Usual and Unusual Patterns of Transformation Among Lymphoid Neoplasms: Diagnostic Considerations for Pathologists No abstract available

B-Lymphoid Blast Phase of Chronic Myeloid Leukemia: A Case Report and Review of the Literature Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell disorder characterized by a reciprocal translocation, t(9;22)(q34.1;q11.2). This leads to fusion of the BCR and ABL1 genes, encoding an active tyrosine kinase that causes unregulated proliferation of the myeloid lineage. The BCR/ABL1 fusion protein is found not only in CML, but also in a subset of de novo B-lymphoblastic leukemia (B-LL). However, the fusion protein in CML is characteristically the slightly longer p210 variant, whereas the p190 variant is more frequently found in B-LL. Without treatment, CML will progress to accelerated and/or blast phase (BP). Disease progression is often characterized by accumulation of additional chromosomal abnormalities. The development of tyrosine kinase inhibitor (TKI) therapy that targets BCR/ABL1 has revolutionized treatment of CML and vastly improved outcomes, although the disease can still progress despite TKI therapy. Blast phase most commonly manifests as myeloid BP; however, up to 30% of BP presents as lymphoid BP (LBP), typically of the B-cell lineage. The B-lymphoblasts of LBP have a phenotype indistinguishable from that of de novo B-LL. However, LBP typically carries the p210 BCR/ABL transcript and may show distinct chromosomal anomalies, including loss of chromosome 9p. The prognosis for CML-BP is poor, although survival has improved with TKI therapy and stem cell transplant, and LBP has been associated with superior survival compared with myeloid BP. Here we present a case of CML in B-lymphoid BP and review the current literature.

Transformed Mycosis Fungoides and Mimics: Exploring the Landscape of CD30: +: Cutaneous T-Cell Lymphomas Mycosis fungoides (MF) is an epidermotropic, primary cutaneous T-cell lymphoma (CTCL) with a generally indolent clinical course, although higher stage and transformed tumors can behave more aggressively. Large cell transformation may demonstrate CD30 expression and histologically resemble other CD30+ CTCLs, including lymphomatoid papulomatosis and cutaneous anaplastic large cell lymphoma. These entities are thought to exist on a spectrum with overlapping histologic features; however, it is of clinical importance that we do our best to accurately classify these entities due to the variability in treatment and prognosis. In this report, we present a case of CD30+ transformed MF and discuss the clues that allow us to make the challenging distinction between transformed MF and other CD30+ CTCLs. We review histologic and clinical features of these different disorders, with a focus on the revised World Health Organization classification of primary cutaneous lymphomas.

Transformed Nodular Lymphocyte-Predominant Hodgkin Lymphoma: Histologic Features and Relationship to T-Cell/Histiocyte–Rich Large B-Cell Lymphoma Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is an uncommon variant of Hodgkin lymphoma, with a generally indolent course in low-stage presentations. Recurrences can demonstrate features of the diffuse variant, resembling T-cell/histiocyte–rich large B-cell lymphoma (THRLBCL). Transformation can additionally occur, either THRLBCL-like lesion or a diffuse large B-cell lymphoma (DLBCL). Transformation to DLBCL may be detected concurrently with NLPHL, prior to NLPHL, or years to decades later. The prognosis of such transformation is controversial, but thought to be worse than NLPHL and similar to that of de novo DLBCL. T-cell/histiocyte–rich large B-cell lymphoma–like transformation is histologically indistinguishable from primary THRLBCL, reflecting significant histologic and genetic overlap between NLPHL and THRLBCL. We present a patient with NLPHL and transformation to DLBCL at 7 years after initial diagnosis, who ultimately developed a therapy-related myeloid neoplasm. We review the histologic spectrum of transformed NLPHL, its relationship with THRLBCL, and recent developments in its molecular pathogenesis. Cases of transformation may prove valuable in understanding complex biologic relationships between a spectrum of overlapping lymphoma entities and may ultimately help refine therapy and improve prognosis.

Transformation of Monoclonal B Lymphocytosis to Epstein-Barr Virus–Positive Large B-Cell Lymphoma With Intermediate Features Between Diffuse Large B-cell Lymphoma and Classic Hodgkin Lymphoma Transformation of chronic lymphocytic leukemia (CLL) to an aggressive lymphoma, so-called Richter syndrome, usually includes diffuse large B-cell lymphoma and classic Hodgkin lymphoma. The transformation can be clonally related to the underlying CLL and is often Epstein-Barr virus (EBV) associated. Here we report the case of an 86-year-old woman with a newly identified CLL-like monoclonal B-lymphocytosis who developed diffuse lymphadenopathy. Biopsy of the left axillary lymph node showed EBV-positive large B-cell lymphoma with morphologic and immunophenotypic features intermediate between diffuse large B-cell lymphoma and classic Hodgkin lymphoma, so-called gray zone lymphoma. Comprehensive immunophenotypic, cytogenetic, and molecular studies demonstrate a clonal relatedness that suggests a transformation from monoclonal B-lymphocytosis to EBV+ gray zone lymphoma.

