Less than 1% of cases of classical Hodgkin lymphoma (CHL) fall into this category.  This variant is manifested by numerous Hodgkin’s/ Reed-Sternberg cells without a significant reactive inflammatory infiltrate.  These cases can easily be mistaken for other types of malignancy or anapestic large cell lymphoma.  Immunophenotyping is critical.  EBV infection is present in >90% of cases,  And is more common in HIV-positive individuals, older adults, and third world countries.  Co-expression of CD30 and PAX-5 is helpful to differentiate from a aplastic large cell lymphoma (ALCL).

 

Characteristic Immunohistochemical Features

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References

This is an uncommon classical Hodgkin lymphoma variant (5% of CHL), which is characterized by a predominant reactive lymphocyte infiltrate without significant histiocytes, plasma cells, and eosinophils that are characteristic of the mixed-cellularity variant.  The difficult differential diagnosis is separating this entity from nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) as both usually have a nodular pattern.  Prior to good immunohistochemical characterization many cases of lymphocyte-rich and NLPHL were misclassified.  EBV infection is present in approximately 40% of cases.  The immunophenotype of lymphocyte-rich Hodgkin lymphoma is the same is other classical Hodgkin lymphomas.  

 

The immunophenotype combined with identification of Reed-Sternberg cells is the main way to differentiate from nodular lymphocyte predominant Hodgkin lymphoma.  CD21 (follicular dendritic marker) is helpful to highlight the nodules (which contain the neoplastic cells) and small/regressed germinal centers usually at the periphery of the nodules (do not contain the neoplastic cells).  Historically, 30% of cases were misclassified (NLPHL vs. LRCHL), and cannot be reliably differentiated without immunohistochemistry.

 

Characteristic Immunohistochemical Features

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References

The second most common Hodgkin lymphoma variant (20–25%), which is characterized by a heterogeneous population of inflammatory cells (T cells, eosinophils, histiocytes, and plasma cells) that are admixed with Hodgkin cells.  Fibrosis is not evident, and EBV infection is present in approximately 70-75% of cases.  The immunophenotype is the same as other classical Hodgkin lymphoma cases.  This is the default category when a case cannot be categorized as another subtype.

 

There may be some interstitial fibrosis, but there are no nodules or broad fibrosis and the capsule is not usually thickened. 

 

Characteristic Immunohistochemical Features

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References

The most common variant of classical Hodgkin’s lymphoma (65–70% of cases), which is characterized by fibrous collagen bands that divide the lymph node into at least one nodule (fibrosis can range from scant to abundant) and neoplastic Hodgkin cells and Reed-Sternberg (HRS) cells with lacunar morphology (formalin fixation artifact with retraction of the cytoplasm).  The lymph node capsule is usually thickened.

 

Syncytial variant – prominent aggregates of neoplastic Hodgkin cells.

 

The immunophenotype of nodular sclerosing variant is shared with the other variants of classical Hodgkin lymphoma (PAX-5+, CD15+, CD30+, and CD45-).  EBV infection is not common in this subtype (10-40%).

 

Characteristic Immunohistochemical Features

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References

NF-κB transcription factor is a common event, which may occur through EBV infection (hence some cases positive for EBV) or other mechanism.  It is thought this process results in survival of germinal center B-cells, which would otherwise undergo apoptosis.  Hodgkin lymphoma cells typically represent a small number within the lesional tissue.  Hodgkin cells secrete varying cytokines that recruit other inflammatory cells, which make up the characteristic milieu (histiocytes, plasma cells, T-cell, and eosinophils).

 

Reed-Sternberg (HRS) cells are defined by two separate nuclear lobes with large nucleoli.  Mononuclear neoplastic cells are referred to as Hodgkin cells.  There is often a spectrum in appearance of the neoplastic cells with some HRS types but they may a minority.  Granulomatous inflammation may be present in biopsy specimens, and it important not to dismiss the granulomatous inflammation as the primary pathology (especially in small biopsy samples).

• Nodular Sclerosing CHL (65-70%), EBV-
• Lymphocyte-Rich CHL (~5%), ~40% EBV+
• Mixed-Cellularity CHL (20-25%), 70% EBV+
• Lymphocyte-Depleted CHL (<1%), >90% EBV+

Characteristic Immunohistochemical Features:

CD30	Positive in the malignant cells in almost all cases.  Membrane staining with Golgi area positivity.
CD15	Positive in the malignant cells in a majority of cases (75-85%).  The staining pattern is similar to CD30.  It should be noted that there is a lot a variability lab to lab in the performance of the antibody.
CD45	Usually negative
PAX_5	Dim expression in the lymphoma cells in >90% of the cases.  Helpful in differentiating cases from anapestic large cell lymphoma, which may be CD45 negative.
CD20	Usually negative, but may have dim variable subset expression in up to 20% of cases.
CD79a	Rarely positive in the lymphoma cells.
MUM1	Usually positive and usually intense.
EBV	Variable
EMA	Rarely positive and usually weak if positive.
OCT-2	Negative in 90% of cases.
BOB.1	Negative in 90% of cases.
ALK	Negative.

References

Nodular Lymphocyte Predominate Hodgkin Lymphoma (NLPHL) epresents approximately 5-10% of Hodgkin lymphoma cases (predominately male, 30-50 y/o) and has slightly different appearing neoplastic cells (popcorn cells – folded/multilobuated usually with multiple nucleoli).  The cellular background is typically composed of small lymphocytes and histiocytes.  Some plasma cells may be present at the peripheral of the nodule.  Neutrophils and eosinophils are not typically present.  The immunophenotype of lymphocyte predominate (LP) cells in NLPHL  is different from classical Hodgkin lymphoma.  The LP  cells express CD20 and BCL 6, but are typically negative for CD30 and CD15.  Dim expression of CD30 can be seen.