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Lymphoma & related disorders

Hodgkin lymphoma

Classic HL


Dragos C. Luca, M.D.

Topic Completed: 1 August 2011

Minor changes: 26 July 2021

Copyright: 2002-2021, PathologyOutlines.com, Inc.

PubMed Search: Classic Hodgkin [title]

Dragos C. Luca, M.D.
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Table of Contents
Definition / general | Terminology | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Case reports | Prognosis and treatment | Postulated Normal Counterpart | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Cytology images | Positive stains | Negative stains | Electron microscopy description | Molecular / cytogenetics description | Differential diagnosis
Cite this page: Luca DC. Classic HL. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lymphomanonBclassic.html. Accessed October 18th, 2021.
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
  • 4 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
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

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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

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EBV+ by ISH (figures A - B)

Cytology images

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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
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
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