Thomas Hodgkin first described this entity in 1832. Until very recently, its nature as inflammatory, infectious, or neoplastic was unknown. Today, it is clearly known that this is a neoplastic proliferation of a peculiar cell known as a Reed-Sternberg cell and its variants, Hodgkin cells. This characteristic cell is most likely an aberrant B lymphocyte. Hodgkin's disease continues to undergo diagnostic refinement through the efforts of pathologists. It is now divided into classic Hodgkin's disease, which is reviewed here, and non-classic or Nodular Lymphocyte Predominance Hodgkin's disease, covered elsewhere in this site.
This lymphoma usually begins as a mass, most commonly an enlarged lymph node. Symptoms are directly related to the location of the disease. Thus patients with bony involvement may experience bone pain. Symptoms such as fever and weight loss may accompany as many as 25% of cases. A recurrent fever, called Pel-Ebstein fever, may last for 1-2 weeks in patients with advanced disease. The disease characteristically spreads through the lymphatics involving contiguous lymph nodes and organs.
Epidemiology Disease Associations Pathogenesis Laboratory/Radiologic/Other Diagnostic Testing Gross Appearance and Clinical Variants Histopathological Features and Variants Special Stains/
Differential Diagnosis Prognosis Treatment Commonly Used Terms Internet Links
EPIDEMIOLOGY CHARACTERIZATION SYNONYMS Hodgkin's lymphoma INCIDENCE 20-30% of all lymphomas
8000 new cases/year/USA
3-4/100,000 in USA
AGE-RANGE AND MEDIAN
Three age ranges:
Childhood 0-14 years
Common in developing countries
Young adulthood 14-40 years
Common in developed countries
Later adulthood 55-74 years SEX (MALE:FEMALE) 1.5:1 (Except for nodular sclerosis type) GEOGRAPHIC DISTRIBUTION
More common in whites
High Incidence Netherlands, Denmark, Israel, United States Low Incidence Japan, Australia Hodgkin Disease in Adult and Juvenile Groups From Two Different Geographic Regions in Brazil
Characterization of Clinicopathologic Aspects and Relationship With Epstein-Barr Virus Infection
Deilson Elgui de Oliveira, MS, Maura M. Bacchi, MD, Eliane S. Abreu, MD, Ligia Niero-Melo, MD, and Carlos E. Bacchi, MD
Am J Clin Pathol 2002;118:25-30 Abstract quote
We analyzed clinicopathologic data, immunophenotype, and Epstein-Barr virus (EBV) status in 96 cases of Hodgkin disease (HD) in juveniles (younger than 20 years) and adults (20 years or older) from 2 distinctive states in Brazil.
We studied 34 juvenile (group 1) and 16 adult (group 2) cases from Ceara and 31 juvenile (group 3) and 15 adult (group 4) cases from São Paulo. Ceara has a socioeconomic profile similar to a developing country; São Paulo is in better economic condition. Mixed cellularity (MC) was the major histologic subtype among groups 1 (22 [65%]), 3 (21 [68%]), and 4 (7 [47%]); nodular sclerosis (NS) was more frequent in group 2 (8 [50%]). EBV infection was observed in 61 cases (64%), including the following (among others): group 1, MC, 22 (65%) and NS, 4 (12%); group 2, NS, 3 (19%) and MC, 2 (12%); group 3, MC, 16 (52%) and NS, 1 (3%); and group 4, MC, 7 (47%).
There was predominance of EBV+ HD cases in group 1 compared with group 3. HD in Brazilian patients is highly associated with EBV infection, but geographic differences reflect histologic subtypes and age distribution.
EPIDEMIOLOGIC ASSOCIATIONS Developing countries Developed countries, especially urban regions Rural areas of developed countries Orient Relatively low incidence
DISEASE ASSOCIATIONS CHARACTERIZATION BREAST CANCER
Breast cancer following radiotherapy and chemotherapy among young women with hodgkin disease.
Travis LB, Hill DA, Dores GM, Gospodarowicz M, Van Leeuwen FE, Holowaty E, Glimelius B, Andersson M, Wiklund T, Lynch CF, Van't Veer MB, Glimelius I, Storm H, Pukkala E, Stovall M, Curtis R, Boice JD Jr, Gilbert E.
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Md.
JAMA. 2003 Jul 23;290(4):465-75. Abstract quote
CONTEXT: Second cancer is the leading cause of death in long-term survivors of Hodgkin disease (HD), with exceptionally high risks of breast cancer among women treated at a young age. Quantitative associations between radiotherapy dose delivered to the breast and administered chemotherapy have not been reported to date in large series, nor has the influence of ovarian exposures on subsequent risk.
OBJECTIVE: To quantify the long-term risk of breast cancer associated with use of radiotherapy and chemotherapy to treat young women with HD.
DESIGN, SETTING, AND SUBJECTS: Matched case-control study of breast cancer within a cohort of 3817 female 1-year survivors of HD diagnosed at age 30 years or younger, between January 1, 1965, and December 31, 1994, and within 6 population-based cancer registries. The study was conducted March 1, 1996, through September 30, 1998.
MAIN OUTCOME MEASURES: Relative risk (RR) of breast cancer associated with radiation dose delivered to site of breast cancer or to ovaries and with cumulative dose of alkylating agents.
RESULTS: Breast cancer occurred in 105 patients with HD who were matched to 266 patients with HD but without breast cancer. A radiation dose of 4 Gy or more delivered to the breast was associated with a 3.2-fold (95% confidence interval [CI], 1.4-8.2) increased risk, compared with the risk in patients who received lower doses and no alkylating agents. Risk increased to 8-fold (95% CI, 2.6-26.4) with a dose of more than 40 Gy (P<.001 for trend). Radiation risk did not vary appreciably by age at exposure or reproductive history. Increased risks persisted for 25 or more years following radiotherapy (RR, 2.3; 95% CI, 0.5-16.5; P =.03 for trend with dose). Treatment with alkylating agents alone resulted in a reduced risk (RR, 0.6; 95% CI, 0.2-2.0) of breast cancer, and combined alkylating agents and radiotherapy in a 1.4-fold (95% CI, 0.6-3.5) increased risk. Risk of breast cancer decreased with increasing number of alkylating agent cycles (P =.003 for trend). Risk also was low (RR, 0.4; 95% CI, 0.1-1.1) among women who received 5 Gy or more delivered to ovaries compared with those who received lower doses.
CONCLUSIONS: Hormonal stimulation appears important for the development of radiation-induced breast cancer, as evidenced by the reduced risk associated with ovarian damage from alkylating agents or radiation. The high radiation-related risk, which did not diminish at the highest doses or the longest follow-up, however, suggests the need for lifetime surveillance and programs of patient and public awareness.
CELLULAR IMMUNITY DEFECTS Lymphocytopenia
Functional defects in T cells
Lymphoplasmacytic Lymphoma/Waldenström Macroglobulinemia Associated With Hodgkin Disease A Report of Two Cases
Cecilia M. Rosales, MD, Pei Lin, MD, Adnan Mansoor, MD, Carlos Bueso-Ramos, MD, PhD, and L. Jeffrey Medeiros, MD
Am J Clin Pathol 2001;116:34-40 Abstract quote
Although the clinical course of lymphoplasmacytic lymphoma (LPL)/Waldenström macroglobulinemia (WM) is usually indolent, high-grade non-Hodgkin lymphoma may develop in a small subset of patients. We have not found any patients with LPL/WM associated with Hodgkin disease (HD) described in the literature, prompting us to report 2 cases. In case 1, the patient had LPL/WM involving bone marrow diagnosed 1 week before left supraclavicular lymph node biopsy revealed LPL/WM and classical HD. In case 2, the patient had a 15-year history of LPL/WM before classical HD developed involving bone marrow, liver, and lymph node. Both cases were positive for IgM, monotypic immunoglobulin light chain, and B-cell antigens and were CD3–. The neoplastic Hodgkin cells were CD15+, CD20+ (case 1), CD30+, CD3–, and CD45– and were negative for Epstein-Barr virus RNA. Both patients were treated with chemotherapy for HD. In case 1, clinical response was excellent with no histologic evidence of HD in subsequent biopsy specimens. In case 2, HD was progressive at last follow-up, despite therapy.
Patients with LPL/WM, similar to patients with other types of low-grade B-cell lymphoma, can develop HD that may respond to chemotherapy.
Simultaneous occurrence of Epstein-Barr virus associated Hodgkin's disease and HHV-8 related multicentric Castleman's disease: a fortuitous event?
Caussinus E, Meggetto F, Delsol G, Brousset P.
Laboratoire d'Anatomie Pathologique and CNRS-CIGH, UPR8291, CHU Purpan, Place du Dr Baylac, 31059 Toulouse, France.
J Clin Pathol 2001 Oct;54(10):790-1 Abstract quote
Previous serological or molecular studies by means of the polymerase chain reaction have failed to show an association between classic Hodgkin's disease (HD) and human herpesvirus 8 (HHV-8).
Using immunohistochemistry, this study re-examines (with anti-LNA1 antibody) the possible association of HHV-8 with HD, particularly in human immunodeficiency virus (HIV) infected patients.
HHV-8 was not detected in the Reed Sternberg cells of the cases examined (33 HIV negative and 17 HIV positive), thus confirming the lack of involvement of HHV-8 in HD. Interestingly, a case of HHV-8 positive multicentric Castleman's disease was associated with Epstein-Barr virus positive HD in the same lymph node, which was probably a fortuitous occurrence.
CD30 POSITIVE LYMPHOMAS
Sequential Development of Hodgkin's Disease and CD30+ Diffuse Large B-Cell Lymphoma in a Patient With MALT-Type Lymphoma: Evidence of Different Clonal Origin of Single Microdissected Reed-Sternberg Cells.
Parrens M, Vergier B, Fitoussi O, Lahet C, Belleannee G, Marit G, Dubus P, De Mascarel A, Delfau-Larue MH, Merlio JP.
Am J Surg Pathol 2002 Dec;26(12):1634-42 Abstract quote
We observed in the same patient the development of a tonsil mucosa-associated lymphoid tissue-type lymphoma in 1994, a mediastinal Hodgkin's disease in 1998, and a colonic CD30+ anaplastic diffuse large B-cell lymphoma in 2000. A same-sized FR3-JH fragment was demonstrated by polymerase chain reaction, both at the level of total DNA and of single micromanipulated cells, showing monocytoid, Reed-Sternberg, or anaplastic morphology.
Moreover, an identical IgH nucleotide sequence was detected in mucosa-associated lymphoid tissue-type lymphoma and colonic CD30+ anaplastic diffuse large B-cell lymphoma, whereas mediastinal Hodgkin's disease IgH rearrangement involved different VH and JH genes. CD30+ Reed-Sternberg and diffuse large B-cell lymphoma cells contained Epstein-Barr virus EBER sequences that were not observed at the level of mucosa-associated lymphoid tissue-type lymphoma.
Therefore, Epstein-Barr virus infection may have played a role in diffuse large B-cell lymphoma transformation of mucosa-associated lymphoid tissue-type lymphoma and in the lymphomagenesis of Hodgkin's disease. In addition to their different clonal origin, Reed-Sternberg cells of Hodgkin's disease expressed a CD15+, CD20+ (rare cells), CD30+, Oct-2-, EBNA2-, LMP1+ phenotype, whereas anaplastic and Reed-Sternberg-like cells of diffuse large B-cell lymphoma were CD15-, CD20+, CD30+, Oct-2+, EBNA2+, and LMP1+.
Interestingly, we also detected scattered CD30+ Epstein-Barr virus- large cells with prominent nucleoli in the initial tonsil mucosa-associated lymphoid tissue-type lymphoma, suggesting that these cells could be prone to Epstein-Barr virus infection and/or large cell transformation.
