Coexisting Nodular Sclerosis Hodgkin Lymphoma and Kimura's Disease: A Case Report and Literature Review.

Kimura's disease (KD) is a rare lymphoproliferative fibroinflammatory disorder that commonly affects the subcutaneous tissue and lymph nodes of the head and neck. The condition is a reactive process involving T helper type 2 cytokines. Concurrent malignancies have not been described. Differential diagnosis with lymphoma can be challenging without tissue biopsy. Here, we present the first reported case of coexisting KD and eosinophilic nodular sclerosis Hodgkin lymphoma of the right cervical lymphatics in a 72-year-old Taiwanese man.

[Pathological characteristics and clinical prognosis of nodular sclerosis grade 2 of classic Hodgkin's lymphoma].

Objective: To investigate the pathological characteristics and clinical prognosis of nodular sclerosis grade 2 of classic Hodgkin's lymphoma (cHL-NS2) in our cancer center. Methods: A retrospective collection of 23 cases of cHL-NS2 admitted in Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College from July 2008 to April 2019 was performed. Fifty-five cases of nodular sclerosis grade 1 of classical Hodgkin's lymphoma (cHL-NS1) during the same period were selected as control group. Survival curves were plotted using the Kaplan-Meier method, and Cox regression model was used to analyze the influencing factors for survival. Results: The median age of 23 cases of cHL-NS2 was 30 years old. Five cases had extra nodal invasion, and 19 cases were Ⅰ-Ⅱ stage based on Ann Arbor system. The pathological morphology of cHL-NS2 showed that the lymph node structure was completely destroyed and was divided into nodules by thick collagen. The tumor cells in the nodules were abundant and proliferated in sheets. The boundaries between the tumor cells were not clear. The incidence of tumor necrosis in cHL-NS2 was 43.5% (10/23), which was significantly higher than 18.2% (10/55) in cHL-NS1 (P=0.040). The 3-year progression-free survival (PFS) rate of patients in the cHL-NS2 group was 58.1%, which was significantly lower than 89.7% in the cHL-NS1 group (P=0.002). In all of 78 cases, the 3-year PFS rate of patients who did not obtain complete response (CR) was 67.1%, which was significantly lower than 92.2% in patients who achieved CR (P=0.030). Multivariate Cox regression analysis demonstrated that both cHL-NS2 and failure to obtain CR by first-line treatment were independent indicators for short PFS time (P<0.05). Conclusions: In cHL-NS2, the morphology of tumor cells are diverse, and tumor necrosis can be easily found. Under the current first-line treatments of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) or bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP), cHL-NS2 is an independent indicator for worse PFS.

Syncytial variant of nodular sclerosing Hodgkin lymphoma in children: A prognostic factor?

Nodular sclerosing Hodgkin lymphoma (HL) has an excellent prognosis in children. The syncytial variant (SV) of HL in adults represents a clinic pathologic entity with a worse outcome. We report the clinical features and the course of the disease of three children with refractory HL. The three patients with SV were analyzed in a retrospective multi-institutional study conducted in Israel in 51 children diagnosed with refractory or recurrent HL between 1997 and 2014. All the three children developed multiple recurrences soon after diagnosis. All three received at least three different chemotherapy combinations with autologous bone marrow transplantation for two patients, allogenic bone marrow transplantation in one, and immunotherapy in one. One patient died of disease, one is in complete response of the disease but developed a second metastatic malignancy, and one is alive without disease. This retrospective study shows that SV histology may be a prognostic factor for poor outcome in children diagnosed with HL.

Primary Hodgkin Lymphoma of the Breast: A Case Report and Literature Review Examining the Use of Different Chemotherapy Regimens.

