Classical Hodgkin's disease

Epidemiology

Classical HL accounts for 95% of all cases of Hodgkin lymphoma. There is a bimodal distribution with age peaks at 15-35 years and in the elderly.

Clinical features

Sites of involvement are commonly cervical (75% of cases), mediastinal (60% of cases, mainly nodular sclerosis HL), axillary and para-aortic. 55% of cases present with stage I or II disease. 20% have splenic involvement and 5% bone marrow involvement. 40% of patients have systemic symptoms.

Histopathology

Classification should be based on pre-treatment biopsy material. Treatment leads to a histological appearance of residual or recurrent disease with numerous atypical Hodgkin and RS cells in a lymphocyte-depleted background.

Nodular sclerosis HL: accounts for 70% of classical HL. Broad collagen bands, arising from a thickened lymph node capsule, surround nodules composed of a highly variable number of RS cells, lymphocytes and other inflammatory cells. RS cells are of lacunar type.

Variants:

NS-CHL: cellular phase. There is clear-cut nodularity without overt collagen band deposition. Lacunar cells are present, often at the periphery of nodules. The lymphocytes are mainly of mantle cell type (CD20+, CD79a+, CD5+, IgM+, IgD+, CD3-)2.
NS-CHL: syncytial. When lacunar cells are highly aggregated, the term syncytial variant has been used. It constitutes 16% of all NS-CHL and runs a more aggressive course, with bulky mediastinal disease and stage III/IV in 88% of patients2.
Grading:

- grade 1; 75% or more of the nodules contain only scattered RS cells in a lymphocyte-rich, mixed cellularity or fibrohistiocytic background.
- grade 2 fulfills one of three patterns2;
  - at least 25% of the nodules contain sheets of RS cells (sufficient to fill a x40 hpf).
  - more than 25% of nodules contain numerous large bizarre/anaplastic cells in the absence of lymphocyte depletion.
  - more than 80% of nodules show a fibrotic or fibrohistiocytic composition

grade 2 constitutes 15-25% of all NS-CHL. EBV-encoded LMP-1 is seen in only 10-40% of cases.

Mixed cellularity HL: accounts for 15-25% of classical HL. Associated with HIV infection and more common in developing countries. Often presents with stage III or IV disease and B symptoms. Scattered classical RS cells in a diffuse or vaguely nodular mixed inflammatory background of lymphocytes, eosinophils, histiocytes and plasma cells, without sclerosis. Variants:
- Interfollicular variant. Sometimes there is an interfollicular (paracortical) growth pattern. 75% of cases show EBV encoded LMP-1. The residual germinal centres may regress to resemble Castleman's disease
- Epithelioid cell rich variant. The prominent epithelioid cell reaction forms granuloma with occasional Langhans cells.
Lymphocyte-rich classical HL; ~5% of all HL. Usually involves peripheral lymph nodes and presents with stage I or II disease. Scattered RS cells in a nodular or, rarely, a diffuse cellular background of small lymphocytes with an absence or paucity of eosinophils and neutrophils. The nodules may retain regressed eccentric germinal centres. Some of the RS cells may be of popcorn type. In diffuse cases, histiocytes may be abundant. The RS cells are of classical cytomorphology and immunophenotype. The small lymphocytes are of mantle cell type (IgM+D+).
- "follicular" variant; classic Reed-Sternberg cells are preferentially located in the mantle zone and centre of reactive follicles where they are ringed by CD57+ T-cells. Unlike NLPHL, the follicles are only mildly expanded and follicles showing PTGC are not seen1.
Lymphocyte-depleted HL. About 1% of all cases of HL. Associated with HIV infection and developing countries. Usually presents with stage II/IV disease, bone marrow involvement in 50% of cases and B symptoms. Diffuse morphology with a high proportion of RS cells. Many cases reassigned as non-Hodgkin lymphoma.

Subtypes:

fibrotic
reticular-sarcomatous

HL, unclassifiable. Cases with ambiguous features or insufficient material should be placed in this category, rather than categorised as MC CHL as was past practice.

Immunohistochemistry

CD3	CD15	CD20	CD30	CD45	CD79a	BSAP	EBV encoded LMP-1	EMA	ALK
var	~80% of cases2	~20% of cases	98% of cases2	usually negative	sometimes	~90% of cases	positive	<5% of cases	negative

Differential diagnosis: see table of differential diagnoses and immunohistochemistry

anaplastic large cell lymphoma: consistently negative for BSAP
primary mediastinal (thymic) large B cell lymphoma. There is probably an overlap between mediastinal large B-cell lymphoma and nodular sclerosing classical Hodgkin lymphoma, sometimes referred to as "mediastinal gray zone lymphoma".
undifferentiated nasopharyngeal carcinoma; early metastasis to laterocervical lymph nodes occurs and may show nodularity, sclerosis, plasmacytosis and an eosinophilic infiltrate.
LR-CHL: NLPHL - immunophenotype is crucial.
syncytial NS-CHL: non-Hodgkin lymphoma, melanoma, sarcoma, thymic carcinoma, germ cell tumour.
MC-CHL, interfollicular variant: Castleman's disease, follicular hyperplasia.
MC-CHL, epithelioid cell rich variant: Lennert's lymphoma (Lennert's lymphoma shows a lymphocyte population with irregular nuclei and has a higher mitotic index.), THRLBCL
LD-CHL: ALCL, peripheral T cell lymphoma, THRLBCL, PMLBCL, syncytial variant of NS-CHL, inflammatory fibrosarcoma, atypical Langerhans cell histiocytosis, inflammatory and giant cell malignant fibrous histiocytoma, lymphocyte-rich well differentiate liposarcoma and undifferentiated nasopharyngeal carcinoma.

Prognosis

With current treatments, 70-80% of patients show long term survival. NS HL has a somewhat better prognosis, although massive mediastinal disease is an adverse risk factor.

References

World Health Organization Classification of Tumours, Tumours of the haematopoietic and lymphoid tissues, IARC Press 2001.

1Jones D. Dismantling the germinal center: comparing the processes of transformation, regression and fragmentation of the lymphoid follicle. Advances in Anatomic Pathology 2002;9:129-138.

2Pileri, S.A., Ascani, S., Leoncini, L., Sabattini, E., Zinzani, P.L., Piccaluga, P.P., Pileri, A., Jr., Giunti, M., Falini, B., Bolis, G.B. and Stein, H. Hodgkin's lymphoma: the pathologist's viewpoint. J Clin Pathol 2002;55:162-76.

This page last revised 3.12.2002.