HIV-1 HIV-Associated Hodgkin LymphomaA Clinicopathologic and Immunophenotypic Study of 45 Cases
Am J Clin Pathol 2004;121:727-738 Abstract quote
We retrospectively analyzed 45 cases of HIV-associated Hodgkin lymphoma (HIV-HL). HIV-HL generally is a disease of young white men (mean age, 40.1 years) who acquired HIV infection by homosexual or bisexual behavior (68%), intravenous drug use (24%), and/or blood transfusion (8%). The mean interval between the diagnosis of HIV and HIV-HL was 5.2 years.
Morphologic classification of nodal biopsy specimens (2001 World Health Organization criteria) included 15 mixed cellularity Hodgkin lymphomas (MCHLs), 14 nodular sclerosis Hodgkin lymphomas (NSHLs), 9 lymphocyte depleted Hodgkin lymphomas (LDHLs), and 7 classic Hodgkin lymphomas, type not further categorized. The Hodgkin–Reed-Sternberg (HRS) cells expressed positive immunoreactivity with fascin (30/30 [100%]), CD30 (35/37 [95%]), CD15 (32/36 [89%]), bcl- XL (25/31 [81%]), bcl-2 (15/29 [52%]), CD20 (4/34 [12%]), bcl-6 (3/28 [11%]), and Epstein-Barr virus latent membrane protein-1 (32/33 [97%]) and were nonreactive for CD138/syndecan-1. CD4 and CD8 immunostaining showed an inverted CD4/CD8 ratio (<1/20) in all cases. At diagnosis, most patients (n = 27) had high-stage disease (IVE) associated with an aggressive course (16% 5-year survival). LDHL behaved more aggressively than MCHL and NSHL (15% vs 40%, 5-year survival, respectively), as did disease with a sarcomatoid pattern (11% 5-year survival).
Chemotherapy and radiotherapy proved efficacious in a minority of these patients.
PATHOGENESIS CHARACTERIZATION CELL CYCLE ANALYSIS
- Aberrant expression of cell cycle regulators in Hodgkin and Reed-Sternberg cells of classical Hodgkin's lymphoma.
Tzankov A, Zimpfer A, Went P, Maurer R, Pileri SA, Geley S, Dirnhofer S.
1Institute of Pathology, Medical University of Innsbruck, Austria.
Mod Pathol. 2005 Jan;18(1):90-6 Abstract quote.
The characteristic Hodgkin and Reed-Sternberg cells of classical Hodgkin's lymphoma, although highly positive for proliferation markers, do not accumulate to excessive cell numbers. These cells are characterized by abortive mitotic cycles, leading to multinucleation or cell death in mitosis. We have previously described high expression of G(1)-phase cyclins in classical Hodgkin's lymphoma, which could explain the high percentage of cells staining for proliferation markers.
To further our understanding of proliferation control in classical Hodgkin's lymphoma, we extended our immunohistochemical analysis to the main S-phase cyclin, cyclin A, and its regulators p21(CIP1) and p27(KIP1). Expression of proliferating cell nuclear antigen (PCNA) was used as an additional marker for cells being in either S- or G(2)-phase. In 47% (112/239) of classical Hodgkin's lymphoma cases p21(CIP1) was detected within a mean frequency of 15% positive Hodgkin's and Reed-Sternberg cells per case. Similarly, 47% (116/249) of the cases stained positively for p27(KIP1) with a mean frequency of expression in Hodgkin's and Reed-Sternberg cells of 12%. In contrast, 90% of the cells in all 246 evaluable classical Hodgkin's lymphoma cases were positive for PCNA. In addition, 98% of Hodgkin's and Reed-Sternberg cells in 99% (250/253) of the cases stained strongly positive for cyclin A.
These findings further corroborate the hypothesis that Hodgkin and Reed-Sternberg cells exhibit a disturbed cell cycle with an abnormally short or even absent G(1)-phase. In contrast to other tumors, expression of PCNA or cyclin A had no prognostic value for patient survival.
- Proliferation profile of classical Hodgkin's lymphomas. Increased expression of the protein cyclin D2 in Hodgkin's and Reed-Sternberg cells.
Bai M, Tsanou E, Agnantis NJ, Kamina S, Grepi C, Stefanaki K, Rontogianni D, Galani V, Kanavaros P.
1Department of Pathology, Medical Faculty, University of Ioannina, Ioannina.
Mod Pathol. 2004 Nov;17(11):1338-45. Abstract quote
There is accumulating evidence that Hodgkin's and Reed-Sternberg cells of classical Hodgkin's lymphomas (cHL) display multiple and concurrent alterations in different pathways and checkpoints of the cell cycle. However, the expression of cyclin D2 and its relation to other major cell cycle proteins has not been analyzed in cHL.
The aim of the present study was to assess expression of cyclin D2, Ki67, cyclin A, cyclin B1, cyclin D1, cyclin D3, cyclin E, p53, Rb, p16 and p27 proteins in order to gain further insight into the proliferation profile of cHL. Overexpression of cyclin D2 in Hodgkin's and Reed-Sternberg cells was detected in 64/89 (72%) cases of cHL. This finding, in view of recent in vitro data showing that constitutive activation of nuclear factor (NF)-kB could upregulate cyclin D2 expression in part via signal transducer and activator of transcription (STAT)-5a, suggests that induction of cyclin D2 expression may support the proliferation of Hodgkin's and Reed-Sternberg cells. In addition, the present study showed that (1) increased p27 expression status was significantly correlated with higher levels of cyclin A expression (P=0.048) and (2) increased p53 expression status was significantly correlated with higher levels of cyclin A (P<0.001) and cyclin B1 (P=0.040) expression.
The association between increased p27 and p53 expression status and higher expression levels of G2/M cyclins suggests that the impairment of the growth inhibitory activity of the p27 and p53 tumor suppressor pathways may promote the proliferation of Hodgkin's and Reed-Sternberg cells.
EPSTEIN-BARR VIRUS (EBV) INFECTION
Prior history of infectious mononucleosis has a 2-4x higher incidence of Hodgkin's disease
Patients with lymphoma usually have higher antibody titers to EBV capsid antigens
EBV genome identified in 40-50% of Reed-Sternberg cells
- Expression of retinoblastoma protein and P16 proteins in classic Hodgkin lymphoma: relationship with expression of p53 and presence of Epstein-Barr virus in the regulation of cell growth and death.
Kim LH, Peh SC, Poppema S.
Department of Pathology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia.
Hum Pathol. 2006 Jan;37(1):92-100. Abstract quote
Deregulation of several genes involved in cell cycle control has been reported in classic Hodgkin lymphoma (cHL).
This study aimed to investigate the expression of tumor suppressor proteins (P16(INK4A), retinoblastoma protein, and p53) in cHL in relation to the proliferation and apoptosis of Hodgkin/Reed-Sternberg (H/RS) cells, correlating with the status of Epstein-Barr virus (EBV). A total of 66 cHL cases and 10 nonneoplastic reactive lymphoid tissues were retrieved from the archives. Immunohistochemistry technique was used for the detection of protein expression. Presence of EBV infection was detected by EBV early RNA in situ hybridization. p16(INK4A) gene deletion status was assessed by fluorescence in situ hybridization technique. Expression of P16(INK4A) was observed in 49.2% of the cases, whereas positive retinoblastoma protein and p53 expressions in the H/RS cells were detected in 89.1% and 81.5% of the cases, respectively. Epstein-Barr virus positivity was detected in 53.0% of the cases.
Proliferation marker, Ki-67 expression, was observed in 86.7% of the cases. There was no significant correlation between the expression of the various tumor suppressor proteins and Ki-67. Retinoblastoma protein and p53 were also not associated with the presence of EBV. An inverse relationship was observed between the expression of P16(INK4A) and the presence of EBV. There were no significant homozygous or hemizygous deletions of the p16(INK4A) gene. However, an aberrant copy number of chromosome 9 with the loss of one or more p16(INK4A) loci was detected in all cases assessable by fluorescence in situ hybridization.
Loss of function of one or more tumor suppressor proteins may be involved in defective cell regulation of H/RS cells. Epstein-Barr virus may have a role in inhibiting P16(INK4A) expression, thus resulting in a perturbed p16(INK4A)-Rb cell cycle checkpoint.
- Epstein-Barr virus is associated with all histological subtypes of Hodgkin lymphoma in Vietnamese children with special emphasis on the entity of lymphocyte predominance subtype.
Chang KC, Khen NT, Jones D, Su IJ.
Department of Pathology, Medical College, National Cheng Kung University, Tainan 704, Taiwan.
Hum Pathol. 2005 Jul;36(7):747-55. Abstract quote
Early acquisition of Epstein-Barr virus (EBV) infection is prevalent in developing countries.
We studied infectious mononucleosis (IM) and the subtypes of Hodgkin lymphoma (HL) with the status of EBV infection in Vietnamese children. Among the 46 cases of HL, the male-to-female ratio was 38:8, and the mean age at presentation was 6.6 years.
Similar to the subtype distribution in developed countries, cases were classified as nodular sclerosis (NSHL) subtype in 56.5% (n = 26), mixed cellularity (MCHL) in 23.9% (n = 11), lymphocyte-rich classic (LRCHL) in 8.7% (n = 4), lymphocyte depletion (LDHL) subtype in 4.4% (n = 2), and nodular lymphocyte predominance (NLPHL) subtype in 6.5% (n = 3). However, in situ hybridization for EBV-encoded RNA revealed that the tumor cells were positive in 93.2% (41/44) of cases, including all 3 cases of nodular lymphocyte predominance HL. Expression of CD20 on Reed-Sternberg cells could be demonstrated in 17% (7/42) of classic HL. The high incidence of EBV in these cases of HL was correlated with an earlier mean age of presentation of primary EBV infection (ie, IM), at 5.3 years, in this patient population, compared with an average of 15 to 19 years reported in developed countries.
This study demonstrates that in an area with an earlier mean age of onset of EBV infection, nearly all cases of pediatric HL, including all histological patterns, may be related to EBV infection. The association of NLPHL with EBV is unusual, and the literature is reviewed and discussed.
Presence of Epstein-Barr virus in Hodgkin's disease is not exclusive to Reed-Sternberg cells.
Khan G, Coates PJ, Gupta RK, Kangro HO, Slavin G.
Department of Histopathology, St. Bartholomew's Hospital Medical College, West Smithfield, London, United Kingdom.
Am J Pathol 1992 Apr;140(4):757-62 Abstract quote
Thirty-three cases of Hodgkin's disease (HD) have been studied for the presence of Epstein-Barr virus (EBV) using a novel nonisotopic in situ hybridization procedure, based on the detection of Epstein-Barr encoded RNAs with oligonucleotide probes.
An intense and morphologically distinct nuclear staining, sparing the nucleolus was seen in a total of 12 cases (36%). In six of these cases, the signal was located to the Hodgkin and Reed-Sternberg cells (HR-S); in the other six positive cases, the signal was observed only in the non-neoplastic small lymphocytes. These lymphocytes were few in number and immunocytochemistry results were consistent with a B-cell phenotype. The presence of EBV in those cases characterized by nuclear staining of small lymphocytes was confirmed by the polymerase chain reaction (PCR) analysis.
The authors report the detection of EBV in small lymphocytes in HD by in situ hybridization and discuss the implications of these findings in relation to the proposed etiologic association between EBV and HD.
Presence of Epstein-Barr virus harbouring small and intermediate-sized cells in Hodgkin's disease. Is there a relationship with Reed-Sternberg cells?
Jiwa NM, Kanavaros P, De Bruin PC, van der Valk P, Horstman A, Vos W, Mullink H, Walboomers JM, Meijer CJ.
Department of Pathology, Free University Hospital, Amsterdam, The Netherlands.