Primary classic Hodgkin lymphoma (HL) of the breast is a rare type of breast disease. The diagnosis is mostly confirmed by an excisional biopsy. The first line of treatment commonly used for Hodgkin lymphoma is doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). Our case report is about a 48-year-old lady who was diagnosed with bilateral breast Hodgkin lymphoma following an excisional biopsy and was treated with brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (BV-AVD). The patient responded positively after the initiation of the regimen. There is scarce data on the classic Hodgkin lymphoma of the breast, and even with the wide use of first-line treatment using ABVD, the disease is still difficult to manage. Hence, patients with breast masses should be screened for classic HL of the breast, and larger studies are needed to establish specific treatment guidelines concerning HL of the breast to prevent relapse and other complications.

Distinctive patterns of marrow involvement by classic Hodgkin lymphoma are clues for diagnosis and subtyping.

Classic Hodgkin lymphoma (CHL) is a lymphoid neoplasm deriving from B cells in a rich inflammatory background. There are four histological subtypes with different epidemiological features. Bone marrow involvement by CHL is infrequent, and subtyping CHL from the bone marrow is not suggested as there might be discordant histopathology between the primary tumors and bone marrow specimens. In this study, we aimed to identify the histopathological features of bone marrow involved by CHL and tried to correlate these features with their subtypes. Among the 23 recruited cases, the frequencies of mixed cellularity (MC; 48%, 11/23) and nodular sclerosis (NS; 44%, 10/23) were similar. There were two patterns of marrow involvement: pattern A (fibrous), space-occupying lesions with alternating hypo- and hypercellular areas against a fibrotic background with dilated sinusoids and pattern B (histiocyte-rich), ill-defined granuloma-like lesions in which histiocytes merged with normal hematopoietic and inflammatory cells. Pattern A was more frequent in patients with CHL-NS than CHL-MC (100% vs. 18.2%; p < 0.001). Diagnostic Hodgkin cells and Reed-Sternberg (HRS) cells were identified in all cases, while HRS variant lacunar cells were occasionally discovered, particularly in the CHL-NS subtype (NS 100% vs. MC 9%; p < 0.001). The frequency of EBV association was higher in MC (64%) than that in NS (36%) subtype, but not statistically significant. Of the two patterns of marrow involvement, pattern A was more commonly associated with the NS subtype and less frequently associated with EBV. Recognizing the patterns of marrow involvement is important for diagnosis and may contribute to the subtyping of CHL.

CD20 expression is closely associated with Epstein-Barr virus infection and an inferior survival in nodular sclerosis classical Hodgkin lymphoma.

Background: Nodular sclerosis classical Hodgkin lymphoma (NSCHL) is a rare disease in which Epstein-Barr virus (EBV) and CD20 can be detected. The clinical significance of EBV infection, CD20 expression and their relationship are still unclear in NSCHL presently. The aim of this research was to systematically explore the clinical significance of EBV infection, expression of CD20 and their relationship in NSCHL. Methods: 109 NSCHL patients diagnosed in Qingdao University's Affiliated Hospital were chosen from January 2010 to July 2019, and the clinical and survival data of all patients were collected retrospectively. Results: Among 109 patients, 33 patients were assigned to the group of EBV-positives, following the results of the EBV-encoded RNA (EBER1). Compared with EBV-negative group patients, those in the group of EBV-positive were older (P=0.004) and their ß2-microglobulin (ß2-MG) levels were higher (P=0.006). The CD20 positivity rate in the group of EBV-positive was substantially higher than that in the EBV-negative group (54.5% vs 27.6%, P=0.007). Among 109 patients, EBV+ and CD20+ double positive patients acquired the least overall survival (OS), and patients with EBV- and CD20- double negative had the best OS (P < 0.001). Although old age, gender, EBV infection and CD20 positive were the risk factors for OS in NSCHL, multivariate analysis showed that CD20 positivity was the only characteristic that showed to be an independent risk factor for OS in NSCHL patients. Conclusion: CD20 was found to be strongly expressed in NSCHL patients who had been infected with EBV, and it was found to be an independent risk factor for NSCHL patients' survival.

Clinicopathological features of syncytial variant nodular sclerosis Hodgkin lymphoma.

