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Histopathological methods based on 2 μm thin sections are routinely used in pathological anatomical diagnosis. Many medical disciplines already rely on a 3D representation, regarding visualization and imaging techniques. Pathology in particular uses different tissue visualizations to make the final diagnosis. Thereby, a standard 2D histological section only represents a flat snapshot of a three-dimensional complex cell system. Despite that, 3D cell analysis is not yet standardly used in clinical routine. This work used 3D analysis systems to investigate the morphological alterations of the fibroblastic reticular cell network inside human lymph nodes during neoplastic transformation and evaluates the added value of 3D visualizations in tissue interpretation. We investigated the surface and volume quotient, cell cross-linking and percentage cell volume of the fibroblastic reticular cell (FRC) network inside Lymphadenopathy (follicular hyperplasia) (LAD), Follicular Lymphoma Grade 1 (FL1), Nodular Sclerosis classical Hodgkin Lymphoma (NScHL) and Angioimmunoblastic T-Cell Lymphoma (AITL). We found that the average quotient of LAD and FL1 differed from those of NScHL and AITL, indicating that the surface and volume quotient changes in the course of neoplastic transformation. This is probably due to an increased network convolution, while the total cell volume remains the same at about 2%. In conclusion, this paper describes the tumor-related morphological changes of the FRC network, which would have been difficult to achieve without the use of 3D analysis systems.

Smooth muscle myosin heavy chain (SMMHC) is a major structural component of the contractile apparatus in smooth muscle cells. Even though it is considered a relatively specific marker for terminal smooth muscle cell differentiation, expression in other cell types such as follicular dendritic cells (FDCs) has rarely been reported. To determine whether SMMHC represents an effective FDC marker in lymphoid tissues, we compared the immunohistochemical results for SMMHC with those of the traditional FDC markers podoplanin (D2-40) and CD21. Paraffin sections of 44 lymphoid tissues were analyzed, including 31 cases of follicular hyperplasia, 6 cases of follicular lymphoma, 2 cases of peripheral T-cell lymphoma, 3 cases of diffuse large B-cell lymphoma arising in follicular lymphoma, 1 case of nodular sclerosis classical Hodgkin lymphoma, and 1 case of small lymphocytic lymphoma. There was no statistically significant difference between the number of SMMHC-positive and D2-40-positive or CD21 lymph nodes (P>0.05). The extent and intensity of SMMHC-positive FDCs were similar to those of D2-40-positive FDCs (P=0.127 and 0.733, respectively), but significantly lower compared with those of CD21 cells (P=0.009 and 0.00002, respectively). However, in contrast to CD21 which was also positive in some germinal center B cells, SMMHC expression was restricted to FDCs. Our results indicate that SMMHC is an excellent marker for FDCs and can be particularly helpful in demonstrating the underlying architecture in lymphoid processes.

Human immunodeficiency virus (HIV) is associated with an increased risk of developing Hodgkin lymphoma (HL). South Africa (SA) has the highest HIV prevalence rate in the world. There is currently no outcome-based data for HIV-associated HL from SA. A bone marrow database was compiled of all bone marrow biopsies (BMB) reported at National Health Laboratory Service (NHLS) Groote Schuur Hospital (GSH) between January 2005 and December 2012. Patients who had a BMB performed for staging of HL or where HL was diagnosed on the BMB were included for further analysis. Clinical and laboratory data was extracted from medical and laboratory records. Primary outcome measures included histological subtype, bone marrow infiltration (BMI) by HL, CD4 count, HIV-viral load (HIV-VL), tuberculosis (TB) data, treatment with chemotherapy and 5-year overall survival (OS). The database included 6569 BMB and 219 patients of these had HL and were included for analysis. The median age at presentation (32 years) was similar in the HIV+ and HIV− populations. While males predominated in the HIV− group, females predominated in the HIV+ group (male:female ratio of 1.5:1 vs 0.7:1, respectively). The majority of patients (71%) were HIV negative (HIV−) and 29% were HIV positive (HIV+). The diagnosis of HL was made on BMB in 17% of cases. BMI was seen in 37% (82/219) overall, and was found in more HIV+ patients (61%; 39/64) than HIV− patients (28%; 43/155; p = 0.03). The histological subtype varied according to HIV status with nodular sclerosis classical Hodgkin lymphoma (NSCHL) being most frequent in the HIV− group and classical Hodgkin lymphoma (CHL)-unclassifiable the most frequent in the HIV+ group. HIV+ patients had a median CD4 count of 149 × 106/L and 39% were anti-retroviral therapy (cART) naive at HL diagnosis. HIV+ patients had received anti-TB therapy more frequently than HIV− patients (72% vs 17%; p = 0.007). More HIV+ patients did not receive chemotherapy than HIV− patients (31% vs 3%; p = 0.001). The 5-year OS was 56%. HIV+ patients with BMI had a 5-year OS of 18%. BMI, HIV status, low CD4 count, histological subtype and TB therapy had a statistical significant impact on 5-year OS (p

