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Lymphoma - Non B cell neoplasms

Hodgkin lymphoma

Classic Hodgkin – general

Reviewer: Dragos Luca, M.D. (see Reviewers page)
Revised: 6 October 2014, last major update August 2011
Copyright: (c) 2001-2014, PathologyOutlines.com, Inc.


● Classic Hodgkin lymphoma (CHL) is a monoclonal lymphoid neoplasm (in most instances derived from B cells) composed of mononuclear Hodgkin and multinucleated Hodgkin Reed-Sternberg (HRS) cells residing in an infiltrate containing a variable mixture of non-neoplastic small lymphocytes, eosinophils, neutrophils, histiocytes, plasma cells, fibroblasts and collagen fibers (WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th Edition, Lyon 2008)


● Four histological subtypes: lymphocyte-rich CHL (LRCHL), nodular sclerosis CHL (NSCHL), mixed cellularity CHL (MCCHL) and lymphocyte-depleted CHL (LDCHL)
● The 4 subtypes have identical immunophenotypic and genetic features, but different clinical features and EBV association


● 95% of all Hodgkin lymphoma (the other 5% are "non-classic")
Developed countries: bimodal age distribution with one peak at 15-35 years of age and the second one in late life (after 54)
Developing countries: early peak in childhood; for children younger than 10 years, may be related to EBV infection; higher incidence of mixed cellularity subbtype (Arch Pathol Lab Med 2003;127:1325)
● HIV patients have increased incidence, usually higher stage
● Higher incidence in patients with history of infectious mononucleosis
● Familial and geographical clustering has been reported


● EBV more common in mixed cellularity and lymphocyte depleted subtypes
● No other virus identified
● Loss of immune surveillance may predispose to EBV+ disease
● Almost 100% are associated with EBV+ in tropical regions


● Cervical (75%), mediastinal, axillary and paraaortic lymph nodes
● Rarely in non-axial lymph nodes (mesenteric, epitrochlear) or Waldeyer ring; primary extranodal involvement also rare
● Localized disease (stage I & II) in >60% of patients
● Mediastinal involvement in ~60% (mostly nodular sclerosing subtype)
● Splenic involvement: 20%, bone marrow: 5%
● Splenic and abdominal involvement more frequent in mixed cellularity subtype


● HRS cells are derived from germinal center B cells with “crippling” mutations of IgH variable region segment; associated with EBV in 30% of cases (may prevent apoptosis)
● HRS cells probably secrete cytokines to recruit reactive cells; IL-5 attracts eosinophils, which produce TGF-beta (transforming growth factor-beta), which causes fibrosis; also a predominance of Th2 cells in the T cell population
● Expression of FasL in most HRS cells plus loss of FasL expression in the follicular dendritic cells (FDC) of the germinal center suggests a disturbed FDC microenvironment that may contribute to its pathogenesis (Am J Surg Pathol 2001;25:388)

Clinical features

● Peripheral lymphadenopathy (1-2 lymph node areas), painless enlargement of lymph nodes
B symptoms (up to 40% of patients): fever, night sweats, weight loss (10% of body weight), pruritus (by some authors); associated with stage 3 or 4, mixed cellularity and lymphocyte depleted subtypes
● Pain in lymph nodes may occur with alcohol consumption (paraneoplastic symptom)
● Most patients have cutaneous anergy that persists even after treatment

Case reports

● 38 year old man with primary tumor in terminal ileum (Arch Pathol Lab Med 2001;125:424)
● 40 year old man with involvement of ear canal (Arch Pathol Lab Med 2003;127:E101)
● 42 year old woman with colon involvement (Arch Pathol Lab Med 2000;124:1824)
● 56 year old man with coexisting diffuse large B lymphoma (Am J Clin Pathol 2006;126:222)
● 60 year old man with prior mycosis fungoides (Mod Pathol 2001;14:91)
● 73 year old man with coexisting follicular lymphoma (Arch Pathol Lab Med 2000;124:1376)
● Cases with coexisting mantle cell lymphoma (Am J Surg Pathol 2003;27:1577)
● With nemaline myopathy after radiotherapy (Hum Pathol 2003;34:816)
● Apparent T cell origin derived from CD30+ cutaneous leg lymphoma (Hum Pathol 2001;32:1269)

Treatment and prognosis

5-year survival: Stage 1 or 2a-90%, Stage 4-60%
● Increased risk of second cancers (breast cancer in women treated with radiation during adolescence, solid tumors after radiation, AML and myelodysplasia after chemotherapy); also pulmonary fibrosis and accelerated atherosclerosis
Post-bone marrow transplant: recurrences showed increased sclerosis, but otherwise similar (Am J Clin Pathol 1997;107:74)
● Modern therapy: >85% curable, histologic subtype less important
● Important prognostic indicator: FDG-PET evaluation of response after 2 courses of ABVD chemotherapy