The syncytial variant of nodular sclerosis Hodgkin lymphoma (SV-NSHL) is uncommon, and its clinicopathological features have not been well analyzed. In this study, we collected 142 cases of SV-NSHL. There were 76 (53.5%) males and 66 (46.5%) females with a median age of 28 years (range, 12-78); 59.9% were younger than 30 years. Patients usually presented with a mediastinal mass (97.6%) and often with bulky (35.7%) and advanced stage disease (3 or 4) (39.7%). Follow-up showed that 61.1% of patients developed relapse after standard therapy. Morphologically, the neoplasms were composed of sheets or large clusters of pleomorphic neoplastic cells with a cohesive appearance that were frequently associated with necrosis. Neutrophils and eosinophils were frequent in the background, whereas small lymphocytes were decreased. Immunohistochemical analysis showed that the following markers were frequently positive: CD30 (100%), MUM1/IRF4 (96%), PAX5 (95%), PD-L1 (91%), and CD15 (80%). CD45 was negative in all cases. Epstein-Barr virus-encoded small RNA (EBER) was detected in 19% of cases. In this cohort, age above 30 years (P = .0430), presence of B-type symptoms (P = .0394), elevated serum lactate dehydrogenase level (P = .0004), and disease relapse (P = .0108) were associated with a poorer overall survival. In contrast, patients with EBER-positive neoplasms had a better survival (P = .0418). Compared with a control group of non-SV-NSHL patients, patients with SV-NSHL were associated with a poorer overall survival (P = .011). These data suggest that SV morphology is associated with a poorer prognosis in patients treated with traditional standard-of-care therapy for classic Hodgkin lymphoma.

Epstein-Barr Virus Expression in Classic Hodgkin Lymphoma in an Indian Cohort and its Association with Clinical and Histomorphological Parameters.

Epstein Barr virus (EBV) associated Hodgkin lymphoma (HL) has been defined as cases with clonal EBV infection, EBV genome and gene products in the Reed Sternberg cells. We evaluated the prevalence and clinico-pathological association of EBV in North Indian HL patients. Eighty-eight cases of histologically confirmed classic HL were evaluated for EBV by both IHC expression of LMP1 and real time PCR on formalin fixed lymph node tissue. The expression pattern was analyzed for any association with clinical and histomorphological parameters. Nodular sclerosis subtype was seen in 79.5% patients and mixed cellularity was seen in the remaining patients. Ninety percent of the cases were positive for EBV. The detection rate of EBV by IHC was higher. The EBV positive cases presented with higher disease stage (p < 0.05). The presence of histomorphological features like granuloma formation (5/5), atypical lymphocytes (8/8), histiocyte clusters (26/28), large area of necrosis (11/12), less prominent inflammatory response (25/27) was associated with EBV positivity (p > 0.05). In our study population a high proportion of HL cases showed positivity for EBV indicating a pathogenic role. The positivity was independent of age, gender and histological subtype. Further evaluation of EBV positivity in modulation of tumor immunity may provide insights into variable treatment outcome in EBV positive cases.

Classical Hodgkin Lymphoma: Clinicopathologic Features, Prognostic Factors, and Outcomes From a 28-Year Single Institutional Experience.

