GUEST EDITORS

Syed A. Abutalib, MD

L. Jeffrey Medeiros, MD

Dr. Abutalib is Assistant Director, Hematology and Hematopoietic Cell Transplantation Direc-tor, Hematopoietic Cell Transplant Apheresis Service, Cancer Treatment Centers of Ameri-ca, Zion, Illinois, Editor-in-Chief, Advances in Cell & Gene Therapy. Dr. Medeiros is Professor and Chair, Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston.

The ASCO Post is pleased to present Hematology Expert Review, an ongoing feature that quizzes readers on issues in hematology. In this installment, Syed Ali Abutalib, MD, and L. Jeffrey Medeiros, MD, explore the updated World Health Organization (WHO) classification of hematopoietic and lymphoid tissue malignancies, focusing on the nodular sclerosis type of classic Hodgkin lymphoma. For each quiz question that follows, select the one best answer. The correct answers and accompanying discussions appear below.

Question 1

Which of the following statements about nodular sclerosis classic Hodgkin lymphoma is correct?

A. Nodular sclerosis classic Hodgkin lymphoma has a male predominance.
B. Epstein-Barr virus is positive in more than 95% of cases of nodular sclerosis classic Hodgkin lymphoma.
C. Nodular sclerosis classic Hodgkin lymphoma is derived from B cells at the germinal center stage of differentiation.
D. Nodular sclerosis classic Hodgkin lymphoma accounts for less than 40% of all cases of classic Hodgkin lymphoma in the United States and Europe.

Question 2

Which of the following statements about morphology in nodular sclerosis classic Hodgkin lymphoma is correct?

A. Nodular sclerosis classic Hodgkin lymphoma is characterized by a diffuse growth pattern and frequent eosinophilia.
B. Nodular sclerosis classic Hodgkin lymphoma is characterized by Hodgkin and Reed-Sternberg cells with a lacunar-type -morphology.
C. The presence of central areas of necrosis argues against the diagnosis of nodular sclerosis classic Hodgkin lymphoma.
D. Hodgkin and Reed-Sternberg cells in nodular sclerosis classic Hodgkin lymphoma tend to have less-segmented nuclei with a larger amount of cytoplasm than do Hodgkin and Reed-Sternberg cells in other subtypes of classic Hodgkin lymphoma.

Question 3

Which of the following statements about immune histology in nodular sclerosis classic Hodgkin lymphoma is correct?

A. CD30 is expressed in nearly all cases.
B. PAX5 is weakly positive in nearly all cases.
C. CD15 may be negative in 15% to 25% of cases, and CD45 is negative in nearly all cases.
D. All of the above

Question 4

Approximately what proportion of nodular sclerosis classic Hodgkin lymphoma cases aberrantly express T-cell antigen(s)?

A. Less than 10%
B. 40% to 50%
C. 80% to 90%
D. None of the above

Answers to Hematology Expert Review Questions

Question 1

Which of the following statements about nodular sclerosis classic Hodgkin lymphoma is correct?

Correct answer: C. Nodular sclerosis classic Hodgkin lymphoma is derived from B cells at the germinal center stage of differentiation.

Expert Perspective

Classic Hodgkin lymphoma is a monoclonal lymphoid neoplasm derived from B cells, composed of mononuclear Hodgkin cells and multinucleated Reed-Sternberg cells in a background containing a variable mixture of non-neoplastic reactive immune cells, including small lymphocytes, eosinophils, neutrophils, histiocytes, and plasma cells.^1,2 Approximately 90% of cases are classic Hodgkin lymphoma, and approximately 10% of cases are nodular lymphocyte predominant Hodgkin lymphoma.

Four histologic types are distinguished in classic Hodgkin lymphoma: nodular sclerosis, lymphocyte-rich classic, mixed cellularity, and lymphocyte-depleted. There is a male predominance for most classic Hodgkin lymphoma types, with the exception of nodular lymphocyte predominant Hodgkin lymphoma, in which the incidence is approximately 1:1 male to female.

Epstein-Barr virus (EBV) is found in only a proportion of nodular sclerosis classic Hodgkin lymphoma cases (about 10% to 25%). In more than 98% of cases, the neoplastic cells are derived from B cells at the germinal center stage of differentiation and contain clonal immunoglobulin gene rearrangements. Approximately 60% of cases, most with nodular sclerosis classic Hodgkin lymphoma, have mediastinal involvement at diagnosis.^1,2 Nodular sclerosis classic Hodgkin lymphoma accounts for approximately 70% of all classic Hodgkin lymphoma cases in Europe and the -United States.^1,2

Question 2

Which of the following statements about morphology in nodular sclerosis classic Hodgkin lymphoma is correct?

Correct answer: B. Nodular sclerosis classic Hodgkin lymphoma is characterized by Hodgkin and Reed-Sternberg cells with a lacunar-type -morphology.

