Nodular Sclerosing Disease Research Articles

A Complicated Neighborhood: Insights into the Hodgkin Lymphoma Microenvironment

Classical Hodgkin Lymphoma (cHL) is a heterogenous and complex biological entity. Whereas early studies focussed on characterization of the Reed-Sternberg (RS) cell, there is now increasing recognition of the importance of the tumor microenvironment (TME). This critical but only partially understood component of cHL biology is likely to impact pathogenesis, chemo-sensitivity and long-term outcome. Here, the non-malignant infiltrate is variably comprised of macrophages, regulatory T cells, and stroma, with the relative composition varying by histological sub-type. Notably, relative to other B cell lymphomas, cHL expresses high levels of immune checkpoint receptors such as PD-1 and LAG3, and immune checkpoint ligands such as PD-L1, PD-L2, the latter of which are frequently the subject of genetic amplifications. Hence the bi-directional relationship between the microenvironment and the malignant cell is now a valid target. Breakthroughs in our understanding of the TME in cHL have contributed to its status as the 'poster-child' for how checkpoint blockade can de-activate tumor-tolerance to induce meaningful clinical benefit. A further layer of complexity within the TME is the potential aetiological relationship between cHL and the Epstein-Barr virus, a ubiquitous virus found to reside within the RS cells in 40% of cases, particularly in those cases that have mixed cellularity. Unlike benign EBV-infected B cells, within RS cells the virus is in a highly aberrant latency state with expression of the viral oncoprotein LMP1, a virus that is known to induce immunosuppression and drive PD-L1 expression through the NFkB and the JAK-STAT pathways. But numerous unanswered mechanistic questions remain, not least in the light of the frequent genetically driven deficiencies in antigen presentation present in RS cells, particularly in cases of nodular sclerosing disease. This has reignited debate about the relative roles of adaptive and innate immunity in this disease. Remaining questions that need to be addressed include the evolution of the interaction between the TME and the malignant compartment during the course of cHL, the role of other immune checkpoints and their impact on combinatorial immune based strategies, and the contribution to immune-evasion played by stromal cells. Further understanding will assist the rational development of new immune-based strategies, and potentially one day a chemo-free regimen that is as clinically efficacious but less toxic than current chemotherapies. Disclosures Gandhi: Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Research Funding; Roche: Honoraria, Other: Travel Support; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria.

Intensity of FDG Uptake on PET Scan Varies by Histologic Subtype of Hodgkin Lymphoma.

FDG-PET scanning has demonstrated utility in the staging and prognostication of Hodgkin lymphoma, but PET characteristics of discrete histologic subsets of Hodgkin lymphoma have never been reported. Further, while studies in this disease have focused on classical Hodgkin lymphoma, the PET features of nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) have not been addressed to date. NLPHL represents less than 5% of all cases of Hodgkin lymphoma and has distinct clinicopathologic features, natural history, and treatment from classical subtypes. Diagnosis may be difficult as it exists in a “gray zone” between Hodgkin and non-Hodgkin lymphomas (NHL), and shares immunophenotypic and histologic features with the T-cell rich variant of diffuse large B-cell lymphoma. Clinically, NLPHL follows a natural history more akin to indolent B-cell NHLs than to classical Hodgkin lymphomas. We retrospectively identified 7 cases of NLPHL diagnosed at our institution since 2003 with available PET staging data. Consistent with prior series of this disease, the majority of patients were male (6:1) and the median age was 32 years. All 7 patients presented with limited stage disease (3 stage I, 4 stage II) and without “B” symptoms. All 7 cases demonstrated increased FDG avidity on PET scanning. The mean Standard Uptake Value (SUV) max was 6.1 (range 1.1–8.8), and mean SUV mean was 5.6 (range 1.0–8.3). We compared these results to recently diagnosed patients with nodular sclerosis and mixed cellularity subtypes of classical Hodgkin lymphoma. Among 13 patients with nodular sclerosis Hodgkin lymphoma (NSHL), the mean SUV max was 10.1 (range 4.8–15.8), while among the 7 patients with mixed cellularity histology (MCHL), the mean SUV max was 5.6 (range 4.0–9.8). Patients with NLPHL had significantly decreased SUV max compared to NSHL patients (p=0.022), but were similar to patients with MCHL (Figure 1). Mixed cellularity histology similarly demonstrated significantly decreased SUV max compared to patients with nodular sclerosing disease (p=0.005). PET intensity therefore highlights differences between classical subtypes of Hodgkin lymphoma, as well as between classical and non-classical variants. When compared to published PET SUV data in aggressive B-cell lymphomas, the maximal SUVs we observe in NLPHL fall well below those reported in aggressive B-cell lymphomas, which may aid in the diagnosis of these occasionally similar appearing neoplasms. We conclude that PET scans identify differences in FDG avidity across classical and non-classical Hodgkin lymphoma subtypes, likely reflecting underlying biological differences. We also demonstrate for the first time that despite its indolent behavior, NLPHL is a uniformly FDG-avid neoplasm, and so PET scans may have a role in the staging and surveillance of this uncommon disease variant. [Display omitted]