Postulated normal counterpart

● Mature B cell at the germinal center stage of differentiation (>98% of cases) or peripheral (post-thymic) T cell (rare)

Gross description

● Enlarged, encapsulated lymph node with fish-flesh appearance on cut surface
● Nodular sclerosing subtype: prominent nodularity, dense fibrotic bands, thickened capsule
● Spleen: scattered nodules, sometimes large masses
● Thymus: may have cystic degeneration and epithelial hyperplasia

Gross images

Fleshy lymph node


Liver with multifocal involvement

Micro description

● Hodgkin Reed-Sternberg (HRS) cell classically is large (15-45 μ) with abundant basophilic/amphophilic cytoplasm; binucleate or bilobed nucleus; 2 halves are mirror images; may have single/multiple multilobate nucleoli or large, inclusion like, owl-eyed eosinophilic nucleoli (5-7 μ) surrounded by clear halo; thick, irregular nuclear membrane
● Diagnostic Reed-Sternberg cells must have at least 2 nucleoli in 2 separate nuclear lobes
● Mononuclear RS variant: termed Hodgkin cell, single round or oblong nucleus with large inclusion-like nucleoli
● “Mummified” cells: HRS cells with condensed cytoplasm and pyknotic reddish nuclei
● “Lacunar” cells: HRS cells surrounded by formalin retraction artifact, characteristic for nodular sclerosing subtype
● Neoplastic cells are 0.1 to 10% of cellular infiltrate
● Rich inflammatory/reactive background is present, varies somewhat by subtype
● In secondary sites (bone marrow, liver), is sufficient to see CD30+ Hodgkin cells in the appropriate background (if CHL diagnosed elsewhere, no need for RS cells)

Micro images

Terminal ileum: various images

Colonic tumor: various images

Composite lymphoma with follicular lymphoma

EBV+ by ISH (figures A-B)

Cytology images

Hodgkin Reed-Sternberg cell

Positive stains

● CD30 (almost all cases, membrane & Golgi zone), CD15 (75-85%, may be restricted to the Golgi zone), CD20 (30-40%), CD79a (10%), IRF4/MUM1, BLIMP1 (25%), EMA (rare), Ki67, fascin
● PAX5/BSAP shows weak nuclear expression in ~95% of cases, which demonstrates the B cell origin of HRS cells
● EBV (40-60% of MCCHL and NSCHL, but not LRCHL); see also individual subtypes; if positive, the HRS cells express LMP1 and EBNA-1 but not EBNA-2 (latency type II)
● May rarely show weak T cell antigen expression in a minority of HRS cels

Negative stains

● ALK, TIA1, CD3, CD45 (may have focal globular cytoplasmic staining), J-chain, CD75, CD68 (PGM-1), CD138, OCT-2 (90%), BOB.1 (90%), PU.1

EM description

● Diagnostic RS cell actually contains a single nucleus in most cases; impression of multiple nuclei is created by an extreme degree of nuclear cleavage and indentation
● Chromatin marginated or clustered into dense areas (“spotted nuclei”)
● 2-3 very large nucleoli (3-4 μ) with condensed structure containing abundant RNA, sharply demarcated, resembling an inclusion body
● Well-developed Golgi body in the cytoplasm

Genetics and molecular

● HRS cell is aneuploid, but has no consistent cytogenetic abnormalities; TNF receptor-associated factors 1 & 2 are characteristic in HRS cells (Mod Pathol 2000;13:1324)
● Clonal Ig gene rearrangements (>98% of cases) or clonal TCR gene rearrangements (rare), detectable only in isolated HRS DNA and not in whole tissue DNA
● High load of somatic hypermutations in the variable region of Ig heavy chain genes (IGHV@) – supports derivation from germinal center B cells
● NFκB constitutively activated in HRS cells; also, blockage of the negative feedback loop of the JAK/STAT5 pathway
● EBV: highest frequency (75%) – mixed cellularity, lowest (10-40%) – nodular sclerosing subtype; almost 100% in resource poor regions and HIV patients
● EBV: resource-rich countries – strain 1, resource-poor – strain 2
● Aneuploidy and hypertetraploidy are consistent with multinucleation
● Comparative genomic hybridization: gains on 2p, 9p, 12q and amplifications of 4p16, 4q23-q24, 9p23-p24

Differential diagnosis

● Infectious mononucleosis: particularly in children/young adults, image
● Peripheral T cell lymphoma: expresses T cell markers but may be CD15+, CD30+ (Am J Surg Pathol 2003;27:1513)
● ALK1+ anaplastic (Ki-1) large cell lymphoma: positive for ALK1, t(2,5), EMA, TIA1 (Am J Surg Pathol 2001;25:297)
● Non-Hodgkin lymphoma: particularly if disease in Waldeyer’s ring, skin, GI tract

End of Lymphoma - Non B cell neoplasms > Hodgkin lymphoma > Classic Hodgkin – general

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