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Diagnosis and Discussion: Case 1180

Final Diagnosis

Classic Hodgkin lymphoma

Discussion

Classic Hodgkin lymphoma (CHL) is a germinal-center B-cell neoplasm characterized by a population of scattered neoplastic Hodgkin and Reed-Sternberg cells within an abundant inflammatory background [1]. Despite originating from germinal center B-cells, the neoplastic cells lack most of their B-cell antigen phenotype [1].

CHL is rare in children, has a bimodal age distribution (25-35 years and again after 55 years), typically presents with painless lymphadenopathy (cervical, supraclavicular, and mediastinal), and patients may experience B symptoms (fever, weight loss, and night sweats) which are more frequently seen in advanced-stage disease [1,2]. Risk factors for CHL include Epstein-Barr virus infection, immune dysregulation (HIV/AIDS, transplantation, immunosuppressive drugs, autoimmunity), and familial predisposition [2,3]. Immunosenescence may contribute to the second peak of CHL seen in some populations after 55 years [1,2].

CHL demonstrates presence of the characteristic HRS cells, which are at least 4-5 times as large as the background lymphocytes and exhibit large nuclei with prominent eosinophilic nucleoli [1]. Hodgkin cells are mononuclear, whereas Reed-Sternberg cells are binuclear or multinuclear, arising from Hodgkin cells through a process of incomplete cytokinesis [1,4]. Notably, HRS cells constitute only 0.1-10% of the infiltrate, and their scarcity and uneven distribution can make detection challenging, particularly on core needle biopsies [1,3]. HRS cells express CD30 and CD15 in the majority of cases; the staining pattern is membranous with accentuation in the Golgi area of the cytoplasm [1]. One of the few consistently positive B cell markers in HRS cells is PAX5 (~95% of cases) with a weak nuclear staining pattern; CD20 is negative or only weakly/variably positive in some cases, and other B cell markers including CD19, CD79a, OCT2, BOB1, PU.1, and BCL6 are negative in most cases [1]. HRS cells are also typically negative for CD45 [1]. The surrounding tumor microenvironment consists predominantly of T lymphocytes, along with B lymphocytes, plasma cells, histiocytes/macrophages, neutrophils, eosinophils, mast cells, mesenchymal stromal cells, and endothelial cells; epithelioid granulomas may also be seen [1,2].

There are four recognized histologic subtypes of CHL: nodular sclerosis (NSCHL), mixed cellularity (MCCHL), lymphocyte-rich (LRCHL), and lymphocyte-depleted (LDCHL). In the United States, the majority of cases are NSCHL (70-75%) and less than 1% are LDCHL [2,3]. However, subtyping may not be as prognostically valuable in the context of modern therapy [1,2].

Diagnosis requires primary nodal or mediastinal presentation and an adequate biopsy with the characteristic HRS cell morphology and immunophenotype within a polymorphous inflammatory infiltrate [1,3]. CHL most frequently involves the supradiaphragmatic lymph nodes, and fewer than 5% of patients present with exclusive infradiaphragmatic involvement of the abdominopelvic lymph nodes and/or spleen [1]. The main differential diagnoses are mediastinal gray zone lymphoma, nodular lymphocyte-predominant B-cell lymphoma, T-cell/histiocyte-rich large B-cell lymphoma, angioimmunoblastic T-cell lymphoma, peripheral/nodal T-follicular helper (TFH) T-cell lymphomas with HRS-like cells, anaplastic large cell lymphoma, and EBV-positive DLBCL, which are distinguished primarily by a preserved B-cell program, CD30/CD15/EBV status, and clonality studies [1,2].

References

  1. Borges AM, Delabi J, Viel P, d'Amore ESG, Hebeda KM, Diepstra A, Naresh KN, Garcia JF, Tamaru J, Laskar S, Fromm J, Anagnostopoulos I, Nicolae A, Steidl C, Borchmann P, Küppers R. Classic Hodgkin Lymphoma. In: WHO Classification of Tumours Editorial Board. Haematolymphoid tumours [Internet]. Lyon (France): International Agency for Research on Cancer; 2024 [cited 2026 Nov 01]. (WHO classification of tumours series, 5th ed.; vol. 11). Available from: https://tumourclassification.iarc.who.int/chapters/63.
  2. Brousset P, Ansell SM, LaCasce A, Smith LB, Syrykh C, Tousseyn TA, Venkataraman G. Classic Hodgkin Lymphoma. In: Arber DA, Borowitz MJ, Cook JR, de Leval L, Goodlad JR, Hasserjian RP, King RL, Kvasnicka HM, Orazi A, editors. The International Consensus Classification of Myeloid and Lymphoid Neoplasms. 1st ed. Philadelphia (PA): Lippincott Williams & Wilkins; 2025. p. 931-958.
  3. Patel KK, Moskowitz AJ. Classic Hodgkin Lymphoma: A Review. JAMA. 2026 Sep 8;336(10):868-881. doi: 10.1001/jama.2026.13402. PMID: 42545803.
  4. Rengstl B, Newrzela S, Heinrich T, Weiser C, Thalheimer FB, Schmid F, Warner K, Hartmann S, Schroeder T, Küppers R, Rieger MA, Hansmann ML. Incomplete cytokinesis and re-fusion of small mononucleated Hodgkin cells lead to giant multinucleated Reed-Sternberg cells. Proc Natl Acad Sci U S A. 2013 Dec 17;110(51):20729-34. doi: 10.1073/pnas.1312509110. Epub 2013 Dec 3. PMID: 24302766; PMCID: PMC3870723.