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 2016. © 2016 American Cancer Society.

Syncytial variant of nodular sclerosis (SV-NS) classical Hodgkin lymphoma (cHL) with its histologic features and clinical presentation is uncommon in adults and extremely rare in children. Here, we report a female teenager presenting with long-standing B symptoms, prominent soft tissue and bone involvement mimicking sarcoma and significant nodal disease who is diagnosed with advanced SV-NS cHL. Rare Reed-Sternberg-like cells displaying neutrophil and erythrocyte emperipolesis were seen on bone marrow aspiration slides. Despite initial complete response to chemotherapy and radiotherapy, the patient experienced early relapse suggestive of high-risk biology. This variant may constitute a unique entity.

Primary mediastinal B-cell lymphoma is an established subtype of non-Hodgkin Lymphoma with distinguishable histopathological and clinical features. It characteristically presents with a bulky mediastinal mass and in a younger, predominantly female population. Advanced age, high LDH levels, and poor performance status are associated with poorer prognosis. Endobronchial ultrasound-guided transbronchial needle aspiration may be a valuable tool for establishing the diagnosis. At a molecular level, it has overlapping traits with nodular sclerosis classical Hodgkin Lymphoma. There is a variety of treatment options, with no standardized regimen. The use of rituximab combined with chemotherapy has correlated with good outcomes. The use of consolidative radiotherapy is controversial, with questionable benefit and established long-term toxicity, including secondary malignancy and cardiovascular disease. An FDG-PET scan is indicated when monitoring for response, because a residual mediastinal mass is commonly seen upon treatment completion but does not always indicate active disease. Relapse usually occurs within the first year, but overall survival is similar to that for diffuse large B-cell lymphoma.

To investigate the clinicopathological and prognostic significance of a nodular pattern and immunophenotypes in primary mediastinal large B-cell lymphoma (PMBL), histopathological features, including a nodular pattern and immunophenotypes, were analyzed in 58 Japanese PMBL patients. The patients were 23 men and 35 women with a median age of 31 years. The 4-year progression free survival (PFS) rate was 78%, and the 4-year overall survival (OS) rate was 89%. Among the histopathological and immunohistochemical features, Bcl6(+) (P = 0.013), MUM1(+) (P = 0.091), and pale cytoplasm (P = 0.064) were favorable prognostic indicators of PFS, and Bcl6(+) (P = 0.051) and MUM1(+) (P = 0.07) were favorable prognostic indicators of OS. Patients with Bcl2 negativity (n = 11) had 4-year PFS and OS rates of 100%. Histologically, a nodular pattern, resembling nodular sclerosis classical Hodgkin lymphoma (CHL), was observed in 22 patients (38%). However, this was not a significant prognostic indicator. In conclusion, Bcl6(+) , MUM1(+) , Bcl2(-) , and pale cytoplasm are candidate favorable prognostic indicators for PMBL and should be further examined in larger studies. We suggest that PMBL with a nodular pattern may belong to the same histological spectrum as nodular sclerosis CHL.