Role of bone marrow examination in staging Hodgkin's disease: experience in México.

We assessed the value of bone marrow biopsy prospectively in a group of 91 individuals with Hodgkin's disease. The median age of our population was 29 years (range 4-87 years); 59 were males. Most patients (45%) had nodular sclerosing disease and most patients (44%) were in pathological stage II at diagnosis. The bone marrow biopsy showed infiltration by Hodgkin's disease in only three individuals (3.3%); two of these patients displayed constitutional symptoms and had been assigned to stage III before the biopsy. In one case, bone marrow biopsy was the diagnostic procedure, which was performed as part of the investigation of fever of unknown origin. Follow-up periods ranged between 1 and 117 months (median 16 months). All patients achieved complete remission, seven patients relapsed and four were given autologous stem cell transplants. The median survival of the whole group was 117 months, while the 3500-day survival was 76%. As bone marrow biopsy was the diagnostic procedure in one case, bone marrow biopsy was a useful staging procedure in only 2.2% of patients (two out of 90 patients). We suggest that bone marrow biopsy should be only be performed as a staging procedure in a selected subset of patients with Hodgkin's disease (clinical stage III, B symptoms, etc.).

Hodgkin's disease in children in the West Midlands, 1957-1986: a large population-based study.

One hundred forty-one children were diagnosed with Hodgkin's disease between 1957 and 1986 in the West Midlands Health Authority Region (1991 population, 1.1 million children). Eighty-seven were boys and 54 were girls, representing a significant male:female ratio of 1.5:1 (P < 0.01). The average age-standardized incidence rate was 3.6 per million per year with a significant increase in the older age group (> or = 10 years) in the second half of the period (P = 0.02). The mixed cellularity subtype was more common in those younger than 10 years, with nodular sclerosing disease being seen more in those < or = 10 years. Overall survival at 5 years was 76% (65% at 10 years) with a significant difference (P < 0.001) in survival between the first and last decades. There was six second malignancies, five of which could have been treatment related. A positive history of cancer in close relatives was found in 11 patients, and higher social class was found in more older than younger children. These findings support the hypothesis that Hodgkin's disease may have a viral etiology and may be linked with socioeconomic conditions.

Analysis of antigen receptor genes in Hodgkin's disease.

To analyse the configuration of the antigen receptor genes in Hodgkin's disease. DNA extracted from 45 samples of Hodgkin's disease was analysed using Southern blotting and DNA hybridisation, using probes to the joining region of the immunoglobulin heavy chain gene, the constant region of kappa immunoglobulin light chain gene, and the constant region of the beta chain of the T cell receptor gene. A single case of nodular sclerosing disease showed clonal rearrangement of the immunoglobulin heavy and light chain genes, all other samples having germline immunoglobulin genes. The nature of the clonal population in the diseased tissue is uncertain, because the intensity of the rearranged bands did not correlate with the percentage of Reed-Sternberg cells present. The T cell receptor genes were in germline configuration in all the samples. Antigen receptor gene rearrangement is a rare finding in unselected cases of Hodgkin's disease.

