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2013 — November Case of the Month

Posted November 19, 2013

CLINICAL SUMMARY: Lymph node, left axilla  

CAP Foundation Online Case of the Month

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After reading the summary, try answering the three related multiple-choice questions below.

A 32-year-old man with no significant past medical history presented with a left axillary mass. He also noted generalized itching for the past two weeks and drenching night sweats. He had no significant weight loss or fevers. An excisional biopsy revealed an encapsulated specimen with a uniformly tan and vaguely lobular cut surface. Immunoperoxidase stains reveal that the large atypical cells are strongly positive for CD30 and variably positive for CD15 (subset); these cells are also positive for EBV-encoded RNA hybridization studies (EBER). CD20 and CD45 (LCA) highlight most of the background small lymphocytes, but are negative within the large atypical cells. CD3 shows scattered small lymphocytes in between the nodules.

Archive Case and Diagnosis:
This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2010, case 37, and is a nodular sclerosis classical Hodgkin lymphoma.

Criteria for Diagnosis and Comments:
The H&E slides of the resected lymph node reveal a thick capsule and fibro-collagenous sclerotic bands separating the lymph node into variably sized nodules. The nodules are composed of small lymphocytes with scattered eosinophils and plasma cells and interspersed large atypical cells, some of which are bi-nucleated. The nuclei of these large cells have vesicular chromatin and very prominent eosinophilic nucleoli. Peri-nuclear and peri-nucleolar clearing can be seen in some cells.

The correct diagnosis is nodular sclerosis classical Hodgkin lymphoma (NSCHL). Patients with NSCHL typically present with painless peripheral lymphadenopathy in one or two areas that are typically contiguous. Mediastinal involvement is frequently seen. Forty percent of patients will present with B symptoms, namely fever, night sweats, and weight loss. NSCHL comprises 70% of all newly diagnosed classical Hodgkin lymphomas. While Hodgkin lymphoma overall has a bimodal distribution of age in the western world, NSCHL is seen mostly in ages 15-34 and is seen equally among both sexes. Grossly, the lymph nodes are frequently enlarged and feel firm (“rubbery”); the cut surface has a tan “fish flesh” appearance which may show grossly visible nodules. The histologic appearance was described above.

The neoplastic cells are the Reed-Sternberg (RS) cells, which are derived from B-cells. RS cells are large bi-nucleate cells with abundant basophilic cytoplasm. The nuclei have slightly irregular membranes and prominent eosinophilic nucleoli. Often a peri-nuclear and peri-nucleolar halo is seen. RS cells (an eponymous term best reserved for bi-nucleate cells) and Hodgkin cells (best used to describe the mono-nuclear variants) and other variants (multinucleated or atypical, lacking one or more of the cytological features described above) comprise only 0.1-10% of the infiltrate. Even though Hodgkin lymphoma is a clonal B-cell process, clonality studies are frequently negative because these neoplastic cells are rare. A background of eosinophils, histiocytes, small lymphocytes, and neutrophils is typically seen. It is thought that eosinophils elaborate cytokines, that evoke fibrosis and hence eosinophils are often prominent at the leading edges of fibrosis and the fibro-collagenous bands.

The immunophenotype of NSCHL is the same as that of other sub-types of classical Hodgkin lymphoma. RS cells are CD30 and CD15 positive, CD45 and CD79a negative. Variable CD20 staining of RS cells is seen in 30-40% of cases of CHL. In addition, CD15 may be absent in a subset of RS cells. In these instances,
PAX-5 is a useful immunostain adjunct since it marks the RS cells weakly in >95% of cases. In cases of CHL associated with immunosuppression (such as post-transplant or in HIV patients), EBV is often present and EBV stains (EBER or LMP-1) are frequently positive within the EBV infected RS cells.

As opposed to classical Hodgkin lymphoma, which is a B-cell malignancy, anaplastic large cell lymphoma (ALCL) is a T-cell lymphoma and can show a broad range of morphology. The neoplastic cells in ALCL may have large, irregularly shaped nuclei, which may be mistaken for RS cells when they are multinucleated. Unlike RS cells, the chromatin of these cells is clumpy and the nucleoli are small and basophilic. A “Hodgkin-like” growth pattern, similar to NSCHL, may be seen in 3% of ALCL. In addition, most cases are CD30-positive and hence can present a diagnostic challenge in a subset of cases. However, being a T-cell lymphoma, the neoplastic cells will mark with T-cell markers, and will be negative for CD15 and PAX-5. In addition, EBER or LMP-1 will be negative.