Classical Hodgkin lymphoma (cHL) is frequently related to Epstein-Barr virus (EBV) infection. Its malignant capacity is attributed to disruption of an EBV-host balance influenced by environmental and genetic drivers. EBV structures activate Type I interferon (IFN) pathway of the innate immunity, therefore, genetic polymorphisms could influence this response. We explored the impact of four single nucleotide polymorphisms (SNPs) on EBV-associated cHL susceptibility. Toll-like receptors 9 (TLR9_rs5743836), and 3 (TLR3_rs3775291), Interleukin-28B (IL28B_rs12979860), and DEAD-box polypeptide 58 (DDX58_rs10813831) were genotyped in 73 EBV-positive and 106 EBV-negative cHL patients and 396 controls. Only DDX58_rs10813831 T-allele was decreased among EBV-positive cHL compared to controls. A stratified analysis in EBV-positive cHL showed that the reduced rate was associated with younger age and nodular sclerosis. In conclusion, DDX58_rs10813831 T-allele may be associated with a reduced risk of nodular sclerosis EBV-related cHL, which suggests a role for RIG-I (retinoic acid-inducible gene I), encoded by DDX58, in these cases.

Primary mediastinal (thymic) large B-cell lymphoma (PMLBCL) and nodular sclerosing classical Hodgkin lymphoma (NSCHL) are the major histological types of lymphoma affecting the mediastinum. We reviewed 27 patients with PMLBCL and 14 patients with NSCHL. A poor performance status, high serum lactate dehydrogenase level and strong positivity for PAX5 were all significantly more common in patients with PMLBCL than in those with NSCHL. Severe fibrosis was frequent in NSCHL, but not in PMLBCL. PDL1 was expressed by 11/25 PMLBCLs (44.0%) vs. 1/9 NSCHLs (11.1%). Expression of BCL6 was significantly more frequent in PDL1-positive PMLBCL than in PDL1-negative PMLBCL, but there were no clinical differences between these two groups. Two patients with PMLBCL with a poor prognosis had CD20(-), CD79a(+), CD15(-), and CD30(-), possibly representing a subtype of mediastinal gray zone lymphoma.

We describe a 66-year-old woman with Epstein-Barr virus-associated lymphoproliferative disorder with lung and gastric tumors. We identified two lung tumors measuring 13 and 20 mm in diameter that consisted of CD30-, CD15-, and CD20-positive Hodgkin- and Reed-Sternberg-like cells and heterogeneous cellular infiltrates in a pronounced nodular pattern, with necrosis and vasculitis, diagnosed as nodular sclerosis classical Hodgkin lymphoma. A gastric tumor showed low-grade extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue type. Neoplastic cells in all tumors expressed Epstein-Barr virus-encoded RNA based on in situ hybridization. The present case is a rare composite lymphoma arising from different extranodal organs, associated with EBV infection. Her medical history included gamma-knife therapy for clinical diagnosis with a suspicion of cerebral lymphoma.