Posttransplant Classic Hodgkin Lymphoma: Richter Transformation or Posttransplant Lymphoproliferative Disorder? Richter transformation (RT) is defined as the transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) into high-grade lymphoma. An average of 5% of patients with CLL/SLL will have disease that undergoes RT during their clinical course. While most (75%) of these transformed cases manifest as diffuse large B-cell lymphoma, other variants occur, including a small minority (0.4%–0.7%) that progress to a classic Hodgkin lymphoma variant. Richter transformation portends a poor outcome in comparison to nontransformed CLL/SLL. Allogeneic stem cell transplantation (allo-SCT) can be offered, with a 5-year survival rate of 50% to 70%. In addition to disease relapse, transplantation carries significant risk of nonrelapse morbidity, including posttransplant lymphoproliferative disorder (PTLD). The distinction between disease progression or recurrence and PTLD can be challenging and has critical prognostic and therapeutic implications. In this report, we describe a patient whose initial CLL/SLL transformed to diffuse large B-cell lymphoma, who then received allo-SCT. Subsequent development of classic Hodgkin lymphoma proved to be a diagnostic conundrum, for which PTLD and disease progression/recurrence were both reasonable considerations. This case illustrates the diagnostic dilemma and semantic confusion faced by both pathologists and clinicians when lymphoproliferative disorders emerge within the immunologically complex interface of CLL/SLL, RT, and allo-SCT. As molecular technologies are becoming more commonplace in routine diagnostics, subpopulation clonal analysis may be useful in such cases. It may also be worth reevaluating the classification and criteria for PTLD and different subtypes of RT, especially in light of implications for prognosis and optimal therapies.

Marginal Zone Lymphoma, Immune Dysregulation, and High-Grade Transformation Marginal zone lymphoma (MZL) is a low-grade B-cell lymphoma, which includes mucosa-associated lymphoid tissue lymphoma, splenic MZL, and nodal MZL. Of these, mucosa-associated lymphoid tissue lymphoma is the most frequent. While all 3 subtypes are typically indolent, a subset undergoes transformation to an aggressive B-cell lymphoma resulting in treatment challenges and a worse prognosis. We present a patient with systemic lupus erythematosus and Sjögren disease who developed MZL while on cyclophosphamide and steroids for treatment of her autoimmune disease. Her MZL was associated with a relatively indolent initial course. Unfortunately, her systemic lupus erythematosus continued to progress, and she ultimately required a renal transplant for end-stage renal disease due to lupus nephritis. At transplant, her MZL was thought to be in remission, but shortly thereafter, she developed an enlarging neck mass. A biopsy demonstrated background MZL with focal transformation to diffuse large B-cell lymphoma. Evidence is emerging that the underlying biology of a subset of MZL based on mutational profile, gene expression, and/or cytogenetic factors may affect the risk of transformation. Immune status has not been linked to progression, but chronic inflammation and immune dysregulation in the setting of chronic infection or autoimmune disease may underlie MZL development. In addition, iatrogenic immunosuppression for solid organ transplant or acquired immunodeficiency in the setting of human immunodeficiency virus may also result in increased risk or unusual presentations of MZL. This article features a case-based approach to explore factors related to MZL progression in a patient with a complex history of autoimmunity and immune suppression.

Transformed Follicular Lymphoma: The Role of the Pathologist in Aiding Therapeutic Decision Making Follicular lymphoma (FL) is the second most common subtype of non-Hodgkin lymphoma. Follicular lymphoma is generally an indolent disorder, and despite being incurable with standard chemotherapy, recent advances in treatment strategies have improved clinical outcomes and survival. Over time, FL could acquire additional genetic mutations and transform into diffuse large B-cell lymphoma, a more aggressive B-cell neoplasm, which markedly reduces survival. Treatment of transformed FL is based on combination chemotherapy and immunotherapy. Rituximab has changed the treatment landscape in FL. However, novel approaches to treatment of transformed FL are in development. Here, we present a case of FL with transformation to diffuse large B-cell lymphoma and review diagnostic modalities along with current and upcoming therapies, many of which require assessment of antigen expression patterns from the pathologist. In particular, we will highlight the role the pathologist plays in management decisions.

Richter-like Pleomorphic Mantle Cell Lymphoma Composed of Epstein-Barr Virus–Positive Hodgkin-like Cells, a Diagnostic Challenge Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin lymphoma with distinctive clinicopathologic features including the presence of t(11;14)(q13;q32) in almost all cases. Histologically identifiable variants are well described. Most MCLs are the classic variant, although more aggressive variants including blastoid and pleomorphic exist. The pleomorphic variant is a morphologic subtype composed predominantly of large atypical lymphoid cells. This variant can arise de novo or occur in patients with previous history of MCL as result of disease progression and clonal evolution. Mantle cell lymphoma is characteristically Epstein-Barr virus (EBV) negative. Here, we present an extremely unusual case of pleomorphic MCL that arose in a 69-year-old man with a previous 10-year history of indolent chronic leukemia. This case was unusual and diagnostically challenging because the large and pleomorphic lymphoma cells were EBV positive and had Hodgkin-like morphologic features and only focal cyclin D1 expression. Fluorescence in situ hybridization studies confirmed the presence of the CCND1-IgH gene rearrangement. The disease was clinically aggressive, and the patient died 12 months after diagnosis. Epstein-Barr virus–associated MCL and large cell progressions of MCL are only rarely reported. The additional features we describe, including only focal expression of cyclin D1 and Hodgkin-like morphology, make this an even more unusual and therefore difficult to identify lymphoma. Importantly, this case raises the question as to whether MCL can have histopathologic progressions analogous to the well-established EBV-associated Hodgkin-like Richter transformations of chronic lymphocytic leukemia/small lymphocytic lymphoma.

The Enigma of Goblet Cell Tumors of the Appendix: Erratum. No abstract available

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