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a B-cell lymphoma biologically similar to large B-cell lymphomas, with much sparser neoplastic cells making it morphologically similar to classical Hodgkin lymphoma. NLPHL is characterized by a nodular proliferation of background small lymphocytes in which the neoplastic cells, called “popcorn” or lymphocyte predominant (LP cell; previously termed L&H cells) are scattered. These cells somewhat resemble RS cells with their multilobated nuclei; however, unlike RS cells, the nuclei contain multiple small nucleoli. Also unlike RS cells, the lymphocyte predominant cells stain positive for CD45, and the B-cell markers (CD20, CD79a). They lack CD15 and CD30 staining.

Primary mediastinal large B-cell lymphoma (PMBL) occurs in young adults (females>males) and tends to present with a mediastinal mass. Large cells with multilobated nuclei that resemble Reed-Sternberg cells are seen. The neoplastic cells in PMBL are commonly CD30 positive. In needle biopsies, where the tissue is sparse and the number of neoplastic cells is decreased, the CD30-positive cells may cause diagnostic confusion. However, these cells stain weakly for CD30 and only occasionally for CD15. In addition, the fibrosis and sclerosis in PMBL encircles individual cells. Despite this, there are cases of PMBL with overlapping features of NSCHL that cannot be unequivocally distinguished from each other. Such ‘grey zone’ lymphomas have been categorized as ‘B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma’. (2008 WHO classification scheme).

Lastly, in a few instances of florid reactive follicular hyperplasia, especially those with a viral infection or EBV-driven proliferation, the follicles may have a nodular architecture and there may be B-immunoblasts typically in interfollicular or mantle areas. These large immunoblasts have prominent nucleoli and even though they are seldom as large as RS cells, they are positive for CD30 and thus can frequently be confused with classical Hodgkin lymphoma. However, these cells will be brightly positive for LCA (CD45) and B-cell markers, CD20, CD79a, and PAX-5, and will be negative for CD15. Oct-2 and Bob1 are positive in B-cells and B-cell lymphomas but not classical Hodgkin lymphoma; hence these markers can help distinguishing these lesions from classical Hodgkin lymphoma.

In summary, NSCHL is a B-cell neoplasm with characteristic RS cells. Diagnosing NSCHL is straightforward in most instances based on morphology and immunophenotype. Additional adjunctive stains, as described above should be performed if there are overlapping features with another disease entity. There are rare large B-cell lymphoid proliferations that cannot be completely distinguished from NSCHL and these ‘grey zone’ lymphomas should be described as such (intermediate type lymphomas).

Supplementary Questions:

Question Diagnostic Set
1. Classical Hodgkin lymphoma differs from nodular lymphocyte predominant Hodgkin lymphoma by which of the following feature(s)? A. Multilobated neoplastic cells
B. Neoplastic cells stain positive for CD30 and CD15
C. Nodular growth pattern
D. Sparse neoplastic cells in a background of mixed inflammatory cells
2. Nodular sclerosis classical Hodgkin lymphoma (NSCHL) can be distinguished from mediastinal large B-cell lymphoma by which of the following features? A. NSCHL is CD30 immunostain positive.
B. NSCHL is seldom seen in young patients, whereas PMBL is mostly seen in younger patients.
C. Only PMBL arises in a mediastinal location
D. Sclerotic bands in NSCHL separate nodules, while in PMBL they tend to encircle individual large cells
3. Immunoglobulin Heavy Chain (IGH) gene rearrangement studies in NSCHL are frequently negative. This is because: A. NSCHL is not a B-cell malignancy and only B-cell lymphomas are positive for IGH gene rearrangement studies.
B. NSCHL is not a clonal disorder, it is an inflammatory disease.
C. Neoplastic cells typically make up less than 1% of the sampled specimen.
D. The IGH gene locus is lost in NSCHL.


  1. Pileri, et al. Hodgkin’s lymphoma: the pathologist’s viewpoint. J Clin Pathol. 2002;55:162-176.
  2. Schmid, et al. Expression of B-cell antigens by Hodgkin’s and Reed-Sternberg cells. Am J Pathol. 1991; 139:701-707.
  3. Stein H, et al. Hodgkin and Sternberg-Reed cell antigen(s) detected by an antiserum to a cell line (L428) derived from Hodgkin’s disease. Int J Cancer. 1981;28:425-429.
  4. Stein, et al. Down-regulation of BOB.1/OBF.1 and Oct2 in classical Hodgkin disease but not in lymphocyte predominant Hodgkin disease correlates with immunoglobulin transcription. Blood. 2001;97:496-501.
  5. Swerdlow SH, Campo E., Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. International Agency for Research on Cancer; Lyon. 2008.

Rebecca Pohlmann, MD
Beth Israel Deaconess Medical Center
Boston, MA

Rajan Dewar, MD, PhD
Surgical Pathology Committee
Beth Israel Deaconess Medical Center and Harvard Medical School
Boston, MA