INTRODUCTION: Classical Hodgkin lymphoma (cHL) is a curable malignancy, with a complete remission rate of approximately 90%. However, relapse remains a significant cause of mortality. Prognostic factors are useful in guiding therapy. This is a large, single-institution study defining the clinicopathologic features, prognostic factors, and treatment outcomes of patients with cHL. PATIENTS AND METHODS: We reviewed 727 patients with cHL treated at H. Lee Moffitt Cancer Center and Research Institute from 1990 to 2017. Data on demographics, laboratory studies, and disease statuses were collected from the institutional database and electronic medical records. Statistical analyses, overall survival (OS), progression-free survival (PFS), and multivariate analyses were performed. RESULTS: The median age was 35 years. Fifty-four percent of patients were men; 45.6% had advanced stage disease; 82% were treated with ABVD (doxorubicin hydrochloride [adriamycin], bleomycin sulfate, vincristine, and dacarbazine) as frontline therapy; and 70% achieved complete response. The median PFS after first-line treatment was 16.8 years. The median OS of patients with early stage and advanced stage cHL was 19 and 12.9 years, respectively. Poor prognostic factors for OS included older age, advanced stage disease, presence of B symptoms, and a higher International Prognostic Score. CONCLUSION: Despite high cure rates, cHL accounted for the cause of death in 47% of patients who died during follow-up. Prognostic factors, such as age, stage at diagnosis, International Prognostic Score, and B symptoms, are helpful to guide treatment. Outcomes observed in this study are comparable with those reported in previously published studies.

Finding of pathological thrombomodulin gene variant in a patient with idiopathic nodular glomerulosclerosis and chronic thrombotic microangiopathy-like changes.

Idiopathic nodular glomerulosclerosis is an unusual histopathological finding that has commonly been observed in male smokers with hypertension. It has remained an enigmatic condition and is best described as a diabetic pattern of glomerular injury seen in non-diabetic patients. It is also one of the few nicotine (smoking)-associated/smoking-associated patterns of renal injury. We present an even more unusual manifestation of this pathological finding in a 59-year-old Hispanic female who presented with chronic kidney disease approaching need for renal replacement therapy. The patient had idiopathic nodular glomerulosclerosis on kidney biopsy, despite no prior history of diabetes, nor smoking history, including no secondhand smoking exposure. The patient did have hypertension. The renal biopsy also showed evidence of chronic thrombotic-microangiopathic changes within arteries and arterioles. Genetic testing of the alternative pathway revealed an unusual and likely pathological variant of thrombomodulin supporting complement dysfunction as having a role in the presentation.

Changes in EBV Association Pattern in Pediatric Classic Hodgkin Lymphoma From a Single Institution in Argentina.

In classic Hodgkin lymphoma (cHL), Epstein Barr virus (EBV) association varies worldwide. Aims: Our aim was to analyze EBV association with pediatric cHL for the last 28 years. Methods: EBV presence was evaluated by EBERs in situ hybridization and LMP1 immunohistochemistry. Results: Until 2008, we found in pediatric cHL a similar percentage of EBV presence to those observed in adult cHL from developed populations. Nevertheless, in the last 8 years, an unexpected difference in cHL EBV association was proven, along with a slight bias of EBV association with the nodular sclerosis (NS) subtype. Concerning histological subtype distribution, even though MC still prevailed in the whole series, those cases diagnosed as NS showed a sustained rise from 1989 until today. Conclusion: Variations of EBV association of cHL related to geography, age, ethnicity, and histological type have been largely described when compared with different world regions, but interestingly, this single-center revised series brought to light the dynamic process behind the evolution of this relationship over time.

Fibroblasts in Nodular Sclerosing Classical Hodgkin Lymphoma Are Defined by a Specific Phenotype and Protect Tumor Cells from Brentuximab-Vedotin Induced Injury.