Introduction The most frequently diagnosed mediastinal lymphomas include: Nodular Sclerosis Classical Hodgkin Lymphoma (NSCHL) and Primary Mediastinal Large B-cell Lymphoma (PMBL). In the new, 4th edition of the WHO Classification of Tumors of Hematopoietic and Lymphoid Tissue of 2008, a new category was created: “B-cell Lymphoma, Unclassifiable, with Features Intermediate Between Diffuse Large B-cell Lymphoma and Classical Hodgkin Lymphoma”. It has also been referred to as “Mediastinal Grey Zone Lymphoma”. Aim The aim of this paper was to analyze morphological and phenotypic characteristics of three diagnostically difficult cases of mediastinal and lymph nodes lymphomas. Materials and methods Immunohistochemical analysis was performed in two stages: 1) LCA, CD20, CD3, CD30, CD15, Ki67; 2) the panel was extended to include: antibodies Bcl2, Bcl6, CD10, MUM1, CD23, Fascin, transcription factors – PAX5, Oct2, BOB1; LCA/CD45, CD20, CD30, CD15, CD3, CD23. Case studies The examination encompassed: 2 cases that demonstrated a discordance between the morphology and the phenotype, and 1 case in which two apparently independent neoplastic growths – PMBL and NSCHL – were diagnosed within 4 months. Patients: 2 women (22 and 31 years old) and 1 man (27 years old) – presented large mediastinal masses of diameter larger than 10 cm. Discussion Differential diagnosis between NSCHL and PMBL is sometimes very difficult. However, NSCHL and PMBL demand different therapeutic strategies. In the case of PMBL treatment is more intensive. Thus, unambiguous diagnosis is necessary: either NSCHL or PMBL. In some cases, diagnostic difficulties may occur, sometimes it is even impossible to establish diagnosis. Conclusions Among B-cell lymphomas in mediastinal tumors there are cases of untypical clinical course and untypical morphological and phenotypic characteristics. Thus, it is necessary to re-examine recurrences, including localizations other than the primary one. An adequate, i.e. large enough, specimen taken during mediastinoscopy is the basis for the correct diagnosis. In diagnostically complicated cases, it is necessary to extend the immunohistochemistry panel to include: CD23 and transcription factors: PAX5, Oct2 and BOB1.

A case of Hodgkin lymphoma located in the rectum of a patient with ulcerative colitis is described. The patient was a 44 year old male treated with thiopurines for ulcerative colitis for ten years. He was admitted with malaise, weight loss and abdominal pain. Endoscopy revealed a large ulcerative lesion involving the rectum and distal part of the sigmoid colon. Although it macroscopically resembled a rectal cancer, repeated biopsies did not reveal any malignancy. In order to resolve the symptoms of stenosis and to get the final diagnosis a recto-sigmoid resection was performed. Pathologic examination revealed nodular sclerosis classical Hodgkin lymphoma, positive for Epstein Barr Virus. Subsequent examination revealed disseminated disease involving the pelvic wall, liver, and bone marrow. The patient is currently receiving chemotherapeutic treatment, and follow-up shows disease remission. Hodgkin lymphoma associated with immunosuppressive therapy is rare. However, patients with ulcerative colitis receiving such treatment are at increased risk of lymphoproliferative disordes, potentially due to loss of immunosurveillance and presence of oncogenic viruses (i.e. Epstein-Barr virus). Virtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/6156776351558952

B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma (BCLu-DLBCL/CHL), also known as gray-zone lymphoma, has overlapping clinical and biological characteristics of both diffuse large B-cell lymphoma and classical Hodgkin lymphoma (CHL). These lymphomas are typically associated with mediastinal disease, and extranodal involvement is rare. In the present report, we describe a case of a 78-year-old woman with BCLu-DLBCL/CHL found to have extranodal lesions and no evidence of mediastinal disease. Although biopsy specimens were histologically similar to nodular sclerosis CHL, the tumor cells were positive for CD30 and mature B-cell markers, such as CD20, CD79a, PAX5, BOB.1, and OCT-2, but negative for CD15. Furthermore, the patient had extranodal lesions and an increased level of soluble IL-2 receptor. These findings are unusual in CHL. Therefore, we diagnosed the patient with BCLu-DLBCL/CHL. She received adriamycin, bleomycin, vincristine, and dacarbazine therapy and exhibited partial response. Some cases without mediastinal disease, such as our case, have been reported; however, these cases are rare and further studies are required.

A 58-year-old man with a remote history of diffuse large B-cell lymphoma (DLBCL), status post chemotherapy, radiation, and peripheral blood stem cell transplantation, presented with splenic nodular sclerosis classical Hodgkin lymphoma. He was found to have aortic and mitral valve mass lesions. The mitral valve mass showed typical histologic and immunophenotypic features of nodular sclerosis classical Hodgkin lymphoma, whereas the aortic valve mass and aortic mitral curtain tissue showed DLBCL with necrosis. Both tumors were Epstein-Barr virus positive and were clonally related; however, they were not related to his DLBCL from 14 years prior. This is the first case report of a patient with a composite lymphoma affecting two cardiac valves.