J Pathol 1993 Jun;170(2):129-36 Abstract quote
Forty-four cases of Hodgkin's disease (HD), mostly of the nodular sclerosing type, were investigated for the presence of Epstein-Barr virus (EBV) by polymerase chain reaction (PCR) and DNA and RNA in situ hybridization (DISH, RISH), as well as by immunohistochemistry for the detection of latent membrane protein-1 (LMP-1) of EBV. In situ hybridization (ISH) was combined with immunohistochemistry to correlate the presence and activity of the virus at the cellular level.
In 18/34 (53 per cent) cases, EBV-DNA sequences could be detected with the PCR method. In 12/18 positive cases, DISH and RISH were also positive. In the remaining six EBV-PCR positive cases, two were also positive with RISH and LMP-1, whereas no positive signal with DISH could be obtained. All DISH and/or RISH positive cases were also positive for LMP-1. With RISH, not only the Reed-Sternberg cells and their mononuclear variants (RS cells) stained positive, but also small and intermediate cells frequently reacted with the EBV-specific probes (EBER-1 and -2). Double staining with cellular markers (CD3, CD20, CD45, CD45RO, CD68, and the lectin PNA) revealed that most of the smaller EBER-positive cells frequently did not express T, B, or histiocytic markers, but that they, as well as the RS cells, showed cytoplasmic and membranous staining with PNA. These smaller EBER-positive cells were not found in EBV-PCR negative HD.
EBER-positive RS cells were almost always LMP-1 positive, as well as a substantial proportion of the intermediate-sized cells, whereas the majority of the small EBER-positive cells remained LMP-1 negative.
Detection of Epstein-Barr virus DNA in Hodgkin- and Reed-Sternberg-cells by single cell PCR.
Roth J, Daus H, Gause A, Trumper L, Pfreundschuh M. Innere Medizin I,
Universitatskliniken des Saarlandes, Homburg, Germany.
Leuk Lymphoma 1994 Mar;13(1-2):137-42 Abstract quote
The Epstein-Barr virus (EBV) can be detected in the majority of lymph nodes involved by Hodgkin's lymphoma using the highly sensitive polymerase chain reaction (PCR). However, the rate of EBV-DNA detection by in-situ hybridisation, which allows allocation of EBV to a defined cell population, i.e. the neoplastic H&RS-cells, is lower.
In an attempt to combine the advantages of the high sensitivity of the PCR and the possibility of cellular allocation by in-situ hybridisation, we established a single-cell PCR of Hodgkin- and Reed-Sternberg (H&RS)-cells isolated by micromanipulation from biopsy tissues. We amplified EBV sequences from the BamW-region by single-cell PCR. Using this method we were able to detect EBV-DNA in the H&RS-cells from 4 of 6 patients. In EBV positive cases all H&RS-cells of a given patient were positive, proving the high sensitivity and reproducibility of the method. Other cells in the biopsy tissue involved by EBV-positive H&RS-cells were shown to be negative.
This indicates that EBV may have a role in the pathogenesis of many but not all cases of Hodgkin's disease.
High prevalence of a 30-base pair deletion in the Epstein-Barr virus (EBV) latent membrane protein 1 gene and of strain type B EBV in Mexican classical Hodgkin's disease and reactive lymphoid tissue.
Dirnhofer S, Angeles-Angeles A, Ortiz-Hidalgo C, Reyes E, Gredler E, Krugmann J, Fend F, Quintanilla-Martinez L.
Department of Pathology, University of Innsbruck, Medical School, Austria.
Hum Pathol 1999 Jul;30(7):781-7 Abstract quote
Depending on geographic location and patient age Hodgkin's disease (HD) is associated with Epstein-Barr virus (EBV), mostly type A EBV, in 20% to 100%. The highest prevalence occurs in children of developing countries. Molecular analysis of the oncogene coding for the latent membrane protein 1 (LMP-1) revealed a 30-base pair (bp) deletion in up to 46% of EBV-positive HD.
We investigated the presence of EBV in a series of Mexican classical HD (n = 57) and reactive lymphoid tissues (n = 20) from a private and a public hospital with special emphasis on the prevalence of the 30-bp deletion and the type of EBV. EBV infection was analyzed at the cellular level by Epstein-Barr encoded early RNA transcripts (EBER) in situ hybridization (ISH) and by LMP-1 protein immunohistochemistry (IHC). Molecular analysis of the LMP-1 gene configuration was performed by polymerase chain reaction (PCR) with primers spanning the site of the deletion and subsequent Southern and/or dot blot hybridization using wild-type and deletion-specific probes. The prevalence of type A and type B EBV was investigated by PCR-analysis for divergence in the coding region of Epstein-Barr nuclear antigen (EBNA)-2. EBV was detected in Hodgkin- and Reed-Sternberg cells (H-RS) by LMP-1 IHC and/or EBER ISH in 35/57 (61%) Mexican HD including 18/32 (56%) with nodular sclerosis, 15/20 (75%) with mixed cellularity and 2/4 (50%) with lymphocyte depletion. In addition, LMP-1 gene sequences were detected by PCR in 9 cases of HD without LMP/EBER expression by H-RS cells and in 17/20 (85%) reactive lymph nodes, supposedly originating from rare latently infected B cells. Surprisingly, the 30-bp LMP-1 deletion was found in 28/35 (80%) EBV-positive HD. This deletion, however, was also found in all 9 (100%) HD with H-RS cells negative for EBV and in 10/17 (59%) reactive lymph nodes. Thus, the overall LMP-1 del prevalence in reactive tissue is 73% (19/26). Typing of EBV was successful in 26 cases of EBV-positive HD, 10 of these were infected by type B EBV (38%). Of the reactive lymphoid tissue, 9 (47%) were infected by type A, and 10 (53%) by type B; All 20 cases (100%) associated with type B, whether neoplastic or reactive, displayed the LMP-1 del variant compared with 18/25 (72%) infected by type A EBV. To our knowledge, this is the highest incidence for both the LMP-1 deletion variant and the infection by type B EBV in HD reported so far worldwide.
Our data suggest that EBV infection contributes to the pathogenesis of the majority of Hodgkin's disease cases in Mexico. The specific tumorigenic role of the LMP-1 deletion variant, however, is doubtful with regard to its high frequency in nonneoplastic lesions. Moreover, type B infection frequently occurs in Mexican HD and reactive lymphoid tissue and is consistently associated with the deletion variant pointing to a pathogenetic role of this combined genotype.
Demonstration by single-cell PCR that Reed--Sternberg cells and bystander B lymphocytes are infected by different Epstein--Barr virus strains in Hodgkin's disease.
Faumont N, Al Saati T, Brousset P, Offer C, Delsol G, Meggetto F.
Unite de Physiopathologie Cellulaire et Moleculaire, UPR 2163-CNRS, CHU-Purpan, Avenue de Grande-Bretagne, 31059 Toulouse Cedex, France.
J Gen Virol 2001 May;82(Pt 5):1169-74 Abstract quote
Epstein--Barr virus (EBV) is associated with Hodgkin's disease (HD). However, EBV-positive Reed--Sternberg (RS) cells and EBV-positive B lymphocytes co-exist in the same EBV-positive lymph node affected by HD. In a previous report, using total lymph node DNA, the presence of two distinct EBV strains was demonstrated, but their cellular localization (i.e. RS cells vs B lymphocytes) could not be determined.
To address this question, three patients with EBV-associated HD were selected in the present study and single-cell PCR of the latent membrane protein-1 (LMP-1) gene from isolated RS cells was performed. In one case, it was clear that RS cells and B lymphocytes were infected by different EBV strains. In the two remaining cases, only one band was detected from total lymph node DNA. However, single-cell PCR showed that RS cells in each sample were infected by single EBV strains, which were different from those detected in lymphoblastoid cell lines derived from EBV-positive B lymphocytes of lymph node cell suspensions from these two patients.
Difficult to perform molecular analysis since these cells are so sparse in most cases
p53 has been shown to be overexpressed
FAS Fas Ligand Expression in Hodgkin Lymphoma
Am J Surg Pathol 2001;25:388-394
Because previous investigations suggested involvement of the Fas ligand (FasL) in the selection process in the follicular dendritic cell (FDC)–associated cell cluster of the germinal center, we investigated the expression of FasL in Hodgkin lymphoma (HL) on protein and RNA level, while considering the Epstein-Barr virus status of the Hodgkin and Reed-Sternberg (HRS) cells.
Tumor tissue from 47 patients with classic HL (32 nodular sclerosis [NS], 11 mixed cellularity [MC], and 4 lymphocyte-rich [LR]) was analyzed by immunohistochemistry for FasL, Fas, CD21, and CD23 and by Western blotting for FasL.
FasL mRNA was detected by an exon 4–specific oligonucleotide and Epstein-Barr virus infection by in situ hybridization for Epstein-Barr virus early RNAs (EBER). Western blotting showed soluble and membrane-bound forms of FasL. Immunohistochemistry showed FasL expression in virtually all HRS of 94% of NS cases and 82% of MC cases. FasL expression did not correlate with the Epstein-Barr virus status of the HRS. Low FasL protein expression was found in some HRS of LR cases. FasL mRNA was detected in 39% of NS, 46% of MC, and 33% of LR cases. Seventy percent to 90% of the HRS cells expressed Fas. CD21 immunohistochemistry showed disrupted FDC networks in the tumor tissue with reduced and virtually absent expression of CD23 and FasL.
These observations suggest that FasL expression in HRS cells and the absence of FasL in the FDC cluster represent a disturbed microenvironment that may be involved in the pathogenesis of HL.
Expression of SSX genes in the neoplastic cells of Hodgkin's lymphoma.
Colleoni GW, Capodieci P, Tickoo S, Cossman J, Filippa DA, Ladanyi M.
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Hum Pathol 2002 May;33(5):496-502 Abstract quote
The cancer/testis antigen (CTA) group of tumor-associated proteins have been reported to be expressed in various cancers and in adult testis but they are essentially not found in any other normal adult nonneoplastic tissues.
Prompted by the frequent detection of SSX1 in a previous comprehensive expression profile of the Hodgkin's lymphoma (HL) cell line L428, we analyzed SSX expression by nonnested reverse-transcription polymerase chain reaction (RT-PCR) in 4 HL cell lines (L428, L540, HD-MY-Z, and KM-H2) and 32 tumor samples of HL. The cellular localization of SSX expression in the tumor samples was further analyzed by in situ hybridization (ISH). All 4 HL cell lines were positive by RT-PCR using SSX consensus primers. Using primers specific to individual SSX genes, all 4 cell lines expressed multiple SSX family members. Five tumor samples (15.6%) were positive by RT-PCR using SSX consensus primers and direct sequencing of the RT-PCR products showed that 4 of 5 expressed more than 1 SSX family member. ISH confirmed that SSX expression originated in HL cells in all 5 RT-PCR-positive tumor samples.
Furthermore, ISH demonstrated SSX-positive HL cells in 6 of 11 cases (55%) that were negative by RT-PCR. Our results suggest that members of the SSX family of CTA are expressed in most HL. This subset of HL may be a candidate for immunotherapy approaches directed at SSX proteins.
- Analysis of transcription factor OCT.1, OCT.2 and BOB.1 expression using tissue arrays in classical Hodgkin's lymphoma.
Garcia-Cosio M, Santon A, Martin P, Camarasa N, Montalban C, Garcia JF, Bellas C.
1Department of Pathology, Hospital Ramon y Cajal, Madrid, Spain.
Mod Pathol. 2004 Dec;17(12):1531-8 Abstract quote.
Hodgkin's lymphoma can be considered in most cases a B-cell lymphoma due to the presence of potentially functional immunoglobulin (Ig) gene rearrangements in the neoplastic cells. In contrast to lymphocyte-predominant Hodgkin's lymphoma, Hodgkin/Reed-Sternberg (HRS) cells from classical Hodgkin's lymphoma have low frequency of B-cell marker expression and lack Ig light and Ig heavy messenger RNA. Recent studies have shown transcription machinery deficiency in Hodgkin's lymphoma caused by an absence of the transcription factors OCT.1, OCT.2 and/or BOB.1.
