The diagnosis of HD is based on the recognition of tumor giant cells (Reed-Sternberg cells) surrounded by benign-appearing host inflammatory cells composed singly or in a combination of lymphocytes, histiocytes, and granulocytes, including eosinophils, plasma cells, and fibroblasts. For purposes of diagnosis, tumor cells must have two or more nuclei or nuclear lobes and two or more large, inclusion-like nucleoli. Important exceptions to this rule apply to the categories of nodular sclerosing type and nodular variant lymphocyte predominance type in which peculiar variant forms of the tumor giant cells can be used to establish the diagnosis (lacunar cell variants). The histologic variants in HD are described in Table 15-1.

A revised European-American Classification of Lymphoid Neoplasms (REAL classification) has been proposed. In the REAL classification, HD is subdivided into

Table 15-1. Histopathologic Variants of Hodgkin Disease

Nodular lymphocyte predominance, with or without diffuse areas (LP)

A mixture of lymphocytes and histiocytes, particularly epithelioid histiocytes, is characteristic of nodular lymphocyte-predominant HD. Epithelioid histiocytes are preferentially found in the outer rim of nodular infiltrates. They are arranged in small groups or clusters, and well-formed granulomas may be present in rare cases. Eosinophils and neutrophils are rare. Plasma cells are not common and are seen only between follicles. The neoplastic cells of nodular lymphocyte predominance are the lymphocytic and histiocytic (L&H) cells (popcorn cells) usually found in and around the nodules. In diffuse areas, the L&H cells are still often arranged in a vaguely nodular pattern. Characteristically, L&H cells resemble centroblasts but are larger and have lobulated nuclei and small to moderate-sized basophilic nucleoli, often present and adjacent to the nuclear membrane. The cytoplasm is broad and only slightly basophilic. Ultrastructural studies demonstrate that L&H cells have the appearance of centroblasts of germinal centers. In addition, follicular dendritic cells characteristic of the B-cell follicle can be found in the vicinity of the L&H cells. Classic Hodgkin and Reed-Sternberg cells are few in number or completely lacking. In some cases, L&H cells may resemble lacunar cells because both cell types show irregularly shaped or lobulated nuclei, small nucleoli, and broad pale to slightly basophilic cytoplasm.

Nodular sclerosis (NS)

The nodular sclerosis subtype is characterized by collagenous bands and lacunar cells. The presence of one or more sclerotic bands is the defining feature. These bands usually radiate from a thickened lymph node capsule often following the course of a penetrating artery. These bands are composed of mature, laminated, relatively acellular collagen. They are birefringent in polarized light. In most cases, several broad collagenous bands can be identified, or fibrosis can be so extensive that isolated nodules of lymphoid tissue remain.

The collagenous bands of nodular sclerosis enclose nodules of lymphoid tissue containing variable numbers of Hodgkin cells and reactive infiltrates. Lacunar cells are the most common type of Hodgkin cells present and may be found in large numbers or in sheets. They tend to aggregate at the center of nodules, sometimes forming a rim around central areas of necrosis. Diagnostic Reed-Sternberg cells are usually not easily identified and may not be found in small biopsy specimens. Eosinophils and neutrophils are often numerous but histiocytes and plasma cells are usually less conspicuous.

Mixed cellularity (MC)

This intermediate subtype falls between lymphocyte-rich classical HD and lymphocyte depletion. The capsule is usually intact and of normal thickness. A vague nodularity may be present at low magnification, but the presence of any definite fibrous bands would warrant classification as nodular sclerosis rather than mixed cellularity. At high magnification, a heterogeneous mixture of Hodgkin cells, small lymphocytes, eosinophils, neutrophils, epithelioid and nonepithelioid cells, histiocytes, plasma cells, and fibroblasts is present. Diagnostic Reed-Sternberg cells and mononuclear variants are usually easy to find. Small foci of necrosis may be present, but the extent is much less than that seen in nodular sclerosis.

Table 15-1. (Continued)

Lymphocyte depletion (LD)

Lymphocyte-depletion HD encompasses two variants: diffuse fibrosis and reticular. The most characteristic features are a marked degree of reticulin fibrosis surrounding single cells along with lymphocyte depletion. In contrast to nodular sclerosis, this subtype is not characterized by the presence of thick fibrous bands, and the fibrosis envelops individual cells, not nodules of cells. Hodgkin cells are usually easily identified, but increased numbers of Hodgkin cells are not essential to the diagnosis. In the reticular variant, sheets of Hodgkin cells, often showing pleomorphic features, are found.

Lymphocyte-rich classical HD, nodular or diffuse

Many cases of lymphocyte-rich classical HD have a close resemblance to mixed cellularity HD, with a diffuse or vaguely nodular low-magnification appearance. Hodgkin and Reed-Sternberg cells are relatively rare, and the background is dominated by small mature lymphocytes. Eosinophils and neutrophils are usually restricted to blood vessels. Reed-Sternberg cells and variants are not easy to find but when encountered have identical features to the Hodgkin cells of mixed cellularity. Some cases of lymphocyte-rich HD may show a distinctly nodular appearance that may closely mimic nodular lymphocyte predominance HD and often contain relatively small germinal centers, with Hodgkin and Reed-Sternberg cells present in and near the mantle zone, a pattern that has been called follicular HD.

Unclassified Cases (UC)

UC is defined as histopathology that does not fit into a definite or provisional category (they may be T cell, B cell, or undefined; they may be borderline between HD and NHL).

lymphocyte-predominant, nodular (with or without diffuse areas), and the other forms of classical HD: nodular sclerosis, mixed cellularity, lymphocyte-depletion types, and lymphocyte-rich classic disease. Table 15-2 compares the REAL and Rye classifications. Lymphocyte-rich classic HD is a new subtype of HD (World Health Organization) in which the HD blast immunophenotypically resembles classic HD. A histopathologic classification depicting frequency by age is shown on Table 15-3. With modern treatment, the prognostic significance of these subtypes has diminished although the presenting characteristics and natural history remain significant, particularly for the nodular subtype of lymphocyte-predominant HD (see REAL classification in Table 15-2).

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