Primary mediastinal large B-cell lymphoma (PMBCL) is a separate entity in the World Health Organization’s classification, based on clinicopathologic features and a distinct molecular signature that overlaps with nodular sclerosis classic Hodgkin lymphoma (cHL). Molecular classifiers can distinguish PMBCL from diffuse large B-cell lymphoma (DLBCL) using ribonucleic acid derived from paraffin-embedded tissue and are integral to future studies. However, given that ∼5% of DLBCL can have a molecular PMBCL phenotype in the absence of mediastinal involvement, clinical information remains critical for diagnosis. Studies during the past 10 to 20 years have elucidated the biologic hallmarks of PMBCL that are reminiscent of cHL, including the importance of the JAK-STAT and NF-κB signaling pathways, as well as an immune evasion phenotype through multiple converging genetic aberrations. The outcome of PMBCL has improved in the modern rituximab era; however, whether there is a single standard treatment for all patients and when to integrate radiotherapy remains controversial. Regardless of the frontline therapy, refractory disease can occur in up to 10% of patients and correlates with poor outcome. With emerging data supporting the high efficacy of PD1 inhibitors in PMBCL, studies are underway that integrate them into the up-front setting.

A 19-yr-old Caucasian male presented with left neck lymphadenopathy and flu-like symptoms. A computer tomography (CT) scan of the neck demonstrated extensive left-sided cervical lymphadenopathy suggestive of lymphoproliferative disorder (Fig. 1A). An excisional biopsy was performed, and nodular sclerosis classical Hodgkin lymphoma was diagnosed based on histology features and positive staining of CD30, CD15, Pax5 and EBV. Laboratory investigations showed a pancytopenia with hemoglobin concentration 96 g/L, thrombocytopenia with platelet 92 9 10/L and neutropenia with a neutrophil count of 1.4 9 10/L. Due to the pancytopenia, bone marrow involvement was suspected, and a bone marrow staging was performed. Microscopic evaluation of bone marrow aspirate revealed trilineage hematopoiesis without dysplasia. In one location adjacent to a bone marrow particle, a giant binucleated Reed– Sternberg cell resembling an ‘OWL’s Eye’ appearance with prominent eosinophilic inclusion-like nucleoli (Fig. 1B) was observed. The Reed–Sternberg cell had a 3.5-fold diameter longer than an adjacent band with a bluish cytoplasmic hue and vacuolations. In the touch preparation film, another binucleated atypical Reed–Sternberg cell was found, suggesting a bone marrow involvement of the Hodgkin lymphoma. Bone marrow biopsy demonstrated normal marrow without fibrosis; further immunostaining with CD30, CD15, Pax5 and EBER was equivocal due to the small suboptimal size of the biopsy samplings. A repeat bone marrow biopsy request was declined by the patient. Based on the pancytopenia and patient’s conditions, a clinical diagnosis of stage 4 Hodgkin lymphoma was established. Patient received the standard chemotherapy for Hodgkin lymphoma, but was refractory to the treatment. An autologous bone marrow transplant was performed, but patient died of relapsed Hodgkin lymphoma 6 months post diagnosis. Reed–Sternberg cells are pathognomonic for classical Hodgkin lymphoma. They can be found in the tissue sampling of the bone marrow. Observation of Reed–Sternberg cells in the bone marrow aspirate is rare, possibly due to the fibrotic nature of the disease. But in certain age population especially children and young adult, Reed–Sternberg cells can be detected in the aspirate possible due to the less fibrotic young marrow. Thus, careful examination of bone marrow aspirate in young patients with known Hodgkin lymphoma can be useful in making the clinical decision as shown in this case. Financial support