By using the tissue microarray technique, we have performed an immunohistochemical study of OCT.1, OCT.2 and BOB.1 in 325 classical Hodgkin's lymphoma cases. The results have been correlated with the expression of the B-cell markers CD20, CD79a, B-cell-specific activator protein (BSAP) and MUM.1, the presence of Epstein-Barr virus and the histological subtype. The percentage of CD20 and CD79a positivity was low (18 and 18%, respectively), whereas MUM.1 and BSAP were positive in the majority of cases. Considering the positive cases with independence of the intensity of staining, 62% of them expressed OCT.2, 59% OCT.1 and 37% BOB.1. Nevertheless, when we considered only the strongly positive cases, the results were similar to those previously described by others. No statistical association was found between the transcription factor expression, histological subtype and Epstein-Barr virus presence.
To our knowledge, this is the largest series of classical Hodgkin's lymphoma cases in which the expression of transcription factors has been studied. We have found a notorious percentage of cases displaying weak positivity for OCT.2 and BOB.1 factors in HRS cells. We propose that other mechanisms different from the absence of transcription factors OCT.2 and BOB.1 might be involved in the control of Ig transcription and B lineage in classical Hodgkin's lymphoma.
Macrophage-Derived Chemokine Expression in Classical Hodgkin’s Lymphoma: Application of Tissue Microarrays
Cyrus V. Hedvat, M.D., Ph.D., Elaine S. Jaffe, M.D., Jing Qin, Ph.D., Daniel A. Filippa, M.D., Carlos Cordon-Cardo, M.D., Ph.D., Giovanna Tosato, M.D., Stephen D. Nimer, M.D. and Julie Teruya-Feldstein, M.D.
National Cancer Institute, National Institutes of Health, Bethesda, Maryland (ESJ, GT); Department of Medicine, Molecular Pharmacology and Therapeutics Program, Sloan Kettering Institute, New York, New York (SND); and Departments of Epidemiology and Biostatistics (JQ) and Pathology (DAF, CCC, JTF, CVH), Memorial Sloan Kettering Cancer Center, New York, New York
Mod Pathol 2001;14:1270-1276 Abstract quote
Hodgkin’s disease (HD) is a lymphoid malignancy characterized by the presence of Reed-Sternberg (RS) and Hodgkin’s cells in a background of mixed inflammatory cells and stromal reaction. Studies have documented that HD is a neoplasm associated with abnormal cytokine and chemokine production.
To define the expression of macrophage-derived chemokine (MDC) in HD, 57 cases (18 lymphocyte predominant, 11 mixed cellularity, 28 nodular sclerosis) were stained for MDC by immunohistochemistry and compared with reactive lymph nodes as controls. MDC was expressed by RS cells in classical HD (CHD) and showed a distinct cytoplasmic and Golgi localization. Accumulating evidence suggests that lymphocyte-predominant HD (LPHD) represents an entity distinct from CHD, with different biological properties and clinical course.
On the basis of the high level of MDC staining alone, CHD could be distinguished from LPHD (P < .001), which showed only faint staining of scattered histiocytes similar to control tissues. CHD cases with high MDC mRNA levels showed high levels of MDC protein expression by immunohistochemistry (P < .001) and significant eosinophil infiltration, suggesting that MDC may represent another molecule that plays a critical role in eosinophil recruitment.
We also analyzed 102 cases of non-Hodgkin’s lymphoma and normal spleen, lymph node, and thymic tissue. High levels of MDC expression were specific to CHD cases because only low levels of MDC were observed in a minor subset of LPHD, NHL or normal lymphoid tissues.
CHARACTERIZATION General Enlarged lymph node which may be very firm depending upon the degree of fibrosis Nodular sclerosis 40-70% of cases
Usually involves lower cervical and anterior mediastinal nodes
Mixed cellularity 20-50% of cases Lymphocyte depleted <5% of cases BONE MARROW
Isolated Bone Marrow Manifestation of HIV-Associated Hodgkin Lymphoma
Maurilio Ponzoni, M.D., Luca Fumagalli, M.D., Giuseppe Rossi, M.D., Massimo Freschi, M.D., Alessandro Re, M.D., Maria Grazia Viganò, M.D., Massimo Guidoboni, M.D., Riccardo Dolcetti, M.D., Robert W. McKenna, M.D. and Fabio Facchetti, M.D., Ph.D.
Departments of Pathology (MP, MF) and Infectious Diseases (LF, MGV), S. Raffaele H Scientific Institute, Milan, Italy; Departments of Pathology (FF) and Hematology (GR, AR), Spedali Civili Brescia, Italy; Experimental Oncology 1 (MG, RD), Centro di Riferimento Oncologico, Aviano, Italy; and Department of Pathology (RWM), University of Texas Southwestern Medical Center, Dallas, Texas
Modern Pathology 2002;15:1273-1278 Abstract quote
Human immunodeficiency virus-associated Hodgkin lymphoma frequently involves the bone marrow and is usually recognized at staging after Hodgkin lymphoma diagnosis on a lymph node or other tissue biopsies, but occasionally the marrow involvement is the only apparent manifestation of disease. In the latter setting, diagnosis can be problematic.
From a total of 42 patients with newly diagnosed human immunodeficiency virus–associated Hodgkin lymphoma, 22 subjects had positive marrow involvement at diagnosis; 16 of them had additional substantial histological and/or clinical extramedullary Hodgkin lymphoma. In the remaining 6 patients the bone marrow was the only site of disease at diagnosis. In all six cases, bone marrow biopsy revealed obvious lymphomatous involvement. Reed-Sternberg cells were identified both morphologically and immunophenotypically in all cases. Spared marrow tissue consistently showed fibrosis.
All patients were males with a median age of 35 years (range, 31–58 years). All presented with fever, blood cytopenias, and severe CD4+ lymphocyte depletion (median, 70 cells/mm3). After diagnosis, all staging procedures were negative, and all patients were treated with chemotherapy. Median survival was 4 months (range, 2–118 mo). Longer survival was achieved in the patients who completed chemotherapy regimens; three subjects, however, died shortly before the full completion of chemotherapy, two of them from Hodgkin lymphoma.
Isolated bone marrow HIV-associated Hodgkin lymphoma may be an underestimated condition in HIV-infected patients; in those individuals with unexplained fever and blood cytopenias, bone marrow biopsy should be performed with the aim of assessing for Hodgkin lymphoma, even in the absence of nodal and visceral lymphomatous involvement. A rapid diagnosis of isolated bone marrow HIV-associated Hodgkin lymphoma could expedite therapy.
- Classical Hodgkin lymphoma arising in the rectum.
Valbuena JR, Gualco G, Espejo-Plascencia I, Medeiros LJ.
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Ann Diagn Pathol. 2005 Feb;9(1):38-42. Abstract quote
We report a case of an 81-year-old immunocompetent Mexican man who underwent an abdominal-perineal rectal resection for a mass clinically thought to be carcinoma. Histopathologic diagnosis revealed classical Hodgkin lymphoma, nodular sclerosis type, involving the rectum. The diagnosis was confirmed by immunohistochemical studies that showed that the neoplastic cells were positive for CD15 and CD30 and negative for CD45 (LCA).
In situ hybridization for Epstein-Barr virus small-encoded RNA was also positive in the neoplastic cells. Hodgkin lymphoma arising in the rectum of immunocompetent patients is rare, with only 12 cases (including this one) reported in the literature.
Of these, the diagnosis was confirmed by immunohistochemical studies in only two cases, and this is the first case assessed and shown to be positive for Epstein-Barr virus.
Ann Diagn Pathol. 2006 Apr;10(2):83-8. Abstract quote
A review of the pathological features of Hodgkin lymphoma manifesting with exclusive or preponderant lung involvement is given for 5 patients. Three patients were men and 2 were women, with an age range 17 to 48 years (median, 42 years).
They presented with nonspecific symptoms including dry cough, fever, or chest pain. Initial clinical assessment suggested a lung tumor. Pathological evaluation was carried out on lung biopsy, wedge resection, lobectomy, or pneumonectomy specimens. All the cases showed diagnostic Reed Sternberg cells within the proper background. Immunopositivity for CD15 and CD30 was documented as well. Nodular sclerosing and mixed cellularity were the documented subtypes. Additional histologic features were a pronounced nodular growth pattern with or without necrosis, a diffuse hypersensitivity pneumonia-like picture, or acute pneumonia-like changes.
Our study confirms that the recognition of Hodgkin lymphoma in lung, although based on well-established morphologic criteria, may represent a source of interpretative problems because of the unusual clinical presentation as well as the peculiar histologic changes induced within the pulmonary microenvironment.
- Cutaneous Hodgkin's disease.
Department of Dermatology, the University of Pennsylvania, Philadelphia, USA.
- J Am Acad Dermatol. 2008 Feb;58(2):295-8. Abstract quote
Cutaneous Hodgkin's disease is a rare condition that usually occurs late in the course of Hodgkin's lymphoma. This rare condition is thought to have decreased in incidence in recent decades, likely owing to improved treatment of patients with Hodgkin's disease, who are receiving improved chemotherapy and radiation therapy, and the advent of peripheral blood stem cell transplantation.
We present the case of a man who developed specific cutaneous Hodgkin's lymphoma 6 months after nonmyeloablative allogenic stem cell transplantation for his recurrent systemic disease. The patient's manifestation of relapse was cutaneous dissemination of the tumor, manifested by erythematous papules and ulcerated nodules. At the time of the cutaneous relapse he had minimal systemic disease. This case illustrates an example of this complication of Hodgkin's disease and stresses the importance of a timely diagnosis to direct appropriate therapy.
A review of the literature demonstrates that the patient's lesion morphology and distribution are typical of specific manifestations of cutaneous Hodgkin's disease.
- Indolent course of the cutaneous Hodgkin's disease.
Jurisic V, Bogunovic M, Colovic N, Colovic M.
University of Kragujevac, School of Medicine, Kragujevac, Serbia and Montenengro.
J Cutan Pathol. 2005 Feb;32(2):176-8. Abstract quote
Skin involvement in Hodgkin's disease (HD) is most often a secondary phenomenon representing a rare, late manifestation of dissemination of the disease heralding a grave prognosis. Primary cutaneous HD is very unusual, being reported in 0.5-3.4% of all patients.
Based on the introduction of immunohistochemistry for better detection and classification, we report a case with an ostensibly isolated primary cutaneous HD who developed multiple cutaneous lesions 5 years before enlargement of the lymph node involved during relapse.
Pathohistology of skin lesions and the involved lymph node indeed showed the same subtype (mixed cellularity) of HD characterized by the presence of CD15(+), CD30(+), CD45RO(-) cell-surface markers and by the presence of Epstein-Barr virus(+) marker-analyzed immunohistochemistry.
Skin involvement in Hodgkin's disease.
Smith JL Jr, Butler JJ.
Cancer 1980 Jan 15;45(2):354-61 Abstract quote
Of 1810 patients with Hodgkin's disease seen at M. D. Anderson Hospital and Tumor Institute from 1944 to 1977, nine patients developed skin lesions which were histologically specific for the disease, an incidence of 0.5%.
The initial manifestations were in the form of small papules and nodules that developed in seven of the nine patients in skin immediately distal to lymph nodes containing tumor, supporting the concept that skin involvement most often results from retrograde lymphatic spread from involved lymph nodes. Because the majority of the patients died within a few months following the development of the skin lesions, skin involvement is considered an indication of stage IV disease. Fifteen additional patients had had skin biopsies that were considered either diagnostic or suggestive of Hodgkin's disease, but were ultimately proven to be a variety of other conditions.
