and childhood death. The only definitive treatment to date is allogeneic stem cell transplantation. Here, we share our experience of 2 patients who presented with MHCII deficiency. We will discuss the role of diagnostic modalities and stem cell transplantation.

Human Epidermal Growth Factor Receptor 2 (HER-2/neu)-Directed Therapy for Rare Metastatic Epithelial Tumors with HER-2 Amplification

Case 1: A 67-year-old Asian female was diagnosed with locally advanced high-grade salivary duct carcinoma in June 2011. Molecular analysis revealed human epidermal growth factor receptor 2 (HER-2) amplification. She received adjuvant therapy with carboplatin/paclitaxel/ trastuzumab and maintenance of trastuzumab. Upon disease progression, trastuzumab could not be continued due to lack of financial coverage. Instead, she was treated with compassionate use of lapatinib from April 2013 and standard 5-fluorouracil. Her disease ultimately progressed and she expired later in 2013. Case 2: A 68-year-old Asian male was diagnosed with extramammary Pagets disease of the scrotum with HER-2 amplification in May 2011. He received 6 cycles of adjuvant trastuzumab/docetaxel/carboplatin followed by maintenance trastuzumab, which was changed to compassionate use of lapatinib as his insurance did not cover further administration of trastuzumab. He showed clinical benefits from single-agent lapatinib and a combination of lapatinib/capecitabine upon progression to the single-agent lapatinib. Ultimately, he was started on ado-trastuzumab emtansine, which was approved at that time by the FDA for HER-2-positive breast cancer progressed on trastuzumab. He is having clinical and radiographic complete response based on current imaging and normalization of his tumor markers. Conclusion: HER-2-targeted therapy should be considered for tumors with HER-2 amplification. In our case series, we would like to emphasize this approach in other rare histologies. Specifically, our patient with extramammary Pagets disease of the scrotum represents the first reported case of a non-breast, non-gastric tumor with HER-2 overexpression with complete clinical and radiographic response to HER-2-targeted therapy.

A (1;19) translocation involving TCF3-PBX1 fusion within the context of a hyperdiploid karyotype in adult B-ALL: a case report and review of the literature

BackgroundThe t(1;19)(q23;p13), which can result in the TCF3-PBX1 chimeric gene, is one of the most frequent translocations in B-acute lymphoblastic leukemia (B-ALL) and is observed in both adult and pediatric populations at an overall frequency of 6%. It can occur in a balanced or unbalanced form and as a sole abnormality is associated with an intermediate prognosis. Additionally, this translocation is observed in the context of hyperdiploid B-ALL, in which case it is associated with a poor prognosis. However, due to different translocation partner genes at chromosomes 1 and 19, distinct subtypes of hyperdiploid B-ALL with t(1;19)/der(19)t(1;19) are recognized based on the presence or absence of the TCF3-PBX1 fusion gene, but the cytogenetic and etiologic differences between the two remain understudied.FindingsWe report a case of an adult with a history of relapsed precursor B-ALL whose conventional cytogenetics showed an abnormal female karyotype with both hyperdiploidy and a t(1;19)(q23;p13). Fluorescence in situ hybridization (FISH) on previously G-banded metaphases using the LSI TCF3/PBX1 Dual Color, Dual Fusion Translocation Probe confirmed the presence of the TCF3-PBX1 gene fusion.ConclusionsThis particular pattern with a TCF3-PBX1 fusion within the context of a hyperdiploid karyotype is seen in B-ALL and is usually associated with a poor outcome. This case is one of only a few cases with both hyperdiploidy and a confirmed TCF3-PBX1 fusion, demonstrating the importance of using FISH for proper molecular classification of these cases in order to distinguish them from those with hyperdiploidy but no TCF3-PBX1 fusion gene. Such molecular studies may provide insight into the precise differences between TCF3-PBX1 positive and negative hyperdiploid B-ALL bearing the t(1;19)(q23;p13).

Intraductal Oncocytic Papillary Neoplasms of the Pancreas

Intraductal oncocytic papillary neoplasms (IOPNs) are cystic neoplasms with intraductal growth and complex papillae composed of oncocytic cells. IOPNs have been reported both in the pancreas and biliary tree, and are most likely closely related in these 2 locations. In the pancreas, these rare tumors are now considered 1 of the 4 histologic subtypes of intraductal papillary mucinous neoplasm (IPMN). Significant differences in histology, immunophenotype, and molecular genetics have been reported between IOPNs and other IPMN subtypes. However, there are limited data regarding the clinical behavior and prognosis of IOPNs in comparison to other subtypes of IPMN. We review features of pancreatic IOPNs and discuss the differential diagnosis of other intraductal lesions in the pancreas.