Extracellular Deposition of Eosinophil Granule Major Basic Protein in Lymph Nodes of Patients With Hodgkin’s Disease

Abstract Lymph nodes from each of the four histologic types of Hodgkin's disease were examined for the presence of eosinophils and for eosinophil degranulation by immunofluorescent localization of eosinophil granule major basic protein (MBP). Eosinophil degranulation shown by MBP deposition outside of eosinophils was found in six of eight nodes from patients with nodular sclerosing disease and in two of eight nodes from patients with lymphocyte depletion-type disease. Three nodes of the mixed cellularity type, one node of the lymphocyte predominance type, and one lymph node of the lymphocyte depletion type showed one or two small foci of extracellular MBP deposition. Lymph nodes from patients without Hodgkin's disease showed no extracellular deposition of MBP. Large numbers of eosinophils were found in seven of eight nodes of the nodular sclerosing variant, but were less frequently seen among the other types of Hodgkin's disease. The presence of extracellular MBP in lymph nodes of patients with Hodgkin's disease indicates that eosinophil degranulation commonly occurs and suggests that the released eosinophil granule proteins may participate in the inflammatory reaction in this disorder more extensively than is presently appreciated.

Extracellular deposition of eosinophil granule major basic protein in lymph nodes of patients with Hodgkin's disease

Lymph nodes from each of the four histologic types of Hodgkin's disease were examined for the presence of eosinophils and for eosinophil degranulation by immunofluorescent localization of eosinophil granule major basic protein (MBP). Eosinophil degranulation shown by MBP deposition outside of eosinophils was found in six of eight nodes from patients with nodular sclerosing disease and in two of eight nodes from patients with lymphocyte depletion-type disease. Three nodes of the mixed cellularity type, one node of the lymphocyte predominance type, and one lymph node of the lymphocyte depletion type showed one or two small foci of extracellular MBP deposition. Lymph nodes from patients without Hodgkin's disease showed no extracellular deposition of MBP. Large numbers of eosinophils were found in seven of eight nodes of the nodular sclerosing variant, but were less frequently seen among the other types of Hodgkin's disease. The presence of extracellular MBP in lymph nodes of patients with Hodgkin's disease indicates that eosinophil degranulation commonly occurs and suggests that the released eosinophil granule proteins may participate in the inflammatory reaction in this disorder more extensively than is presently appreciated.

Alternating cycles of combination chemotherapy for patients with recurrent Hodgkin's disease following radiotherapy. A prospectively randomized study by the Cancer and Leukemia Group B.

A randomized clinical trial of combination chemotherapy for patients who relapsed following primary radiation therapy for Hodgkin's disease was conducted from 1975 to 1981 by the Cancer and Leukemia Group B (CALGB). One hundred thirteen patients were prospectively randomized to receive 12 cycles of either CVPP (CCNU, vinblastine, procarbazine, and prednisone), ABOS (bleomycin, vincristine [Oncovin; Lilly, Indianapolis], doxorubicin [Adriamycin, Adria Laboratories, Columbus, Ohio], and streptozotocin), or alternating cycles of CVPP and ABOS. The median length of observation for patients in this report is 4 years. Toxicities of the three treatment programs were primarily hematologic. Frequencies of complete response were 72% for CVPP, 70% for ABOS, and 82% for CVPP/ABOS (P = .37). Females and patients who had nodular sclerosing disease at initial diagnosis had significantly higher complete response rates. The 5-year disease-free survival for the complete responders was 55%; the 5-year overall survival was 60%. There were no significant differences among the treatments on disease-free survival (P = .78) or overall survival (P = .18). Age under 40 years was the only significant positive prognostic factor for disease-free survival (P = .095) and overall survival (P = .003). This study demonstrates no statistically significant advantage for alternating cycles of combination chemotherapy in affecting complete response frequency, disease-free survival, or overall survival as compared with therapy with CVPP or ABOS alone. However, the power to detect differences in these outcome parameters is somewhat limited by the sample sizes.(ABSTRACT TRUNCATED AT 250 WORDS)