Thus, Hodgkin's disease in skin can be simulated by other disease processes, and the diagnosis should be made with caution, particularly in the absence of lymph node involvement.
Cutaneous Hodgkin's disease.
Silverman CL, Strayer DS, Wasserman TH.
Arch Dermatol 1982 Nov;118(11):918-21 Abstract quote
Involvement of the skin in advanced Hodgkin's disease is well known. However, Hodgkin's disease initially seen in the skin is extremely rare. A patient had Hodgkin's disease that was initially seen as a cutaneous lesion on the buttock. Lymphadenopathy developed two months after completion of local radiotherapy to the cutaneous lesion and seven months after initial diagnosis.
The histologic changes in both instances were those of Hodgkin's disease. We discuss problems in the diagnosis and treatment of skin involvement with Hodgkin's disease.
Hodgkin's disease of the skin. A case report.
Heyd J, Weissberg N, Gottschalk S.
Department of Internal Medicine, Shaare Zedek Medical Center, Jerusalem, Israel
Cancer 1989 Mar 1;63(5):924-9 Abstract quote
A 74 year-old woman presented with cutaneous Hodgkin's disease and local bone involvement. Both were secondary to regional lymph flow obstruction by lymph nodes massively involved by nodular sclerosing Hodgkin's disease. Though a temporary remission was achieved by combination chemotherapy, skin lesions were quick to reappear in spite of continued treatment. This was felt to be due to local mechanical factors.
A review of the literature reveals two main patterns of Hodgkin's disease of the skin. In one, the disease is either confined to the skin, or is unrelated to existing nodal or visceral involvement. In the other, skin infiltration is secondary to regional lymph node involvement by Hodgkin's disease, as seen in our patient.
The pattern of skin involvement by Hodgkin's disease should be taken into consideration in assessing its prognostic significance.
Hodgkin's disease presenting in the skin: case report and review of the literature.
Hayes TG, Rabin VR, Rosen T, Zubler MA.
Oncology Service, Veterans Administration Hospital, Houston, TX 77211.
J Am Acad Dermatol 1990 May;22(5 Pt 2):944-7 Abstract quote
Cutaneous manifestations of Hodgkin's disease are relatively uncommon. We present a case of Hodgkin's disease with widespread skin involvement and review the literature on the subject.
Hodgkin's disease in the spleen. A morphological study of 140 biopsy cases.
Falk S, Muller H, Stutte HJ.
Virchows Arch A Pathol Anat Histopathol 1987;411(4):359-64 Abstract quote
140 spleens involved by untreated Hodgkin's disease were studied utilizing conventional histological methods.
Regardless of the subtype of Hodgkin's disease, infiltrates of neoplastic cells were present either in the periarteriolar lymphoid sheath, the marginal zone or in both locations. Initially, infiltrates were confined to the splenic white pulp, later larger nodular foci of Hodgkin's disease developed by coalescence of several infiltrates.
Neoplastic cells in Hodgkin's disease may reach the spleen by both retrograde lymphatic spread or the splenic artery; the presence of neoplastic cells in both T- and B-cell areas of the splenic white pulp implies a preference for Hodgkin's disease in the spleen with regard to a suitable microenvironment. This may be provided by certain macrophage subpopulations.
Mod Pathol. 2005 Dec;18(12):1577-84. Abstract quote
Hodgkin's lymphoma rarely involves the thyroid gland.
We report the clinical and pathologic features of five cases of Hodgkin's lymphoma that presented as thyroid lesions. All five patients were females, aged 29-59 years. Three patients had a history of chronic thyroiditis and hypothyroidism and two were euthyroid. One patient had a remote history of Hodgkin's lymphoma. Imaging studies showed a 'cold' nodule (three cases) or a diffusely enlarged thyroid gland, resembling goiter or fibrosclerosing thyroiditis (two cases). Thyroid fine-needle aspiration was performed before thyroidectomy in all cases; three of these cases contained some atypical cells, raising the possibility of Hodgkin's lymphoma.
Histologically, all cases were classical Hodgkin's lymphoma, nodular sclerosis subtype. The four patients with primary thyroid lymphoma had Stage IIE disease. All patients were treated with surgical excision and chemotherapy, with or without radiation therapy, and were alive after 2 months to 7 years of follow-up. A review of the English literature between 1962 and 2005 revealed 16 cases of thyroid Hodgkin's lymphoma, with a female preponderance and generally favorable outcome similar to the cases in our series. Hodgkin's lymphoma of the thyroid is rare and can mimic a primary thyroid epithelial tumor or thyroiditis clinically. Histologic diagnosis may be difficult due to marked fibrosis.
Hodgkin's lymphoma should be considered in the differential diagnosis of thyroid neoplasms.
WALDEYER RING Hodgkin Lymphoma Involving Waldeyer RingA Clinicopathologic Study of 22 Cases
Maria del Pilar Quiñones-Avila, MD, Abel A. Gonzalez-Longoria, MD, Joan H. Admirand, MD, and L. Jeffrey Medeiros, MD
Am J Clin Pathol 2005;123:651-656 Abstract quote
We report 22 cases of Hodgkin lymphoma involving Waldeyer ring seen at our institution during a 31-year interval. There were 16 males (73%) and 6 females (27%) with a median age of 48 years (range, 5-81 years), and 15 (68%) patients had airway obstruction or tonsillar enlargement. For 19 patients, the clinical stage was as follows: I, 7 (32%); II, 11 (50%); and III, 1 (5%). The 3 patients (14%) whose disease was unstaged had concurrent or a history of non-Hodgkin lymphoma.
Histologically, the neoplasms were classified as follows: lymphocyte-rich classical, 8 (36%); nodular sclerosis, 7 (32%); mixed cellularity, 4 (18%); unclassified, 2 (9%); and lymphocyte depletion, 1 (5%). Of 7 stage I cases, 4 (57%) were the lymphocyte-rich classical type. Reed-Sternberg and Hodgkin cells were positive for CD15 and CD30 in 20 cases assessed. Epstein-Barr virus latent membrane protein type 1 was positive in 12 (67%) of 18 cases assessed.
We conclude that Hodgkin lymphoma rarely involves Waldeyer ring, with the lymphocyte-rich classical type being common at this location.
HISTOLOGICAL TYPES CHARACTERIZATION GENERAL By definition, classic Hodgkin's disease must contain a Reed-Sternberg cell in an appropriate background of mixed benign inflammatory cells Pathologic and Clinical Features of 77 Hodgkin's Lymphoma Patients Treated in a Lymphoma Protocol (LNH87) A GELA Study
Am J Surg Pathol 2001;25:297-306
Between 1987 and 1993, 77 of 2855 lymphomas included in the LNH87 protocol of the GELA as non-Hodgkin lymphoma (NHL) and reviewed by a panel of pathologists had a diagnosis changed to Hodgkin lymphoma (HL). Some of these lymphomas had been initially interpreted as anaplastic large-cell lymphoma Hodgkin-like (ALCL-HL subtype). The purpose of this study was to analyze the histologic pitfalls initially encountered, to define more clearly the diagnostic criteria of lymphomas placed in the gray zone around HL, and to follow the survival of these 77 patients affected with HL and initially treated with NHL regimens. The 77 cases of HL were reviewed by three hematopathologists and immunostained with a large panel of antibodies, including CD30, CD15, CD3, CD20, CD45, CD43, LMP-1, EMA, BNH-9, TiA1, and ALK1. Each case was classified according to the Lukes-Rye system and the British National Lymphoma Investigation (BNLI) grading. The initial clinical presentation of patients was analyzed, and the overall and event-free survival rates of the 77 patients were estimated. Among the 77 HLs, 46 were misinterpreted as NHL by primary individual pathologists (12 as ALCL, 8 as ALCL-HL, 12 as peripheral T-cell lymphoma (PTCL), 6 as B-cell lymphoma, and 8 as unclassifiable NHL). The other 31 cases had been first considered by the panel as consistent with ALCL-HL (n = 18) or with PTCL (n = 13) and were changed later in view of an immunophenotype concordant with HL. Fifty-five percent of the patients completed the full NHL treatment. The 5-year event-free and overall survival rates were 54% and 77%, respectively.
The current results indicate that lymphomas initially called ALCL-HL should not be regarded as a variant of ALCL, but as HL. The clinical consequences of misdiagnoses seem to be a lower event-free survival rate compared with that of classical HL, probably because of more relapses of initially inappropriately treated HL.
Reed-Sternberg cell Large cells (20-50 microns) usually with a large bilobate or multilobate, binucleate or multinucleate nucleus
Vesicular chromatin pattern
Hodgkin cells Considered variants of classic Reed-Sternberg cells: Lacunar cells Present in nodular sclerosing type
Formalin artifactual retraction of cytoplasm around nuclei
Mummified cells Pyknotic nuclei with highly pleomorphic nuclear features Popcorn cells See Lymphocyte Predominance Hodgkin Disease MAIN HISTOLOGIC VARIANTS Progression from one subtype to another rarely occurs Nodular sclerosis Broad bands of collagen dividing the node into nodules
Lacunar cells commonly present
Cellular phase of nodular sclerosis Prominent nodules with lacunar cells but lacking collagen bands Syncytial variant of nodular sclerosis Numerous Hodgkin cells in sheets and cohesive clusters Mixed cellularity Variable cellularity with features intermediate between lymphocyte predominance and lymphocyte depleted
Hodgkin cells easily found
Lymphocyte depleted Overall <5% of cases Diffuse fibrosis type Diffuse effacement of architecture with disorderly reticulin fibrosis enveloping individual cells Reticular type Diffuse effacement of architecture with numerous pleomorphic Hodgkin cells Lymphocyte rich 5% of cases
Nodular subtype and diffuse subtype (less common)
Interfollicular Florid reactive hyperplasia with involvement of interfollicular zones by Hodgkin's disease Fibroblastic Increased fibroblasts without thick collagen deposition OTHER FOLLICULAR
Follicular Hodgkin Lymphoma A Histopathologic Study
Rina Kansal, MD
Timothy P. Singleton, MD
Charles W. Ross, MD
William G. Finn, MD
Ruth F. Padmore, MD
and Bertram Schnitzer, MD
Am J Clin Pathol 2002;117:29-35 Abstract quote
Follicular Hodgkin lymphoma (FHL) is a form of classic Hodgkin lymphoma with morphologic similarity to nodular lymphocyte predominant Hodgkin lymphoma (NLPHL).
We present the clinicopathologic features of 13 FHL cases and compare their morphologic features with 40 cases of NLPHL. Seven males and 6 females had FHL in the lymph nodes of the neck (6 patients), axilla (3 patients), groin (2 patients), and mediastinum (1 patient) and in the nasopharynx (1 patient).
All FHLs had follicles with small, eccentric germinal centers (GCs) and expanded mantle zones containing classic Reed-Sternberg (RS) cells; reactive GCs also were seen in 6 of 13 cases. The RS cells were CD30+, fascin+ in 13 cases; CD15+ in 11 cases; CD20+ in 4 cases; CD79alpha+CD20– in 1 case; and negative for epithelial membrane antigen in 12 cases; they were surrounded by CD3epsilon+ and CD57+ rosettes in 13 and 2 cases, respectively.
Morphologically, FHL may closely simulate NLPHL, and, thus, immunohistochemical analysis is essential to confirm the diagnosis. Clues helpful in diagnosing FHL include the presence of follicles with GCs, classic RS cells, and a relative absence of histiocytes.
MANTLE CELL LYMPHOMA
Composite Hodgkin lymphoma and mantle cell lymphoma: two clonally unrelated tumors.
Caleo A, Sanchez-Aguilera A, Rodriguez S, Dotor AM, Beltran L, de Larrinoa AF, Menarguez FJ, Piris MA, Garcia JF.
