Molecular biology of Hodgkin lymphoma

Classical Hodgkin lymphoma (cHL) is unique among lymphoid malignancies in several key biological features. (i) The Hodgkin and Reed-Sternberg (HRS) tumor cells are rare among an extensive and complex microenvironment. (ii) They derive from B cells, but have largely lost the B-cell typical gene expression program. (iii) Their specific origin appears to be pre-apoptotic germinal center (GC) B cells. (iv) They consistently develop bi- or multinucleated Reed-Sternberg cells from mononuclear Hodgkin cells. (v) They show constitutive activation of numerous signaling pathways. Recent studies have begun to uncover the basis of these specific features of cHL: HRS cells actively orchestrate their complex microenvironment and attract many distinct subsets of immune cells into the affected tissues, to support their survival and proliferation, and to create an immunosuppressive environment. Reed-Sternberg cells are generated by incomplete cytokinesis and refusion of Hodgkin cells. Epstein-Barr virus (EBV) plays a major role in the rescue of crippled GC B cells from apoptosis and hence is a main player in early steps of lymphomagenesis of EBV+ cHL cases. The analysis of the landscape of genetic lesions in HRS cells so far did not reveal any highly recurrent HRS cell-specific lesions, but major roles of genetic lesions in members of the NF-κB and JAK/STAT pathways and of factors of immune evasion. It is perhaps the combination of the genetic lesions and the peculiar cellular origin of HRS cells that are disease defining. A combination of such genetic lesions and multiple cellular interactions with cells in the microenvironment causes the constitutive activation of many signaling pathways, often interacting in complex fashions. In nodular lymphocyte predominant Hodgkin lymphoma, the GC B cell-derived tumor cells have largely retained their typical GC B-cell expression program and follicular microenvironment. For IgD-positive cases, bacterial antigen triggering has recently been implicated in early stages of its pathogenesis.

Bioinformatics analysis quantifies neighborhood preferences of cancer cells in Hodgkin lymphoma

MotivationHodgkin lymphoma is a tumor of the lymphatic system and represents one of the most frequent lymphoma in the Western world. It is characterized by Hodgkin cells and Reed-Sternberg cells, which exhibit a broad morphological spectrum. The cells are visualized by immunohistochemical staining of tissue sections. In pathology, tissue images are mainly manually evaluated, relying on the expertise and experience of pathologists. Computational quantification methods become more and more essential to evaluate tissue images. In particular, the distribution of cancer cells is of great interest.ResultsHere, we systematically quantified and investigated cancer cell properties and their spatial neighborhood relations by applying statistical analyses to whole slide images of Hodgkin lymphoma and lymphadenitis, which describes a non-cancerous inflammation of the lymph node. We differentiated cells by their morphology and studied the spatial neighborhood relation of more than 400,000 immunohistochemically stained cells. We found that, according to their morphological features, the cells exhibited significant preferences for and aversions to cells of specific profiles as nearest neighbor. We quantified differences between Hodgkin lymphoma and lymphadenitis concerning the neighborhood relations of cells and the sizes of cells. The approach can easily be applied to other cancer [email protected]

Primary cerebellar lymphoma with Hodgkin lymphoma–like morphology in a cat

A 4-y-old cat exhibited neurologic signs such as wobbling, right head tilt, and intention tremor, and MRI revealed a mass in the cerebellum. The cat died 5 mo after initial presentation, and no neoplastic lesions, other than the cerebellar mass, were observed at autopsy. Histologically, large atypical cells resembling Hodgkin cells, with single large inclusion-like nucleoli, and those resembling Reed–Sternberg cells, with symmetrically arranged nuclei, had infiltrated the left side of the cerebellum and were admixed with small lymphocytes. These atypical cells were positive for feline leukemia virus (FeLV), CD20, BLA36, vimentin, p16, p53, and Pax5, and negative for CD3, CD79a, and Iba1 by immunohistochemistry. Multiplex PCR for immunoglobulin heavy-chain gene rearrangement revealed monoclonal proliferation of B-lymphocytes. We describe this feline primary cerebellar B-cell lymphoma that displayed Hodgkin lymphoma–like tumor cells with FeLV protein expression.

