Hodgkin lymphoma (HL) is a monoclonal lymphoid neoplasm (in most instances derived from B cells) composed of mononuclear Hodgkin cells and multinucleated Reed-Sternberg (RS) cells residing in a reactive infiltrate containing a variable mixture of nonneoplastic small lymphocytes, eosinophils, neutrophils, histiocytes, plasma cells, fibroblasts, and collagen. There are two histologic types of HL: the nodular lymphocyte predominant HL (NLPHL) and the “classic” HL (CHL). Within CHL, four subtypes have been distinguished, based on the characteristics of the reactive infiltrate and to a certain extent on the morphology of the RS cells: nodular sclerosis CHL, lymphocyte-rich, CHL, mixed cellularity CHL, and lymphocyte-depleted CHL.¹ The most common type of HL to affect the mediastinum is nodular sclerosis CHL (NSCHL). NLPHL does not involve the mediastinum primarily, and fewer than 15% of cases have secondary mediastinal involvement.²

Epstein-Barr virus (EBV) is expressed in about 20% to 25% of NSCHL.^3,4 The incidence of EBV association in NSCHL is generally lower than in other subtypes and varies geographically.^3,5

HL is an uncommon malignancy, with 7,000 to 7,500 new cases diagnosed annually in the United States.⁶ NSCHL is the most frequent subtype, representing ˜70% of all CHL.^7,8 The disease primarily affects young adults.^8,9 In contrast to other forms of CHL and NLPHL, NSCHL demonstrates a female predominance.⁸

In 80% of patients with NSCHL, the mediastinum is involved, and 50% of patients present with bulky disease.⁸ NSCHL of the anterior mediastinum often originates from the thymus or mediastinal lymph nodes, or both may be involved.^10,11 Some patients have simultaneous involvement of supraclavicular or lower cervical lymph nodes. Involvement of extralymphatic organs or bone marrow is not common. The patients often present with symptoms associated with the presence of a large anterior mediastinal mass, such as chest discomfort or dyspnea. Occasionally, asymptomatic patients may be diagnosed by finding an incidental mass lesion on imaging studies performed for other indications. B symptoms occur in ˜40% of all patients.⁶

Mediastinal HL may be restricted to the mediastinum (single lymph node region or lymphoid structure) (stage I) or may involve two or more nodal groups on the same side of the diaphragm (stage II) or nodal groups on both sides of the diaphragm, and rarely the spleen (stage III) or extranodal site(s) such as the liver or bone marrow (designated E if there is, involvement of a single extranodal site, or contiguous or proximal to known nodal site of disease) (stage IV).

The thymus or mediastinal lymph nodes involved by NSCHL show multiple firm grayish-white nodules, with or without visible fibrous bands. The thymus commonly exhibits interspersed cystic spaces.¹⁰

Classical diagnostic RS cells are large with abundant, slightly basophilic cytoplasm and have at least two nuclear lobes or nuclei. The nuclei are large with prominent irregular nuclear membrane, pale chromatin, and usually one prominent eosinophilic nucleolus, with perinuclear clearing, resembling a viral inclusion. Diagnostic RS cells must have at least two nucleoli in two separate lobes. Mononuclear cells are termed Hodgkin cells. NSCHL differs from other subtypes in terms of the growth pattern and the characteristics of the neoplastic cells (Fig. 130.1). In NSCHL, the characteristic RS cell is termed a lacunar cell (Fig. 130.2), because the cytoplasmic membrane is often retracted in formalin-fixed tissues. Compared
with classical RS cells, lacunar cells have smaller nuclei, less prominent nucleoli, and more abundant cytoplasm.⁸ Classic RS cells usually are rare in NSCHL. Lacunar cells are found in cellular nodules, containing variable numbers of small lymphocytes. Neutrophils and eosinophils may be abundant, sometimes forming microabscesses within the nodules. The nodules are surrounded by dense collagen bands poor in fibroblasts. The fibrosis often begins in the lymph node capsule, with invagination into the lymph node along vascular septa.⁸ The reactive background contains variable numbers of B and T lymphocytes, the latter forming inflammatory infiltrate occasional rosettes around individual tumor cells. Some morphologic variations of NSCHL exist. The “syncytial variant” of NSCHL is characterized by cohesive sheets of lacunar cells within the nodules.^12,13 In the “cellular phase” of NSCHL, a nodular growth pattern is present, but concentric fibrous bands are not formed.