Department of Anatomic Pathology and Cytopathology, Faculty of Medicine and Surgery, Universita di Napoli Federico II, Naples, Italy.
Am J Surg Pathol. 2003 Dec;27(12):1577-80. Abstract quote
Association of Hodgkin lymphoma and non-Hodgkin lymphoma is rare and, specifically, the combination of Hodgkin lymphoma and mantle cell lymphoma has not been previously described.
Here we describe composite mantle cell lymphoma and Hodgkin lymphoma affecting the spleen in one case and the eyelid and cervical lymph nodes in a second. In both, nodules of classical Hodgkin lymphoma were intermixed with diffuse or nodular areas of typical mantle cell lymphoma. Immunohistochemical and molecular analyses confirmed cyclin D1 overexpression secondary to the translocation t(11;14) in the small mantle cell lymphoma component; with CD30, CD15, and EBV expression in the Hodgkin and Reed-Sternberg cells. Finally, clonal analysis of rearranged immunoglobulin genes performed on microdissected Hodgkin and Reed-Sternberg and mantle cell lymphoma cells provided definite evidence of separate clonal origins of the two tumors in the patients.
These EBV-positive, clonally unrelated tumors seem to represent true composite neoplasms, in contrast to cases showing merely clonal progression.
Hodgkin's lymphoma of T-cell type: Clonal association with a CD30+ cutaneous lymphoma
Marshall E. Kadin, MD
Reed Drews, MD
Andrew Samel, MD
Annalyn Gilchrist, BS
Olivier Kocher, MD
Hum Pathol 2001;32:1269-1272. Abstract quote
The derivation of Reed-Sternberg cells in Hodgkin's lymphoma has been a subject of great interest. In most cases, Reed-Sternberg cells seem to be derived from germinal center B cells. In few sporadic cases, a T-cell origin has been shown.
This article supports the concept of a T-cell derivation for rare cases of Hodgkin's lymphoma and provides evidence of a novel mechanism of pathogenesis from chronic inflammation in the skin.
CHARACTERIZATION GENERAL Reed-Sternberg cell
Classic immunohistochemical staining pattern:
CD15 (Leu M1)
Also positive for:
B CELL MARKERS CD20 (10-20%)
Expression of B-cell markers in classical hodgkin lymphoma: a tissue microarray analysis of 330 cases.
Tzankov A, Zimpfer A, Pehrs AC, Lugli A, Went P, Maurer R, Pileri S, Dirnhofer S.
Institute of Pathology, University of Basel, Basel, Switzerland.
Mod Pathol. 2003 Nov;16(11):1141-7. Abstract quote
Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma arise from B-lymphocytes. However, classical markers of the B-cell phenotype, such as CD20, are present only in about 25% of the cases.
The aim of the present study was to assess expression of the B-cell-related antigens CD20, CD79a, and CD138 in classical Hodgkin lymphoma using a tissue microarray consisting of 330 classical Hodgkin lymphoma cases. Expression of CD15, CD20, CD30, CD79a, CD138, and latent membrane protein 1 of Epstein-Barr virus was assessed by immunohistochemistry, and the methodology was validated by direct comparison of CD20 expression on the tissue microarray cores with corresponding large sections. The influence of the number of arrayed sample cores on the obtained expression levels of CD20 was analyzed by comparing the results from single, duplicate, and triplicate cores.
Two-hundred fifty-three (77%) of the 330 cases were morphologically representative. CD20 was expressed in 84 cases (33%), CD79a in 26 (10%), and CD138 in 2 (1%), respectively. CD20 and CD79a were co-expressed in 16 cases (P <.005), and expression of CD20 correlated inversely with CD15 (P <.01). Comparing the tissue microarray results with those from conventional sections for expression of CD20 yielded a concordance of 94% (63/67). Examining one, two, and three cores from individual cases revealed positivity for CD20 at 24% (61/253), 32% (82/253), and 33% (84/253), respectively. We conclude that B-cell markers are expressed in 38% of classical Hodgkin lymphoma in the following rank order: CD20>CD79a>>CD138.
The use of two cores per tissue sample renders the tissue microarray technology effectively representative and thus very useful for high-throughput evaluation of heterogeneously expressed markers in classical Hodgkin lymphoma.
Expression status of BCL-6 and syndecan-1 identifies distinct histogenetic subtypes of Hodgkin's disease.
Carbone A, Gloghini A, Gaidano G, Franceschi S, Capello D, Drexler HG, Falini B, Dalla-Favera R.
Division of Pathology, Centro di Riferimento Oncologico, IRCCS, Istituto Nazionale Tumori, Aviano, Italy.
Blood 1998 Oct 1;92(7):2220-8 Abstract quote
The tumor cells in most cases of Hodgkin's disease (HD) have been recently recognized to originate from the B-cell lineage, but their precise differentiation stage is not fully clarified. Recently, we have reported that the histogenesis of B-cell lymphomas may be assessed by monitoring the expression pattern of BCL-6, a transcription factor expressed in germinal center (GC) B cells, and CD138/syndecan-1 (syn-1), a proteoglycan associated with post-GC, terminal B-cell differentiation.
In this study, we have applied these two markers to the study of HD histogenesis. We have found that in nodular lymphocyte predominance HD (NLPHD) tumor cells consistently display the BCL-6(+)/syn-1(-) phenotype, indicating their derivation from GC B cells. Conversely, classic HD (CHD) is heterogeneous because the tumor cells of a fraction of CHD display the BCL-6(-)/syn-1(+) phenotype of post-GC B-cells, whereas another fraction of CHD is constituted by a mixture of tumor cells reflecting the GC (BCL-6(+)/syn-1(-)) or post-GC (BCL-6(-)/syn-1(+)) phenotypes. BCL-6(-)/syn-1(+) tumor cells of CHD are mostly found surrounded by T cells expressing CD40L, consistent with the observation that CD40 signaling downregulates BCL-6 expression.
These data indicate that tumor cells of NLPHD uniformly display a GC B-cell phenotype, whereas the phenotype of tumor cells of CHD appears to be modulated by the surrounding cellular background, particularly CD40L+ reactive T cells.
CD15 AND CD30
Peripheral T-cell lymphomas expressing CD30 and CD15.
Barry TS, Jaffe ES, Sorbara L, Raffeld M, Pittaluga S.
Hematopathology Section, Laboratory of Pathology, National Cancer Intitute, National Institutes of Health, Bethesda, MD 20892, USA.
Am J Surg Pathol. 2003 Dec;27(12):1513-22. Abstract quote
Coexpression of CD30 and CD15 is typically associated with classic Hodgkin's lymphoma (HL). Peripheral T-cell lymphomas (PTCLs) can often display histologic features that simulate classic HL. However, reports of PTCLs coexpressing both CD30 and CD15 have been infrequently described.
We report 11 cases of PTCL in which at least a subset of the neoplastic cells coexpressed CD30 and CD15. The patients included 4 women and 7 men and age ranged from 43 to 83 years (median, 62 years). Nine of 10 patients had advanced stage III or IV disease at presentation. Nodal involvement predominated in 8 of 11 patients, whereas 2 patients presented primarily with skin involvement. Two distinct groups were identified based on morphologic and immunophenotypic features. The first group of 5 cases had histologic features mimicking classic HL with CD30+, CD15+ Reed-Sternberg (RS)-like cells in an inflammatory background of varied extent and composition. The background lymphoid cells showed minimal cytologic atypia. The RS-like cells were negative for CD20 and CD79a in all cases, and CD45 expression was absent in 4 of 5 cases. The RS-like cells expressed CD25 and at least one T-cell-associated marker in all cases. The background T-cell population showed convincing subset predominance in 4 of 5 cases and loss of T-cell-associated antigens in 3 of 5 cases and coexpression of CD30 and CD15 in one case. The second group of 6 cases had morphologic features more in keeping with PTCL than classic HL.
The proportion of neoplastic cells coexpressing CD30 and CD15 varied. Loss of T-cell antigens was noted in all cases and CD4 predominated in 4 of 5 cases. Three of the 6 cases expressed CD45. PCR analysis revealed clonal T-cell receptor gamma (TCR-gamma) chain gene rearrangements in 9 of 11 cases, but no immunoglobulin heavy (IgH) chain gene rearrangements. In situ hybridization studies for Epstein-Barr virus were negative in all cases. In some PTCL cases, the overlap with classic HL can be striking, and combined immunophenotypic and molecular studies are often necessary to confirm the diagnosis.
Guidelines for Interpreting EBER In Situ Hybridization and LMP1 Immunohistochemical Tests for Detecting Epstein-Barr Virus in Hodgkin Lymphoma
Margaret L. Gulley, MD
Sally L. Glaser, PhD
Fiona E. Craig, MD
Michael Borowitz, MD, PhD
Risa B. Mann, MD
Sarah J. Shema, MS
and Richard F. Ambinder, MD, PhD
Am J Clin Pathol 2002;117:259-267 Abstract quote
Histochemical stains demonstrate Epstein-Barr virus (EBV) in approximately 40% of all Hodgkin lymphomas, suggesting a role in tumorigenesis and the potential for EBV-targeted therapy. As research progresses, it is important to define criteria for interpreting histochemical stains. Four hemato-pathologists independently interpreted EBV-encoded RNA (EBER) and latent membrane protein 1 (LMP1) histochemical stains from 40 cases of Hodgkin lymphoma and then reviewed the stains as a group to resolve discrepancies and to develop interpretation guidelines.
To call a Hodgkin case EBV-related, the EBER and/or LMP1 signal must be unequivocally present in Reed-Sternberg/Hodgkin (RS/H) cells. The cytologic features and distribution of stained cells should be matched with those on the corresponding H&E-stained slide to help interpret whether the EBER or LMP1 signal is in malignant or reactive cells. The EBER signal is localized to the nucleus, whereas LMP1 is in the cytoplasm and surface membrane. In some cases, only a fraction of RS/H cells express these factors for technical or biologic reasons.
Before calling a case EBER-negative, it is essential to show that tumor cell RNA is preserved and available for hybridization. LMP1 staining, although usually strong among all tumor cells in a given case, may alternatively be focal and weak, contributing to false-negative interpretation. EBER and LMP1 assays in combination are more effective than either assay alone for identifying EBV-related Hodgkin lymphoma.
Comparison of fascin expression in anaplastic large cell lymphoma and Hodgkin disease.
Fan G, Kotylo P, Neiman RS, Braziel RM.
Department of Pathology, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd, Mail Code L471, Portland, OR 97201, USA.
Am J Clin Pathol 2003 Feb;119(2):199-204 Abstract quote
Diagnostic difficulties sometimes arise in distinguishing anaplastic large cell lymphoma (ALCL) from Hodgkin disease (HD), especially the syncytial variant. Study of the biologic features of diagnostic Reed-Sternberg cells in HD, in search of specific markers for Reed-Sternberg cells, has suggested fascin as a relatively specific and sensitive marker.
We studied the frequency of fascin expression in 30 ALCLs and 34 cases of classic HD, including 17 cases of the syncytial variant. Staining with CD30 and anaplastic lymphoma kinase (ALK)-1 also was performed in all cases. All ALCL and HD cases showed membranous and Golgi zone CD30 positivity. Fascin stained all HD cases but also stained 67% (20/30) of the ALCLs in a cytoplasmic pattern. Fascin positivity was observed in 59% (10/17) of T-cell ALCLs and 77% (10/13) of null-cell ALCLs; ALK-1-positive ALCLs, regardless of origin, were usually fascin-positive (91% [10/11]).
In conclusion, fascin shows strong positivity in all cases of classic HD but also is positive in the majority of ALCLs, including ALK-1-positive and ALK-1-negative cases. Positive staining for fascin is not useful for distinguishing ALCL from HD. In some cases, fascin negativity may help rule out classic HD.
- Gene rearrangement and comparative genomic hybridization studies of classic Hodgkin lymphoma expressing T-cell antigens.