B-lymphoblastic transformation of mantle cell lymphoma/leukemia with “double hit” changes

Mantle cell lymphoma is a mature B-cell neoplasm composed of small to medium-sized atypical lymphocytes and has a characteristic t(11;14)(q13;q32) translocation, with a variably aggressive and overall incurable course. More aggressive histologic variants have been described, as well as rare cases of transformation to other large cell lymphomas. Here, we describe a novel case of large cell blastic transformation of mantle cell lymphoma/leukemia at presentation with unusual immunophenotypic and cytogenetic features, most consistent with B-lymphoblastic leukemia. Morphologic findings include sheets of large blasts replacing the bone marrow, as well as occasional small to medium-sized atypical lymphocytes in the background. The blasts express CD19, PAX5, CD10, Cyclin D1, and TdT but are negative for CD5, CD20, and BCL2 by immunophenotyping. Cytogenetic studies show a complex karyotype with t(11;14), monosomy 13, gains of 8q, and MYC gene rearrangement and amplification among other changes. This unique case of blastic TdT-positive B-cell leukemia arising from mantle cell lymphoma may represent transformation with complex cytogenetic abnormalities including “double hit” changes. This distinctive presentation may expand our understanding of the biology behind mantle cell lymphoma progression.

A quality initiative of postoperative radiographic imaging performed on mastectomy specimens to reduce histology cost and pathology report turnaround time.

Breast pathology relies on gross dissection for accurate diagnostic work, but challenges can necessitate submission of high tissue volumes resulting in excess labor, laboratory costs, and delays. To address these issues, a quality initiative was created through implementation of the Faxitron PathVision specimen radiography system as part of the breast gross dissection protocol; this report documents its impact on workflow and clinical care. Retrospective data from 459 patients who underwent simple or modified radical mastectomy at our institution between May 2012 and December 2014 were collected. Comparison was made between the mastectomy specimen control group before radiography use (233 patients, 340 breasts) and Faxitron group that underwent postoperative radiography (226 patients, 338 breasts). We observed a statistically significant decrease in mean number of blocks between control and Faxitron groups (47.0 vs 39.7 blocks; P<.0001), for calculated cost savings of US

Coexpression of cytokeratin and B cell markers—a rare finding with new implications

146 per mastectomy. A statistically significant decrease in pathology report turnaround time was also observed (4.2 vs 3.8days; P=.038). Postoperative mastectomy specimen radiography has increased workflow efficiency and decreased histology costs and pathology report turnaround time. These findings may underestimate actual benefits and highlight the importance of quality improvement projects in anatomical pathology.

Erratum to: A case of B-cell acute lymphoblastic leukemia in a child with Down syndrome bearing a t(2;12)(p12;p13) involving ETV6 and biallelic IGH@ rearrangements.

A 66 year-old woman presented with a breast mass and bilateral axillary adenopathy. Clinicians were initially concerned for the possibility of breast carcinoma, but a breast biopsy demonstrated reactive changes and no malignancy. A subsequent axillary lymph node biopsy revealed a neoplastic proliferation composed of sheets of large atypical cells with ovoid to angulated nuclei, clumped chromatin, distinct nucleoli, and scant eosinophilic cytoplasm (see Fig. 1a). Immunohistochemical stains were positive for lymphoid and B cell antigens, including CD45, CD20 (see Fig. 1b), PAX5, CD79a, CD5, CD10, BCL2, BCL6, and MUM1, but negative for cyclin D1 and TdT. No kappa or lambda light chain restriction was seen. The Ki67 proliferation index was approximately 90 %. A cMyc stain was positive, and an EBV-EBER in situ hybridization was negative. Interestingly, immunohistochemical stains were also positive for epithelial markers, including pan keratin AE1/AE3 and CAM5.2, showing a golgi or dot-like staining pattern (see Fig. 1c, d), as well as NSE. Other epithelial and neuroendocrine markers were negative, including kerat in 7, kerat in 20, EMA, TTF-1, synaptophysin, and chromogranin. Fluorescence in situ hybridization (FISH) studies showed no evidence of a t(14;18) IGH@-BCL2 translocation, BCL6 gene rearrangement, or MYC gene rearrangement, but did show 3q− in 40 % (120/300) and 18q+ in 40.6 % (122/300) of nuclei examined. Molecular studies were performed, and a VH gene rearrangement study was positive for a clonal B cell gene rearrangement. This case represents a diagnostic challenge between an aggressive B cell lymphoma and Merkel cell carcinoma (MCC). MCC features monomorphic cells and can have similar morphology to blastic and high-grade lymphomas and has recently been shown to express lymphoid markers including PAX5, TdT, and immunoglobulins in addition to their known expression of cytokeratins and neuroendocrine markers [1]. MCC is associated with chronic lymphocytic leukemia (CLL), immunosuppressed states including HIV and organ transplantation, and the recently discovered Merkel cell polyoma virus (MCPyV). Increasing evidence shows overlap between MCC and B cell lymphomas, including a B cell immunophenotype as well as a subset of MCC cases showing positive B cell gene rearrangements. The origin of MCC is not completely understood, and the aforementioned group has postulated that perhaps MCC is derived from precursor B cells [1]. On the other hand, aberrant keratin expression has been reported in high-grade B cell lymphomas [2]. PAX5 binding sites in the CK20 promoter could explain keratin expression in non-epithelial cells [3, 4]. Additionally, cytokeratin expression has been demonstrated in SV40 virally transformed human fibroblast and other non-epithelial tumor cell lines [3, 5]. * Michael E. Kallen mkallen@mednet.ucla.edu

Isolated choroid plexus granulomas: Initial presentation of neurosarcoidosis?

[This corrects the article DOI: 10.1186/s40364-015-0036-1.].