Expert Perspective

Nodular sclerosis classic Hodgkin lymphoma is a type of classic Hodgkin lymphoma characterized by collagen bands that surround at least one nodule (nodular sclerosis) and by Hodgkin and Reed-Sternberg cells with a lacunar-type morphology (Figure 1A).^1,2 The cut surface of lymph nodes typically show a nodular configuration, with cellular nodules surrounded by dense, well-formed collagenous bands. With higher-grade lesions (grade 2), central areas of necrosis may be evident.²

Following therapy, a persistent mass may be present, with diffuse fibrotic replacement and no viable involvement by classic Hodgkin lymphoma. Such lesions may persist radiologically, but they should be negative on positron-emission tomography scan, confirming the absence of active disease. The Hodgkin and Reed-Sternberg cells tend to have more-segmented nuclei with smaller lobes, less-prominent nucleoli, and a larger amount of cytoplasm than do Hodgkin and Reed-Sternberg cells in other types of classic Hodgkin lymphoma (Figure 1B). In formalin-fixed tissues, the cytoplasm of the Hodgkin and Reed-Sternberg cells frequently shows retraction of the cytoplasmic membrane, so the cells seem to be sitting in lacunae.^1,2 Therefore, these cells have been designated lacunar cells.^1,2

Question 3

Which of the following statements about immune histology in nodular sclerosis classic Hodgkin lymphoma is correct?

Correct answer: D. All of the above.

Expert Perspective

CD30 is expressed in nearly all cases, but CD15 may be negative in 15% to 25% of cases. PAX5 and facsin is weakly positive in nearly all cases (Figures 2A and 2B).^1-3 CD45 is negative in nearly all cases.³ CD20 may be variably expressed, but it is usually weak and only on a subset of the neoplastic cells. CD79a is positive in approximately 10% of cases.^1,2

Question 4

Approximately what proportion of nodular sclerosis classic Hodgkin lymphoma cases aberrantly express T-cell antigen(s)?

Correct answer: A. Less than 10%.

Expert Perspective

Approximately 5% of nodular sclerosis classic Hodgkin lymphoma cases aberrantly express T-cell antigens. The T-cell antigens most often expressed are CD4 and CD2, and less commonly CD3; positive cases may be associated with shorter overall and event-free survival compared with classic Hodgkin lymphoma cases negative for T-cell antigens.⁴ Nearly all (> 90%) cases of classic Hodgkin lymphoma with aberrant T-cell antigen expression are positive for the B-cell marker PAX5. The detection of EBV-encoded small RNA or LMP1 also favors classic Hodgkin lymphoma.

Standard gene-rearrangement studies of classic Hodgkin lymphoma using polymerase chain reaction (PCR) methods are usually not helpful, since there are often too few neoplastic cells. However, single-cell PCR studies have shown that the -Hodgkin and Reed-Sternberg cells carry clonal immunoglobulin gene rearrangements and are negative for clonal T-cell receptor gene rearrangements.

The differential diagnosis of classic Hodgkin lymphoma with aberrant T-cell antigen expression includes T-cell lymphomas, such as ALK-negative anaplastic large cell lymphoma and peripheral T-cell lymphoma. Additionally, some T-cell lymphomas express CD30 and CD15, making their distinction from classic Hodgkin lymphoma even more difficult.⁵ Another difficult differential diagnosis is with diffuse large B-cell lymphoma, which displays anaplastic morphology and expresses CD30. ■

DISCLOSURE: Dr. Abutalib is an advisor for AstraZeneca and has served on the advisory board of Jazz Pharmaceuticals. Dr. Medeiros reported no conflicts of interest.

REFERENCES

1. Stein H, Pileri SA, Weiss LM, et al: Hodgkin lymphomas: Introduction, in Swerdlow SH, Campo E, Harris NL et al (eds.): WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, pp 424-430. Lyon, France, International Agency for Research in Cancer, 2017.

2. Stein H, Pileri SA, Maclennan KA, et al: Classic Hodgkin lymphoma, in Swerdlow SH, Campo E, Harris NL et al (eds.): WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, pp 435-442. Lyon, France, International Agency for Research in Cancer, 2017.

3. Naeim F, Rao PN, Song SX, et al: Classic Hodgkin lymphomas, in Atlas of Hematopathology, pp 601-612. New York, Elsevier, 2013.

4. Venkataraman G, Song JY, Tzankov A, et al: Aberrant T-cell antigen expression in classic Hodgkin lymphoma is associated with decreased event-free survival and overall survival. Blood 121:1795-1804, 2013.

5. Barry TS, Jaffe ES, Sorbara L, et al: Peripheral T-cell lymphomas expressing CD30 and CD15. Am J Surg Pathol 27:1513-1522, 2003.