A 48-year-old man complains of a growing tender right neck mass. The patient has no other significant clinical symptoms. At operation, the mass proves to be multiple lymph nodes, the largest of which measures 7.0 cm. Histologic sections show numerous large cells infiltrating lymph nodes. These cells are strongly positive for CD30, variably positive for CD15, dimly positive for PAX5, and negative for CD20 and CD45.
- Anaplastic large cell lymphoma
- Classical Hodgkin lymphoma
- Metastatic melanoma
- Nodular lymphocyte predominant Hodgkin lymphoma
- Peripheral T-cell lymphoma, NOS
Archive Case and Diagnosis
This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2014, case 08 and is a classical Hodgkin lymphoma.
Criteria for Diagnosis and Comments
The section consists of a lymph node partially effaced by a pleomorphic lymphoid population. Numerous interfollicular lymphocytes, histiocytes, plasma cells, and eosinophils are present. In addition, larger lymphoid cells with prominent nucleoli are readily identified. These show a morphologic spectrum, from smaller apoptotic "mummified" cells, to larger multilobated nuclei, to diagnostic Reed-Sternberg cells. These findings are essentially diagnostic of classical Hodgkin lymphoma (CHL). Depending on the slide received, variable amounts of fibrosis are present, but significant numbers of “lacunar cells” are not appreciated. This is most consistent with mixed cellularity CHL.
Hodgkin lymphoma is a morphologically diverse group of monoclonal lymphoproliferative disorders. Approximately 95% of Hodgkin lymphomas are CHL, which based on morphology, is divided into 4 subtypes: nodular sclerosis (~70%), mixed cellularity (20-25%), lymphocyte rich (~5%), and lymphocyte depleted (~1%). The remainder of Hodgkin lymphomas are classified as nodular lymphocyte predominant Hodgkin lymphoma (NLPHL).
All subtypes of CHL share some epidemiologic characteristics. In developed countries, a bimodal age curve is seen (~15-35 years of age and the elderly). Cervical lymph node involvement is common, as well as mediastinal, axillary, and para-aortic lymph nodes. Most patients present with localized disease. Primary extranodal disease and bone marrow involvement are rare. NLPHL also is common in younger patients (~30-50 years of age), and only rarely presents as primary extranodal disease.
Historically, the histologic subtypes were thought to have different prognoses. Nodular sclerosis had a better outcome than either mixed cellularity or lymphocyte-depleted cases. Although there is still some difference in clinical outcomes associated with the separate subtypes, many of these have disappeared with the introduction of modern chemo/radiation therapy. However, cases associated with HIV infection (commonly lymphocyte-depleted subtype) usually have a poorer prognosis.
Recently, the presence of increased macrophages and the overexpression of a macrophage gene expression signature have been found to impart a poor prognosis in multivariate analyses.
An association with Epstein-Barr virus (EBV) has long been known. However, the frequency of associated EBV varies greatly. The highest rate of EBV infection is seen in mixed cellularity CHL, immunodeficient patients, and those from developing countries (especially tropical regions, where up to 100% of cases are EBV positive).
Hodgkin lymphoma is derived from monoclonal B-cells in nearly all instances. Reports of T-cell antigen expression and T-cell receptor gene rearrangements have led some to believe that rare cases are derived from T-cells (~1-2%). However, most cases show some immunohistochemical evidence of B-cell derivation.
All subtypes share a distinctive immunophenotypic pattern, though some variation exists. Despite the lymphoid origin, most Reed-Sternberg/Hodgkin cells are negative for CD45/LCA. Essentially all cases are positive for CD30, and most cases positive for CD15. Most are negative for CD20, though a minority of cases will be dimly positive in a percentage of Reed-Sternberg /Hodgkin cells. PAX5 is usually positive, though dim in intensity. Other B-cell markers, such as CD79a, are usually negative. EMA is usually negative, and ALK is always absent. The surrounding smaller lymphoid infiltrate is typically T-cell rich, with a minority of B-cells present. At present, flow cytometry does not play a major role in the diagnosis of Hodgkin lymphoma. However, Reed-Sternberg/Hodgkin cells can be characterized by sensitive flow cytometric gating strategies.
The nodular architecture provided by the residual germinal center formation may lead to a consideration of NLPHL. Given that some of the malignant cells in CHL are multilobated, they resemble popcorn cells of NLPHL. However, the mixed inflammatory infiltrate, relative predominance of Reed-Sternberg cells, and granulomatous inflammation are all inconsistent with NLPHL. In addition, the immunophenotypic pattern of CD45/CD20 negativity and CD30/CD15 positivity is most commonly seen in CHL, and is inconsistent with NLPHL.
Cytologic findings nearly indistinguishable from Reed-Sternberg cells have been increasingly observed in T-cell lymphomas, particularly peripheral T-cell lymphoma, NOS. CD30 positivity can occasionally be seen in these cases, and even CD15 positivity can rarely be observed. Given that CHL is usually CD20 negative and CHL can aberrantly express T-cell antigens, a misdiagnosis of T-cell lymphoma may occur. However, most CHL cases will be dimly positive for PAX5, a pan B-cell marker.
Metastatic melanoma can be considered, due to similar cytologic findings. These include dyshesive malignant cells, prominent nucleoli, and occasional multinucleation. However, the mixed inflammatory infiltrate and expected immunophenotype will help distinguish between the two.
The interfollicular pattern of neoplastic involvement resembles that seen in anaplastic large cell lymphoma (ALCL). Indeed, the morphologic spectrum of both CHL and ALCL are similar. If one relies solely on morphology and a limited immunohistochemistry panel, ALCL may be incorrectly diagnosed. Virtually all cases of ALCL are positive for CD30 and EMA. EMA positivity can rarely be seen in CHL. However, PAX5 helps distinguish between the two in most instances.
- Which of the following is most correct concerning classical Hodgkin lymphoma (CHL)?
- Aberrant T-cell antigen expression can be seen.
- EBV infection is most common in the nodular sclerosis subtype.
- Extra-axial lymph node involvement is common.
- Mixed cellularity CHL is most common in developed countries.
- The subtypes of CHL have significant differences in their clinical outcomes.
- Which of the following would best differentiate CHL from NLPHL?
- Age of patient
- CD45/CD20 negativity, and CD30/CD15 positivity in large lymphoid cells of CHL
- Extranodal location
- Nodular architecture
- Presence of Reed-Sternberg cells
- Although Reed-Sternberg cells can be characterized by sensitive flow cytometric studies, at present flow cytometry does not play a significant role in the diagnosis of CHL.
- Fromm JR, Kussick SJ, Wood BL. Identification and purification of classical Hodgkin cells from lymph nodes by flow cytometry and flow cytometric cell sorting. Am J Clin Pathol. 2006;126(5):764-780.
- Mani H, Jaffe ES. Hodgkin lymphoma: an update on its biology with new insights into classification. Clin Lymphoma Myelom. 2009;9(3):206-216.
- Steidl C, Lee T, Shah SP, et al. Tumor-associated macrophages and survival in classic Hodgkin's lymphoma. N Engl J Med. 2010;362:875-885.
- Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, Fr: IARC Press; 2008.
Brad Bryan, MD
Surgical Pathology Committee
Central Oregon Pathology Consultants
- Aberrant T-cell antigen expression can be seen. (a).
- CD45/CD20 negativity, and CD30/CD15 positivity in large lymphoid cells of CHL (b).
- True (a).