A rare transition of non-Hodgkin lymphoma into classical Hodgkin disease

<div>An uncommon case of blood cancer non-Hodg- kin lymphoma developing into classical Hodgkin lymphoma was recently described by researchers from the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida in a case report published in this issue of AMOR.</div><p> </p><p>“Through a series of biopsies, we report a unique case of diffuse large B-cell lymphoma (DLBCL) with stepwise development of classical Hodgkin lymphoma (cHL),” said pathologists Dr. Haipeng Shao and Pardis Vafaii from the Department of Hematopathology and Laboratory Medicine. “To the best of our knowledge, this is the first report of an intermediate stage of transformation from DLBCL into cHL,” they added.</p><p> </p><p>Lymphoma, or cancer in the infection-fighting lymphatic part of a human’s immune system, is categorized into two types: Hodgkin lymphoma and non-Hodgkin lymphoma – both with distinct behaviors and different treatment requirements. Classical Hodgkin lymphoma – named after the 19^th century British physician Thomas Hodgkin who first described the abnormalities in lymphatic system – is a less frequently diagnosed lymphoma subtype with tell-tale signs of abnormal lymphoid cells called ‘Reed­Sternberg cells’ which are observed as giant purple nucleoli when examined under light microscopy.</p><p> </p><p>However, 90% of lymphomas are of the non-Hodgkin lymphoma variety and do not exhibit the Reed­Sternberg cells. Of all the non-Hodgkin lymphomas, DLBCL is the most common type, which develops when white blood cells called lymphocytes (specifically the B-cell lymphocytes) start dividing uncontrollably. The distinction between DLBCL and cHL is clinically important as both respond differently to chemotherapeutic regimens, according to Shao and Vafaii. Moreover, “classical Hodgkin lymphoma and non-Hodgkin lymphoma rarely develop in the same patient,” they explained.</p><p> </p><p>In their published case report, however, DLBCL and cHL was found to develop on the same anatomic sites, particularly on the skin of the patient, evidenced by the presence of cHL following the occurrence of DLBCL. The patient was an elderly male with a history of stage IV DLBCL. Biopsies taken from the patient’s left arm and upper back revealed results consistent with DLBCL of the non-germinal center subtype. The patient then underwent chemotherapy, salvage therapy, and an autologous bone marrow transplant. Following the transplant, the patient’s biopsies started manifesting features of cHL, indicating a hybrid intermediate stage, according to the authors. “In the second biopsy…scattered Reed -Sternberg/Hodgkin-like cells were admixed with the DLBCL cells,” Shao and Vafaii wrote of the large atypical lymphoid cells which resemble Reed-Sternberg in cHL but do not develop into cHL.</p><p> </p><p>Nonetheless, despite these Reed-Sternberg/Hodgkin- like cells showing typical immunophenotype of cHL cells and were associated with limited inflammatory cells, “cHL diagnosis requires the presence of expansile lesion with a characteristic mixed inflammatory background as- sociated with Reed-Sternberg/Hodgkin cells,” the authors explained, and “the Reed-Sternberg/Hodgkin-like cells did not seem to elicit a mixed inflammatory reaction and form a discrete mass lesion within the large lymphoid cells,” hence rendering it difficult for the pathologists to diagnose cHL at this stage.</p><p> </p><p>Three months later, however, an excisional biopsy performed on the patient’s lymph node no longer showed evidence of DLBCL but instead exhibited “many scattered clusters of Reed-Sternberg/Hodgkin cells with prominent cherry-red nucleoli in a background of small mature lymphocytes and granulocytes,” which are findings consistent with a cHL of the nodular sclerosis subtype, Shao and Vafaii reported.</p><p> </p><p>The diagnosis of cHL established in the final lymph node biopsy therefore demonstrated that the Reed- Sternberg/Hodgkin-like cells found in the intermediate stage signaled the progression of DLBCL into cHL. “While Reed-Sternberg/Hodgkin-like cells are not uncommonly seen in a variety of non-Hodgkin lymphomas, the subsequent development of cHL in this patient indicated that the scattered Reed-Sternberg/Hodgkin cells among DLBCL cells truly represented a precursor of cHL,” the authors said, adding that the transformation would be possible for pathologists to diagnose, albeit very challenging.</p><p> </p><p>Furthermore, “the identification of a hybrid intermediate stage suggested that [cHL and DLBCL] were clonally related,” they said. Further analysis of the genetic changes responsible for cHL transformation could possibly be done by examining individual Reed-Sternberg/ Hodgkin-like cells in the precursor stage, as well as the cHL cells in later stages, with subsequent molecular studies such as laser capture microdissection or next generation sequencing, their report proposed.</p><p> </p><p>According to Shao and Vafaii, the case report was unique in which a stepwise transformation from DLBCL into cHL was demonstrated through a series of biopsies, which highlights the importance of repeated biopsies in diagnostically-challenging case. “Precursor or early lesions that could not be initially established diagnostically would eventually manifest themselves in later biopsies,” the authors concluded. </p><div> </div><p> </p>

Stepwise development of classical Hodgkin lymphoma from diffuse large B-cell lymphoma

Classical Hodgkin lymphoma (cHL) and non-Hodgkin lymphoma rarely develop in the same patient synchronously or metachronously. Through a series of biopsies, we report a unique case of diffuse large B-cell lymphoma (DLBCL) with stepwise development of classical Hodgkin lymphoma. An intermediate stage of transformation was identified with scattered Reed-Sternberg/Hodgkin cells present in a background of the DLBCL cells. These Reed- Sternberg/Hodgkin cells showed typical immunophenotype of cHL cells and were associated with limited inflammatory cells. While Reed-Sternberg/Hodgkin-like cells are not uncommonly seen in a variety of non-Hodgkin lymphomas, the subsequent development of cHL in this patient indicated that the scattered Reed-Sternberg/Hodgkin cells among DLBCL cells truly represented a precursor of cHL. This would be extremely challenging, if not impossible, for pathologists to diagnose. We also highlight the importance of clinicopathological correlation and the crucial role of additional biopsies.