- Aguilera NS,
- Chen J,
- Bijwaard KE,
- Director-Myska AE,
- Barekman CL,
- Millward C,
- Lichy J,
- Abbondanzo SL.
Department of Hematopathology, Armed Forces Institute of Pathology, 6825 16th St, NW, Bldg 54, Room 2051, Washington, DC 20306-6000, USA.
- Arch Pathol Lab Med. 2006 Dec;130(12):1772-9 Abstract quote
CONTEXT: Reed-Sternberg cells in classic Hodgkin lymphoma are enigmatic and difficult to study because they are so sparse. Tissue microdissection allows for the isolation of single Reed-Sternberg cells. Isolated Reed-Sternberg cells show clonal immunoglobulin gene rearrangement indicating a B-cell origin. Rarely, Reed-Sternberg cells in classic Hodgkin lymphoma express T-cell antigens, suggesting a possible T-cell origin.
OBJECTIVE: To determine whether there is a difference in genotype between classic Hodgkin lymphoma and classic Hodgkin lymphoma expressing T-cell antigens and to document T-cell clonality. DESIGN: We studied 4 cases of Hodgkin lymphoma with a characteristic phenotype and immunoreactivity for CD2 and CD3. Single CD30+ Reed-Sternberg cells from each case were isolated by laser capture microdissection for immunoglobulin heavy chain and T-cell receptor-gamma genes by polymerase chain reaction studies. Comparative genomic hybridization was performed in all cases.
RESULTS: Two of 4 cases showed clonal rearrangement of the T-cell receptor-gamma; none showed immunoglobulin heavy chain rearrangement. Two control cases were negative for T cell receptor-gamma but 1 showed immunoglobulin heavy chain rearrangement. Comparative genomic hybridization analysis revealed significant overlap in genomic alteration in Hodgkin lymphoma cases regardless of genotype or phenotype and several regions of imbalance specific to CD3+ Hodgkin lymphoma cases. All patients are alive with no evidence of disease from 10 to 44 months.
CONCLUSIONS: Our findings suggest that a T-cell phenotype classic Hodgkin lymphoma can be supported by genotypic studies and that there may be cytogenetic differences between classic Hodgkin lymphoma and Hodgkin lymphoma expressing T-cell antigens.
Mod Pathol. 2005 Dec;18(12):1542-9 Abstract quote.
Hodgkin's and Reed-Sternberg cells of classical Hodgkin's lymphoma are primarily of B-cell origin, although there are instances of T-cell antigen expression suggesting T-cell origin.
We comprehensively analyzed expression of various T-cell antigens in 259 classical Hodgkin's lymphoma cases using the tissue microarray technique. Expression of the T-cell antigens CD2, CD3, CD4, CD5, CD7 and CD8 was assessed by immunohistochemistry. Hodgkin's and Reed-Sternberg cells of T-cell marker-positive cases were microdissected and analyzed by a multiplex polymerase chain reaction for clonal immunoglobulin heavy chain- and T-cell receptor gamma gene rearrangements. In all, 12 cases (5%) expressed at least one T-cell marker in the following order: CD2 in 11 cases, CD4 in five, CD3 in two, and CD5 and CD8 in one case each; there were no CD7-positive cases, and five cases (2%) expressed more than one T-cell antigen. In positive cases, a mean fraction of 40% of the Hodgkin's and Reed-Sternberg cells (range 20-100%) expressed the analyzed T-cell markers. Two cases (<1%) evidenced clonal T-cell receptor gamma gene rearrangement.
Phenotypic expression of T-cell antigens in Hodgkin's and Reed-Sternberg cells of classical Hodgkin's lymphoma is rare (5%), while genotypically, less than 1% of classical Hodgkin's lymphomas are of possible T-cell origin. Therefore, T-cell antigen expression on Hodgkin's and Reed-Sternberg cells is aberrant in the majority of cases and only infrequently classical Hodgkin's lymphomas are of T-cell origin.
TARC, a CC Chemokine, Is Frequently Expressed in Classic Hodgkin's Lymphoma But Not in NLP Hodgkin's Lymphoma, T-Cell-Rich B-Cell Lymphoma, and Most Cases of Anaplastic Large Cell Lymphoma
S. C. Peh, M.B.B.S., F.R.C.Path.; L. H. Kim, B.BMed.Sc.; S. Poppema, M.D., Ph.D., F.R.C.P.
From the Department of Pathology, Faculty of Medicine, University of Malaya, Kuala Lumpur and Department of Pathology and Laboratory Medicine, University Hospital Groningen, The Netherlands.
Am J Surg Pathol 2001;25:925-929 Abstract quote
Thymus and activation-regulated chemokine (TARC) has been identified as a lymphocyte-directed CC chemokine that attracts activated T-helper type 2 (Th2) cells in humans. Recent studies showed that the T cells surrounding Reed-Sternberg cells in Hodgkin's lymphomas (HL) are Th2 type. Anaplastic large cell lymphomas (ALCL), T-cell-rich B-cell lymphoma (TCRBCL) can mimic HL in some instances.
This study aimed to establish the pattern of TARC expression in these diseases. Immunohistochemical stain using a polyclonal goat anti-human antibody to TARC was performed on 119 cases of confirmed HL; 99 were classical type (43 mixed cellularity, 43 nodular sclerosis, 5 lymphocyte depleted, 4 lymphocyte rich, 4 unclassifiable) and 20 lymphocyte predominant HL. Additional 27 ALCL (9 T-, 18 null-cell phenotype), 16 T-cell and 8 B-cell non-Hodgkin's lymphoma (NHL) were studied.
A total of 85.8% of the classical HL, one case of ALCL, and one case of large cell B-cell lymphoma with anaplastic morphology showed positive TARC expression in the tumor cells. The expression was paranuclear and/or diffuse in the cell cytoplasm. The tumor cells in all cases of lymphocyte predominant HL, TCRBCL, null ALCL, and T-NHL did not express TARC.
The high frequency of TARC expression in the Reed-Sternberg cells of classical HL may explain the characteristic T-cell infiltrate in this disease. The absence in other types that may be morphologically similar indicates that staining for TARC may aid in differential diagnosis.
TRAF1 Expression and c-Rel Activation Are Useful Adjuncts in Distinguishing Classical Hodgkin Lymphoma From a Subset of Morphologically or Immunophenotypically Similar Lymphomas.
Rodig SJ, Savage KJ, Nguyen V, Pinkus GS, Shipp MA, Aster JC, Kutok JL.
From the *Department of Pathology, Brigham & Women's Hospital and daggerDepartment of Medicine, Dana Farber Cancer Institute, Boston, MA. The current address of Dr. Savage is British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
Am J Surg Pathol. 2005 Feb;29(2):196-203. Abstract quote
We demonstrate that the expression of TRAF1 and activated c-Rel, two proteins that function in signaling events downstream of activated CD30 in Reed-Sternberg cells, reliably distinguish classical Hodgkin lymphoma from anaplastic large cell lymphoma, nodular lymphocyte predominant Hodgkin lymphoma, and nonmediastinal diffuse large B-cell lymphoma.
By immunohistochemistry, we found strong TRAF1 staining in 21 of 25 cases of classical Hodgkin lymphoma. In contrast, strong TRAF1 staining was present in only 1 of 17 cases of anaplastic large cell lymphoma, 0 of 15 cases of lymphocyte predominant Hodgkin lymphoma, and 2 of 36 cases of nonmediastinal diffuse large B-cell lymphoma. Nuclear staining for c-Rel, a pattern consistent with NFkappaB activation, was observed in the Reed-Sternberg cells in 23 of 25 cases of classical Hodgkin lymphoma but only in 1 of 15 cases of anaplastic large cell lymphoma and 3 of 15 cases of nodular lymphocyte predominant Hodgkin lymphoma. A heterogeneous pattern of subcellular c-Rel localization was found in nonmediastinal diffuse large B-cell lymphoma. Taken together, the combination of strong cytoplasmic TRAF1 expression and nuclear c-Rel was present in 80% of cases of classical Hodgkin lymphoma (n = 25) but in only 3% of cases of the other malignant lymphomas tested (n = 62).
Thus, the differential expression patterns of downstream components in the CD30 signaling pathway may prove a useful adjunct in distinguishing cases of classical Hodgkin lymphoma from other malignant lymphomas in routine clinical practice.
DIFFERENTIAL DIAGNOSIS NODULAR LYMPHOCYTE-RICH CLASSICAL HODGKIN LYMPHOMA NODULAR LYMPHOCYTE PREDOMINANCE HODGKIN LYMPHOMA SIMILARITIES Sex M>F Same Mediastinal involvement Rare Same Stage Most commonly stage I/II (70-80%) Same B symptoms Rare Same Morphologic pattern Usually fairly closely packed large lymphoid nodules containing neoplastic large cells Same Immunophenotype of background cells Nodules composed of small B cells, punctuated by small cavities populated by the large neoplastic cells which are rosetted by T cells Same DIFFERENCES Age Slightly older (mean 43 years) Mean age 35 years Relapse pattern Relapses are usually single Repeated relapses, often delayed Treatment response at relapse Not good Good Clinical outcome Good (5 YRS 80%) but slightly worse than N-LPHL Very good (5YRS 98%) Morphological pattern of nodules Germinal centers commonly found in the nodules, and the neoplastic cells are concentrated in the expanded mantle zones Nodules do not have germinal centers
Neoplastic cells are concentrated within the nodules, but can also be found in the internodular areas
Cytology of neoplastic cells Reed-Sternberg cells and variants Popcorn (L and H) cells Immunophenotype of neoplastic cells CD20-/+, CD30+, CD15+/-, bcl-6- CD20+, CD30-, CD15-, bcl-6+ EBV association ~40% (but varies according to population) None
ANAPLASTIC LARGE CELL LYMPHOMA (CD30)
- ALK-Positive Anaplastic Large Cell Lymphoma Mimicking Nodular Sclerosis Hodgkin's Lymphoma: Report of 10 Cases.
Vassallo J, Lamant L, Brugieres L, Gaillard F, Campo E, Brousset P, Delsol G.
From *Centre de Physiopathologie de
Toulouse-Purpan, Department of Oncogenesis and Signalling in Hematopoietic Cells and Laboratory of Pathology,
Hopital Purpan, Centre Hospitalier Universitaire, University of Toulouse,
Toulouse, France; daggerDepartment of Pathology of the Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, Sao Paulo, Brazil; double daggerInstitut Gustave Roussy, Villejuif Cedex, France; section signDepartment of Pathology, Centre Hospitalier Universitaire de Nantes, France; and parallelLaboratory of Pathology, Hospital Clinic, University of Barcelona, Spain.
Am J Surg Pathol. 2006 Feb;30(2):223-229. Abstract quote
Anaplastic large cell lymphoma (ALCL) and Hodgkin lymphoma (HL) are recognized as biologically distinct entities. However, occasionally, these two entities may share some morphologic features responsible for diagnostic difficulties.
In the last 10 years, we have collected 380 cases of ALK-positive ALCL of which 10 cases were originally diagnosed as nodular sclerosis classic HL (NSHL) on conventional histopathological examination. After immunostaining, these cases proved to be ALK-positive ALCL mimicking HL (so-called Hodgkin-like ALCL). These cases account for 2.6% of our cases of ALK-positive ALCL (10 of 380 cases). Median age was 11 years (3-92 years) with a female predominance (male/female ratio, 3:7). Characteristically, these lesions showed thick nodular fibrosing bands highly suggestive of NSHL. Neoplastic cells were scarce in 6 cases, whereas in the 4 remaining cases, sheets of tumor cells were also present. A perivascular and a sinusoidal growth pattern was observed in various degrees in all cases. Few binucleated Reed-Sternberg-like cells were present in every case in a background of small lymphocytes. Inflammatory cells (ie, granulocytes, eosinophils, and histiocytes) were rare. Neoplastic cells were positive for CD30 (10 of 10 cases), ALK protein (10 of 10 cases), epithelial membrane antigen (EMA) (9 of 9 cases), CD43 (6 of 9 cases), and perforin (8 of 8 cases), but negative for CD15 (10 of 10 cases), CD20 (10 of 10 cases), Pax5/BSAP (6 of 6 cases), and EBV (8 of 8 cases). In addition, in 7 cases, neoplastic cells were of T-phenotype, whereas the 3 remaining cases were considered to be of null/undetermined phenotype.
