Histologic Types of Hodgkin Lymphoma

The Reed-Sternberg (RS) Cell - The Hallmark

Classic binucleate RS cell with large inclusion-like nucleoli - the "owl-eye" appearance (Robbins Pathology)

Category 1: Classic Hodgkin Lymphoma (cHL)

1. Nodular Sclerosis (NS-HL)

• Lacunar cells - the characteristic RS variant. These have a single multilobate nucleus with multiple small nucleoli and abundant pale cytoplasm. In formalin-fixed tissue, the cytoplasm retracts, leaving the nucleus sitting in an empty "lacune" (space).
• Broad bands of collagen that divide the lymphoid tissue into circumscribed cellular nodules - this is what gives the subtype its name.
• Background: lymphocytes, eosinophils, macrophages.
• Grading: Grade 2 (syncytial variant) when sheets of neoplastic cells occupy ≥25% of nodules, often associated with necrosis.

Lacunar cell in nodular sclerosis HL (Robbins Pathology, Fig. 10.24)

Low-power view: broad collagen bands creating discrete lymphoid nodules - the hallmark of nodular sclerosis (Robbins Pathology, Fig. 10.25)

2. Mixed Cellularity (MC-HL)

• Classic RS cells are plentiful - this is the subtype where you see the most "textbook" owl-eye RS cells.
• Diffuse polymorphic infiltrate: small lymphocytes, eosinophils, plasma cells, histiocytes, and RS cells.
• No collagen bands (unlike NS).
• Necrosis and disorderly fibrosis may be present.
• More likely to present with B symptoms and systemic manifestations than NS.

Mixed cellularity HL: classic RS cell with owl-eye nucleoli surrounded by a mixed inflammatory infiltrate (Robbins Pathology, Fig. 10.26)

3. Lymphocyte-Rich (LR-HL)

• Diagnostic RS cells with classic cHL immunophenotype (CD15+, CD30+).
• Background dominated by lymphocytes; eosinophils and plasma cells are scarce.
• Defined by the tissue reaction (lymphocyte predominance) but RS cells have classic cHL immunophenotype - distinguishing this from NLPHL is important and requires immunohistochemistry.

4. Lymphocyte Depletion (LD-HL)

• Neoplastic cells predominate; lymphocytes are relatively diminished (the opposite of lymphocyte-rich).
• Two patterns: diffuse fibrosis (paucicellular, hypocellular stroma with fibrosis) or reticular pattern (sheets of pleomorphic RS cells and variants).
• Normocytic anemia in ~50% of cases.
• BM involvement is common; lymphocytosis and thrombocytosis (seen in other HL subtypes) are usually absent.

Category 2: Nodular Lymphocyte-Predominant HL (NLPHL)

• Architecture effaced by a nodular infiltrate of small B cells with an associated follicular dendritic network.
• The neoplastic cells are L&H (lymphocytic and histiocytic) cells, also called "popcorn cells" - large cells with delicate, multilobed nuclei with vesicular chromatin resembling popped popcorn. Nucleoli are less prominent than in classic RS cells.
• Classic RS cells are rare.
• Background: predominantly small B cells; CD3+/CD57+ T cells form rosettes around L&H cells (diagnostically helpful).
• Six immunoarchitectural patterns have been recognized.

Summary Comparison Table

Key Pathogenetic Points

• All HL subtypes originate from germinal center B cells (proven by identical IgH gene rearrangements with somatic hypermutation in single microdissected RS cells).
• Classic cHL RS cells escape immune surveillance by: (1) losing β2-microglobulin/MHC-I expression, and (2) overexpressing PD-L1/PD-L2 - the basis for the dramatic response to anti-PD-1 therapy (e.g., pembrolizumab, nivolumab).
• RS cells secrete IL-5 (eosinophil recruitment), TGF-β (fibrosis), and IL-13 (autocrine growth).