Classic HL

Lymphoma & related disorders

Hodgkin lymphoma

Classic HL

Author: Dragos C. Luca, M.D.

Topic Completed: 1 August 2011

Minor changes: 5 July 2020

Copyright: 2002-2020, PathologyOutlines.com, Inc.

PubMed Search: Classic Hodgkin [title]

Page views in 2019: 26,225

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Table of Contents

Cite this page: Luca D. Classic HL. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lymphomanonBclassic.html. Accessed August 7th, 2020.

Definition / general

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 nonneoplastic small lymphocytes, eosinophils, neutrophils, histiocytes, plasma cells, fibroblasts and collagen fibers (WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th Edition, Lyon 2008)

Terminology

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

Epidemiology

95% of all Hodgkin lymphoma (the other 5% are "nonclassic")
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

Sites

Cervical (75%), mediastinal, axillary and paraaortic lymph nodes
Rarely in nonaxial lymph nodes (mesenteric, epitrochlear) or Waldeyer's 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

Pathophysiology

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)

Etiology

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

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
Primary bone lymphoma:
- Extremely rare (Ann Oncol 2008;19 Suppl 4:iv77)
- WHO: lymphoma presenting in an osseous site with no evidence of disease elsewhere for at least 6 months
- Involvement of regional lymph nodes does not exclude diagnosis (Joint Bone Spine 2000;67:446)
- Symptoms: bone pain, pathologic fracture, mass, B symptoms; neurologic symptoms if vertebral involvement

Case reports

7 year old boy with primary multifocal osseous lymphoma (World J Surg Oncol 2008;6:34)
21 year old man with primary multifocal osseous Hodgkin lymphoma (J Cancer Res Clin Oncol 2005;131:163)
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)

Prognosis and treatment

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 (postthymic) 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

Images hosted on other servers:

Fleshy lymph node

Liver with multifocal involvement

Microscopic (histologic) 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)

Microscopic (histologic) images

Images hosted on other servers:

Terminal ileum: various images

Colonic tumor: various images

Composite lymphoma with follicular lymphoma

EBV+ by ISH (figures A - B)

Cytology images

Images hosted on other servers:

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 EBNA1 but not EBNA2 (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 (PGM1), CD138, OCT2 (90%), BOB.1 (90%), PU.1

Electron microscopy 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

Molecular / cytogenetics description

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
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