Although rare, Hodgkin-like ALCL may mimic NSHL, and it is advisable to include EMA in the first line panel and to ask for ALK staining in EMA-positive, CD15-negative lesions with morphologic features suggestive of NSHL.
GRAY ZONE LYMPHOMA
Mediastinal Gray Zone Lymphoma: The Missing Link Between Classic Hodgkin's Lymphoma and Mediastinal Large B-Cell Lymphoma.
Traverse-Glehen A, Pittaluga S, Gaulard P, Sorbara L, Alonso MA, Raffeld M, Jaffe ES.
From the *Hematopathology Section, Laboratory of
Institutes of Health, Bethesda, MD; daggerDepartement de Pathologie, Hopital Henri Mondor, Creteil, France; and double daggerCentro de
Biologia Molecular "Severo Ochoa," Universidad Autonoma de Madrid, Madrid, Spain. The current address for
Dr. Traverse-Glehen is Laboratory of Anatomic Pathology, Centre Hospitalier Lyon-Sud, Lyon, France.
Am J Surg Pathol. 2005 Nov;29(11):1411-1421. Abstract quote
In recent years, overlap in biologic and morphologic features has been identified between classic Hodgkin lymphoma (cHL) and B-cell non-Hodgkin lymphoma. Nevertheless, the therapeutic approaches for these diseases remain different.
We undertook a study of "mediastinal gray zone lymphomas" (MGZL), with features transitional between cHL nodular sclerosis (NS) and primary mediastinal large B-cell lymphoma (MLBCL) to better understand the morphologic and immunophenotypic spectrum of such cases. Twenty-one MGZL cases were identified over a 20-year period. We also studied 6 cases of composite or synchronous lymphoma with two distinct components at the same time (cHL-NS and MLBCL) and 9 sequential cases with MLBCL and cHL-NS at different times. All patients had a large mediastinal mass. Immunohistochemical studies focused on markers known to discriminate between cHL and MLBCL, including B-cell transcription factors. VJ-PCR was performed in 8 cases to look at clonality of the immunoglobulin heavy chain gene (IgH).
Of the gray zone cases, 11 had morphology reminiscent of cHL-NS, but with unusual features, including a large number of mononuclear variants, diminished inflammatory background, absence of classic Hodgkin phenotype, and strong CD20 expression (11 of 11). Ten cases had morphology of MLBCL, but with admixed Hodgkin/Reed-Sternberg and lacunar cells, absent (3 of 10) or weak (7 of 10) CD20 expression, and positivity for CD15 in 7 cases. B-cell transcription factor expression in the gray zone cases more closely resembled MLBCL than cHL with expression of Pax5, Oct2, and BOB.1 in all but 1 case studied (14 of 15). MAL staining was found in 7 of 10 MGZL, and in at least one component of 6 of 7 evaluable composite or sequential MLBCL/cHL cases. Two cases of sequential lymphoma showed rearrangements of the IgH gene of identical size: one in which MLBCL was the first diagnosis and one in which MLBCL was diagnosed at relapse, indicating clonal identity for the two components of cHL and MLBCL.
There is accumulating evidence that MLBCL and cHL are related entities. Further support for a relationship between MLBCL and cHL-NS is provided by composite and metachronous lymphomas in the same patient, as well as the existence of MGZL with transitional morphology and phenotype.
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSTIC FACTORS Stage is the most important prognostic factor Poor prognostic factors Older patients
Elevated serum LDH, beta-2 microglobulin, ESR
Elevated serum CD30, CD25
Good prognostic factors Noncaseating granulomas
Extensive dendritic cells
ADDITIONAL PROGNOSTIC FACTORS EPSTEIN-BARR VIRUS LATENT MEMBRANE PROTEIN
Longer failure-free survival interval of Epstein-Barr virus-associated classical Hodgkin's lymphoma: a single-institution study.
Krugmann J, Tzankov A, Gschwendtner A, Fischhofer M, Greil R, Fend F, Dirnhofer S.
Institute of Pathology, University of Innsbruck, Austria.
Mod Pathol. 2003 Jun;16(6):566-73. Abstract quote
We analyzed Epstein-Barr virus association in classical Hodgkin's lymphoma from a single center in Austria with special emphasis on the latent membrane protein1 gene configuration and clinical outcome.
All 119 (65 male, 54 female) patients were treated from 1974 to 1999 in the Division of Hematology and Oncology at the Department of Internal Medicine, University of Innsbruck, Austria. The mean follow-up time was 122 months (range, 3-333 mo). Epstein-Barr virus was examined by latent membrane protein1 immunohistochemistry and by in situ hybridization for Epstein-Barr virus-encoded early ribonuclein acid transcripts. For assessment of the Epstein-Barr virus subtype (A/B) and latent membrane protein1 gene configuration, the polymerase chain reaction was employed. Fifty-four reactive tonsils were used as the control population.
These results as well as clinical parameters such as age, gender, tumor stage, risk factors, and B symptoms were correlated with failure-free and overall survival. Latent membrane protein1 was detected in 31/119 (26%) classical Hodgkin's lymphoma, and Epstein-Barr virus subtyping was successful in 19 of the 31 virus-infected classical Hodgkin's lymphoma cases, as well as in 28 of 54 reactive tonsils. Subtype A was observed in all classical Hodgkin's lymphoma patients and in 26/28 (93%) tonsils. The 30-base pair latent membrane protein1 gene deletion was found in only 4/31 (13%) Epstein-Barr virus-associated classical Hodgkin's lymphoma as well as in 20/54 (37%) reactive tonsils.
Patients with Epstein-Barr virus-associated classical Hodgkin's lymphoma showed a significantly longer mean time to first relapse of 99 months, as compared with 49 months for the Epstein-Barr virus-negative cases (P <.02), and were more frequent in those aged >45 years (P <.04). Epstein-Barr virus-associated classical Hodgkin's lymphoma were predominantly of the mixed-cellularity subtype and occurred more frequently in male patients, in patients with Stage III and IV, and in patients with B symptoms as well as risk factors. However, overall survival did not correlate with Epstein-Barr virus association. The 30-base pair latent membrane protein1 gene deletion had no influence on overall survival and failure-free survival time. Although the number of patients with this specific mutation was low, it further shows that an increased oncogenic potential of the latent membrane protein1 deletion variant is unlikely.
This large single-center study demonstrates a low prevalence of Epstein-Barr virus positivity in classical Hodgkin's lymphoma in western Europe. In accordance with results of similar studies, the presence of Epstein-Barr virus has a beneficial effect on the length of failure-free survival despite the higher frequency of risk factors such as higher tumor stage or advanced age.
Co-expression of Epstein-Barr virus latent membrane protein and vimentin in "aggressive" histological subtypes of Hodgkin's disease.
Carbone A, Gloghini A, Zanette I, Canal B, Rizzo A, Volpe R.
Division of Pathology, Istituto Nazionale di Ricovero e Cura a Carattere Scientifico, Aviano, Italy.
Virchows Arch A Pathol Anat Histopathol 1993;422(1):39-45 Abstract quote
The presence of Epstein-Barr virus (EBV) genome in Hodgkin's and Reed-Sternberg (HRS) cells, as detected using in situ hybridization (ISH) with biotinylated BamHI "V" probes, along with the expression of EBV-encoded latent membrane protein (LMP) and vimentin was examined in paraffin-embedded sections of 39 immunomorphologically characterized cases of Hodgkin's disease (HD).
ISH demonstrated EBV in HRS cells in 15 of 39 cases, whereas LMP expression was detected in 11 of 39 cases, only in the presence of EBV genome detection. With the exception of 1 case, in which HRS cells expressed B-cell-associated antigens, the LMP-positive cases included specimens in which HRS cells were of non-B, non-T phenotype. LMP expression showed a stronger association with lymphocyte depletion (LD) (3/3) and mixed cellularity (MC) (6/11) than with lymphocyte predominance (0/5) or nodular sclerosis (2/20) subtypes. Vimentin expression on HRS cells was found in all the LMP-expressing cases and only in a fraction (13/28) of LMP-negative cases.
This study supports the view that HD represents a heterogeneous group of diseases also in terms of EBV association, LMP expression being strongly related to the "aggressive" LD and MC histological subtypes. In light of the supposed interactions between vimentin and LMP, their co-expression on HRS cells, as detected in this study, provides further evidence for a significant role of EBV in the development of a proportion of HD cases.
Ann Arbor Staging Characteristics I Only a single lymph node site or single extranodal site (IE) is involved II Two or more lymph node sites on one side of the diaphragm are involved, or limited contiguous extranodal site involvement (IIE) III
Lymph node sites on both sides of the diaphragm are involved, with splenic (IIIS) or limited contiguous extradodal site involvement (IIIE), or both (IIISE)
III1: With or without splenic hilar, celiac, or portal nodes
III2: With para-aortic, iliac, or mesenteric nodes
IV Extensive involvement of extranodal sites, with or without lymph node involvement A Asymptomatic B Fever>38C previous month, sweats, weight loss >10% of body weight from previous 6 months X Bulky disease defined as:
>10 cm for lymph node
>1/3 of internal transverse diameter of thorax at 5/6 on a posteroanterior chest radiograph
5 Year Survival With treatment, overall 75% survival Stage 5 year disease free survival I 90% II 75-90% III 50-85% IV 40-65% TREATMENT Chemotherapy with/without radiation therapy
High-dose therapy and autologous stem cell rescue for patients with Hodgkin's disease in first relapse after chemotherapy: results from the EBMT. Lymphoma Working Party of the European Group for Blood and Marrow Transplantation.
Sweetenham JW, Taghipour G, Milligan D, Blystad AK, Caballero D, Fassas A, Goldstone AH.
CRC Wessex Medical Oncology Unit, University of Southampton, UK.
Bone Marrow Transplant 1997 Nov;20(9):745-52 Abstract quote
The purpose of this study was to investigate the results of high-dose therapy and autologous stem cell transplantation in adult patients with Hodgkin's disease in first relapse after chemotherapy, to determine the overall and progression-free survival, identify prognostic factors for outcome, and to define the role of conventional dose salvage therapy given prior to the high dose regimen.
A retrospective analysis of 139 adult patients reported to the lymphoma registry of the European Group for Blood and Marrow Transplantation (EBMT) between February 1984 and July 1995 is considered. Data on all patients were reviewed and prognostic factors determined in univariate analysis. The actuarial 5-year overall survival (OS) and progression-free survival (PFS) for the entire group of 139 patients were 49.4 and 44.7%, respectively. In univariate analysis for OS, disease bulk at the time of high-dose therapy, second-line regimen, initial remission duration and status at transplant had no predictive value. Status at transplant was predictive for OS when patients in second complete remission (CR) were analysed separately from those in chemosensitive relapse. Similar trends were observed for PFS.
We concluded that high-dose therapy and autologous stem cell transplantation is an effective strategy for patients with Hodgkin's disease in first relapse after chemotherapy. These results suggest that it should be used regardless of initial remission duration. The role of conventional-dose salvage given prior to high-dose therapy is unclear, since disease status, disease bulk at the time of transplantation, and the second-line regimen had no significant effect on outcome. However, in view of the low patient numbers, no firm conclusion is possible, and this issue requires prospective assessment.
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