An immunohistological study of the cellular constituents of Hodgkin's disease using a monoclonal antibody panel

Cryostat sections of lymphoid tissue from 44 cases of Hodgkin's disease were analysed by immunoperoxidase staining using a panel of monoclonal antibodies which included reagents reactive with T cells and their subsets, B cells, HLA-DR, Ig, dendritic reticulum cells and C3b receptor. A wide spectrum of immunohistological patterns was observed ranging from cases in which T cells were numerous (B cells being absent or present in only small numbers) to cases in which very prominent B cell follicles were present. These follicles contained a meshwork of dendritic reticulum cells and were composed of polyclonal B cells (as assessed by light chain expression). T cells were present in small numbers within these B cell follicles, often clustered in a thin rim around individual Reed-Sternberg and Hodgkin's cells. All B cell-rich cases were examples of lymphocyte predominant Hodgkin's disease. Assessment of the T cell helper/suppressor ratios was hindered by the fact that both anti-helper antibodies (OKT4 and anti-Leu 3a) reacted with macrophages. However the majority of cases appeared to contain a normal excess of T helper cells. HLA-DR was strongly expressed in T cell rich areas, on Reed-Sternberg and Hodgkin's cells, on vascular endothelium and on numerous infiltrating cells in the fibrous tissue areas in cases of nodular sclerosing disease. Reed-Sternberg and Hodgkin's cells were not labelled by either anti-fibronectin or by antibodies reactive with dendritic reticulum cells (anti-C3b receptor and antibody R4/23).

Infradiaphragmatic presentation of Hodgkin's disease

Twenty patients with infradiaphragmatic presentations of Hodgkin's disease were seen at the Royal Marsden Hospital, London, between 1970 and 1977, 13% of the total number of patients with Stage I and II Hodgkin's disease seen in this period (20 out of 153). All the patients were male. Lymphocyte predominance was seen in 35%, nodular sclerosis in 30%, mixed cellularity in 30% and lymphocyte depletion in 5%. There is a lower incidence of nodular sclerosis than seen with supradiaphragmatic presentations. The average age was highest in patients with nodular sclerosing disease. All clinical Stage I patients had negative laparotomies. An approach to staging and treatment similar to that used for clinical supradiaphragmatic disease appears to yield equally good results.

Prognostic significance of histologic subdivision of Hodgkin's disease nodular sclerosis.

Sixty-seven patients with nodular sclerosis (Hodgkin's disease stages I and II) have been subclassified according to the cellular composition and the amount of fibrosis. Predominance of mature lymphocytes and rarity of Reed Sternberg cells were associated with less extensive disease at presentation and more favourable outcome. A less definite correlation to the amount of fibrosis was found.

Malignant lymphomas: patterns of progression and factors influencing recurrence.

In a series of 200 patients with Hodgkin’s disease treated by radiation therapy, recurrent disease occurred in 52 per cent of the patients; in 74 per cent of these, the recurrent disease involved the contiguous lymph node regions. In 300 patients with lymphosarcoma, 63 per cent of the patients experienced recurrent disease; and of these patients, 33 per cent had recurrences in the contiguous lymph node regions (Table xv).Of the patients with Hodgkin’s disease, those who had nodular sclerosing disease had a lower (4 per cent) recurrence rate. Of the patients with lymphosarcoma, those with giant follicular lymphosarcoma had a lower recurrence rate (24 per cent) than those with lymphocytic lymphosarcoma or reticulum cell sarcoma.It would appear that those patients who received the maximum radiation therapy— i.e., 3,500+ rads to the primary site and 3,000+ rads to the adjacent lymph node regions—had the lower recurrence rate.Further studies, on host immunity and tumor virulence, appear to be warranted.