Clinical and immunopathological studies in Hodgkin's disease with special reference to prognosis

Hodgkin's disease (HD) and non-Hodgkin lymphoma (NHL) have certain features in common, but also distinct clinical and pathological differences. Thus, HD has many features of both an infectious (fever, leukocytosis, eosinophilia, night sweats, lymphadenopathy, splenomegaly) and a malignant process with few tumour cells, T-cell accumulation and sclerosis. Today, current therapies fail to cure about 1/3 of patients with advanced HD. The main purpose of the present study has been to improve the understanding of certain biological and clinical features of HD and look for their clinical applications with regard to diagnosis, treatment and prognosis.

A morphological review with immunostainings of 238 biopsies diagnosed as HD showed reclassifications to other diagnoses in 11%, with T-cell-rich B-cell lymphoma and anaplastic large cell lymphoma as the most frequent misdiagnosed entities. Thus, immunohistochemistry makes it possible to identify NHL, that are morphologically difficult to distinguish from HD.

The proportion of Epstein-Barr virus (EBV)-positive HD tumours was 40%, detected by latent membrane protein 1 (LMP1; immunohistochemistry) and EBV-encoded RNA (EBER; in situ hybridisation). Apart from EBV-positive tumours being more common in patients with the subtype mixed cellularity (MC), clinical features, blood lymphocyte function and outcome were not related to tumour EBV status. Patients with EBV-positive tumours had elevated soluble (s)CD54 serum levels, higher antibody titres to EBV early antigen restricted and decreased total white blood cell counts. A potential causal relationship between EBV tumour status and these findings needs to be further explored.

A high eosinophil infiltration in HD tumour tissue was seen in 1/3 of 259 untreated patients, most pronounced in younger patients, nodular sclerosis (NS) type 2 and bulky disease. The degree of eosinophilia was not associated with the number of Hodgkin-Reed-Sternberg cells, the phenotype distribution of small lymphocytes, EBV tumour status or clinical outcome. Thus, determination of tissue eosinophilia is of limited diagnostic and prognostic value in HD. Mixed cellularity HD tumours had significantly higher numbers of lymphocytes positive for CD8, T-cell intracellular antigen-1 and granzyme B, respectively, than NS. This T and NK cell infiltration in MC might be explained by the high levels (mRNA and protein level) of the chemokines IP-10 and Mig previously observed in MC.

Tumour infiltrating lymphocytes had a decreased expression of the CD3-zeta-chain in 66% of biopsies. Among a number of biological markers under study, high serum levels of interleukin-10 and sCD30 were found to be associated with a poor prognosis, and may add prognostic information to that achieved by the International Prognostic Score.

In a randomised study, fixed vs response adapted chemotherapy was evaluated in responding patients with advanced HD. The policy to give 6-8 courses of chemotherapy to this patient group seems valid. The price, however, for such an approach is the overtreatment of a subset of already cured patients.

List of scientific papers

I. Björkholm M, Axdorph U, Grimfors G, Merk K, Johansson B, Landgren O, Svedmyr E, Mellstedt H, Holm G (1995). "Fixed versus response-adapted MOPP/ABVD chemotherapy in Hodgkin´s disease. A prospective randomized trial" Ann Oncol 6(9): 895-9
https://pubmed.ncbi.nlm.nih.gov/8624292

II. Axdorph U, Porwit-MacDonald A, Sjöberg J, Grimfors G, Björkholm M (2001). "T-cell-rich B-cell lymphoma - primarily diagnosed and treated as Hodgkin´s disease" (Submitted)

III. Axdorph U, Porwit-MacDonald A, Sjöberg J, Grimfors G, Björkholm M (2001). "Tissue eosinophilia in relation to immunopathological and clinical characteristics in Hodgkin´s disease" (Submitted)

IV. Axdorph U, Porwit-MacDonald A, Sjöberg J, Grimfors G, Ekman M, Wang W, Biberfeld P, Björkholm M (1999). "Epstein-Barr virus expression in Hodgkin´s disease in relation to patient characteristics, serum factors and blood lymphocyte function" Br J Cancer 81(7): 1182-7
https://pubmed.ncbi.nlm.nih.gov/10584880

V. Axdorph U, Sjöberg J, Grimfors G, Landgren O, Porwit-MacDonald A, Björkholm M (2000). "Biological markers may add to prediction of outcome achieved by the International Prognostic Score in Hodgkin´s disease" Ann Oncol 11(11): 1405-11
https://pubmed.ncbi.nlm.nih.gov/11142480