Classical Hodgkin lymphoma (cHL) is one of the most common malignant lymphomas in Western Europe. The nodular sclerosing subtype of cHL (NS cHL) is characterized by a proliferation of fibroblasts in the tumor microenvironment, leading to fibrotic bands surrounding the lymphoma infiltrate. Several studies have described a crosstalk between the tumour cells of cHL, the Hodgkin- and Reed-Sternberg (HRS) cells, and cancer-associated fibroblasts. However, to date a deep molecular characterization of these fibroblasts is lacking. Thus, the aim of the present study is a comprehensive characterization of these fibroblasts. Gene expression profiling and methylation profiles of fibroblasts isolated from primary lymph node suspensions revealed persistent differences between fibroblasts obtained from NS cHL and lymphadenitis. NS cHL derived fibroblasts exhibit a myofibroblastic phenotype characterized by myocardin (MYOCD) expression. Moreover, TIMP3, an inhibitor of matrix metalloproteinases, was strongly upregulated in NS cHL fibroblasts, likely contributing to the accumulation of collagen in sclerotic bands of NS cHL. As previously shown for other types of cancer-associated fibroblasts, treatment by luteolin could reverse this fibroblast phenotype and decrease TIMP3 secretion. NS cHL fibroblasts showed enhanced proliferation when they were exposed to soluble factors released from HRS cells. For HRS cells, soluble factors from fibroblasts were not sufficient to protect them from Brentuximab-Vedotin induced cell death. However, HRS cells adherent to fibroblasts were protected from Brentuximab-Vedotin induced injury. In summary, we confirm the importance of fibroblasts for HRS cell survival and identify TIMP3 which probably contributes as a major factor to the typical fibrosis observed in NS cHL.

Primary and isolated thyroid Hodgkin's lymphoma: A case report.

INTRODUCTION: Hodgkin's lymphoma rarely involves the thyroid gland. It is typically presented as a fast growing neck mass that is sometimes accompanied by respiratory compression symptoms. CASE REPORT: We report one of the few (the seventeenth) case of primary and isolated Hodgkin's thyroid lymphoma presented by a 65 years old man, consulting for a fast growing neck mass with Hodgkin's symptoms. The patient had total thyroidectomy and short courses of chemotherapy, then total resolution of symptomatology. CONCLUSION: Most thyroid Hodgkin's lymphoma are presented by women, rarely man, isolated and primary. Since 1962, we only found sixteen cases described in the literature. Hodgkin's lymphoma should be considered in the differential diagnosis of patients with a thyroid mass for rapid management.

Differences in outcome of patients with syncytial variant Hodgkin lymphoma compared with typical nodular sclerosis Hodgkin lymphoma.

BACKGROUND: Nodular sclerosis Hodgkin lymphoma (NS-HL) is the most common subtype of HL and usually has a good prognosis. A variant of NS, the syncytial variant (SV) has well-established histopathologic features but little is known about its clinical behavior. Small case series have suggested that SV patients present with advanced disease and have a comparatively aggressive course. The objective of this study was to determine the clinical characteristics and outcome of SV patients. METHODS: A total of 167 adult patients with NS-HL including 43 patients with SV and 124 patients with typical NS (t-NS) were included in our analysis following institutional review board (IRB) approval. The Kaplan-Meier method was used to calculate the progression-free survival (PFS) and overall survival (OS). Log-rank test was used to determine the differences in survival. RESULTS: Of the 167 patients, 43 were confirmed as SV based on morphology and immunophenotype. Doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) was the most frequent induction regimen administered in 91% of all patients. The rate of complete response (CR) in the SV group was 74% versus 87% in the t-NS group (p = 0.05). At 49 months follow up, the PFS was 17 months in the SV group and not reached in the t-NS group [p < 0.0001; hazard ratio (HR) = 3.695; 95% confidence interval (CI) = 3.0, 11.07]. The median OS was not reached in both groups (p = 0.32). CONCLUSIONS: Our results show that SV histology represents a poor risk group with lower CR rate and shorter PFS and this should be considered in the risk stratification of classical HL patients.

Nodular sclerosis classical Hodgkin lymphoma grade 2: A diagnostic challenge to the cytopathologists.

