Lymphoma & related disorders
Hodgkin lymphoma
Classic HL
Author: Dragos C. Luca, M.D.
Topic Completed: 1 August 2011
Minor changes: 29 December 2020
Copyright: 2002-2021, PathologyOutlines.com, Inc.
PubMed Search: Classic Hodgkin [title]
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 diagnosisCite this page: Luca DC. Classic HL. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lymphomanonBclassic.html. Accessed January 20th, 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
- 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:
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
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