BACKGROUND: Grade 2 nodular sclerosis classical Hodgkin lymphoma (NSCHL) is less common than grade 1 lymphoma and has a worse overall prognosis. To the best of the authors' knowledge, no study of a large series of cases has been performed until now. The objective of this study was to assess the diagnostic efficacy of cytology for grade 2 NSCHL versus grade 1 NSCHL and study the morphological features of grade 2 NSCHL in fine-needle aspiration cytology (FNAC). METHODS: Fifteen of 51 histopathology-proven cases of NSCHL (18 FNAC procedures) were grade 2, and 36 were grade 1. The efficacy of FNAC for detecting grade 1 and 2 NSCHL was assessed, and the frequency of misdiagnosis was compared. The clinical details and cytomorphological features of grade 2 NSCHL were studied in detail. RESULTS: Among the grade 1 NSCHL patients, 58.4% were diagnosed with Hodgkin lymphoma (HL) or had findings suggestive of HL, whereas 20% of the grade 2 patients were diagnosed HL or suggestive of HL. Two cases of grade 2 NSCHL were misdiagnosed as anaplastic large cell lymphoma, and 4 were misdiagnosed as malignant neoplasms. Grade 2 NSCHL cases showed clusters and sheets of mononuclear, multinucleated, and bizarre cells, with some cases showing a suppurative background. However, extensive searching showed occasional Reed-Sternberg (RS) cells in most of the cases, and lacunar cells were seen in 12 cases. CONCLUSIONS: The diagnostic efficacy of FNAC is much lower for grade 2 NSCHL versus grade 1 NSCHL. The search for an occasional RS cell and the identification of lacunar cells can provide a clue for the diagnosis. Cancer Cytopathol 2017;125:104-113. © 2016 American Cancer Society.

A case of concomitant Hodgkin's lymphoma with tuberculosis.

Tuberculosis (TB) presenting with Hodgkin's Lymphoma is a rare and difficult clinical situation for any physician to identify and to manage because of very similar clinical presentation. Herein we report a case of 29 year old woman who presented with enlarged lymph nodes, diagnosed and initiated on therapy for TB, based on the cervical node biopsy that showed granulomatous lymphadenitis suggestive of TB. Despite being on regular isoniazid, rifampicin, pyrazinamide and ethambutol regimen, she did not improve but worsened clinically! After an extensive work up that included endobronchial ultrasound (EBUS) and mediastinoscopy, a diagnosis of Hodgkin's disease of nodular sclerosis type was made. She was treated with chemotherapy and radiotherapy along with her TB therapy. Patient showed significant improvement following therapy.

Image database analysis of Hodgkin lymphoma.

Hodgkin lymphoma (HL) is a special type of B cell lymphoma, arising from germinal center B-cells. Morphological and immunohistochemical features of HL as well as the spatial distribution of malignant cells differ from other lymphoma and cancer types. Sophisticated protocols for immunostaining and the acquisition of high-resolution images become routine in pathological labs. Large and daily growing databases of high-resolution digital images are currently emerging. A systematic tissue image analysis and computer-aided exploration may provide new insights into HL pathology. The automated analysis of high resolution images, however, is a hard task in terms of required computing time and memory. Special concepts and pipelines for analyzing high-resolution images can boost the exploration of image databases. In this paper, we report an analysis of digital color images recorded in high-resolution of HL tissue slides. Applying a protocol of CD30 immunostaining to identify malignant cells, we implement a pipeline to handle and explore image data of stained HL tissue images. To the best of our knowledge, this is the first systematic application of image analysis to HL tissue slides. To illustrate the concept and methods we analyze images of two different HL types, nodular sclerosis and mixed cellularity as the most common forms and reactive lymphoid tissue for comparison. We implemented a pipeline which is adapted to the special requirements of whole slide images of HL tissue and identifies relevant regions that contain malignant cells. Using a preprocessing approach, we separate the relevant tissue region from the background. We assign pixels in the images to one of the six predefined classes: Hematoxylin(+), CD30(+), Nonspecific red, Unstained, Background, and Low intensity, applying a supervised recognition method. Local areas with pixels assigned to the class CD30(+) identify regions of interest. As expected, an increased amount of CD30(+) pixels is a characteristic feature of nodular sclerosis, and the non-lymphoma cases show a characteristically low amount of CD30(+) stain. Images of mixed cellularity samples include cases of high CD30(+) coloring as well as cases of low CD30(+) coloring.