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1608 Part XI: Malignant Lymphoid Diseases Chapter 97: Hodgkin Lymphoma 1609

CLINICAL AND PATHOLOGIC LYMPHOCYTE-RICH SUBTYPE

CORRELATION The lymphocyte-rich subtype of cHL was introduced by the World
Health Organization classification in 1999 (see Table 97–1) following
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NODULAR LYMPHOCYTE PREDOMINANCE an expert pathology review of cases of NLPHL. The two subtypes dif-
fer subtly on morphologic grounds, but the major difference is that the
SUBTYPE Hodgkin and Reed-Sternberg cells in lymphocyte-rich cHL exhibit the
There is a strong correlation between age at onset, the anatomic extent classic CD30+ CD20− immunophenotype. The presenting features are
of disease and histologic subtype of Hodgkin lymphoma. Approxi- very similar although patients with the lymphocyte-rich subtype tend
mately 5 to 10 percent of patients present with NLPHL, which is con- to be older compared with NLPHL patients. A higher rate of multiple
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sidered to be a distinct subtype, discrete from cHL. 103,104 Progressive relapses and a more favorable prognosis upon relapse is characteristic
transformation of germinal centers may precede or follow NLPHL in of NLPHL.
other sites. The cellular composition is predominantly benign B lym-
phocytes with or without histiocytes. The characteristic multilobated,
CD20+ lymphocyte and histiocytic cells are relatively abundant (see ANATOMIC DISTRIBUTION OF DISEASE
Chap. 96, Fig. 96–40). Patients most commonly present with stage I In approximately 70 percent of patients, cHL presents in the cervical
disease (70 percent) in peripheral lymph node sites, particularly in the nodes; in 12 percent, in the axillary nodes; and in 9 percent, in the
axillae, and there is a 3 to 4:1 male predominance. 103,104 NLPHL may be inguinal nodes. A small minority of patients presents exclusively
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associated with diffuse large B-cell non-Hodgkin lymphoma as a com- with subdiaphragmatic disease. In an historical series of 285 consec-
posite tumor or a large cell lymphoma may develop at a later date. 105,106 utive, unselected, and untreated patients evaluated at Stanford Uni-
The large cell variant, T-cell–rich B-cell lymphoma, may be difficult to versity, involvement of abdominal lymph nodes and the spleen was
distinguish from NLPHL and may occur concurrently or subsequently documented in 272 upon laparotomy, a surgical diagnostic procedure
(Chap. 98). 107 in which the intraabdominal and pelvic lymph nodes are biopsied, the
spleen is removed and examined pathologically in thin slices, the liver
NODULAR SCLEROSIS SUBTYPE is biopsied by needle and wedge technique, and the marrow is biop-
cHL is characterized by Hodgkin and Reed-Sternberg cells that express sied. The frequency of splenic involvement at laparotomy in untreated
patients averaged 37 percent in 17 published series. Involvement of
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CD30 and CD15+ but usually not typical B-cell surface markers such as the spleen was strongly dependent on histologic subtype: it was involved
CD20 or CD79B. The nodular sclerosis subtype constitutes 40 to 70 per- in 60 percent of mixed cellularity and lymphocyte-depleted cases com-
cent of cHL and is distinguished by its distinctive clinical and histologic pared with 34 percent of nodular lymphocyte-predominant and nodular
features. This subtype typically involves lower cervical, supraclavicular, sclerosis cases. Hepatic and marrow disease were invariably associated
and mediastinal lymph nodes in adolescents and young adults, partic- with splenic involvement.
ularly females. Approximately 70 percent of patients with the nodular Two different theories, the “contiguity” theory of Kaplan and
sclerosis subtype present with limited stage disease. A characteristic his- Rosenberg and the “susceptibility” theory of Smithers, have been
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tologic feature is the lacunar cell, a Reed-Sternberg variant that results proposed for the mode of spread of cHL. In support of the former, most
from retraction of the cytoplasm of Hodgkin and Reed-Sternberg cells cases of cHL appear to spread via lymphatic channels to contiguous
during formalin fixation (see Chap. 96, Fig. 96–38). Another typical fea- lymphatic structures in a predictable, nonrandom pattern. Controversy
ture is the thickened capsule and fibrous bands that divide the lymphoid has surrounded the mode of spread to the spleen, which lacks affer-
tissue into cellular nodules.
ent lymphatics. When four or more lymph node regions are involved,
spread by hematogenous distribution appears likely. Disseminated dis-
MIXED CELLULARITY SUBTYPE ease is more common in mixed cellularity and lymphocyte-depleted
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Mixed cellularity cHL involves both pediatric and older age groups cases, consistent with the presence of reported vascular invasion.
and is more commonly associated with advanced stage disease, con- Whereas vascular invasion is controversial, it is more common in the
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stitutional symptoms, and immunodeficiency. Approximately 30 to spleen than in lymph nodes and connotes a poor prognosis.
50 percent of patients present with this histology. Classic Hodgkin and
Reed-Sternberg cells are easily found amid a cellular background com- STAGING
posed of lymphocytes, eosinophils, plasma cells, and histiocytes (see
Chap. 96, Fig. 96–39). A worse prognosis has been reported for this Optimal management of Hodgkin lymphoma relies on knowledge of
subtype. 108 the extent of disease dissemination, which is determined by performing
a careful physical examination, supplemented by laboratory tests and
radiographic imaging studies (Chap. 95). This process, known as “stag-
LYMPHOCYTE-DEPLETED SUBTYPE ing,” has been refined by a series of international working groups. The
Lymphocyte-depleted cHL has two morphologic variants: reticular current 2014 Lugano staging system is a refinement of the historical
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and diffuse fibrosis. The reticular variant contains abundant pleomor- Ann Arbor classification and assigns patients to one of four stages as
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phic neoplastic cells whereas the diffuse fibrosis variant has a promi- indicated in Table 97–2. The classification for Hodgkin lymphoma is
nent fibroblastic proliferation with few normal lymphocytes. Hodgkin further refined by designating the presence or absence of constitutional
and Reed-Sternberg cells are sparse. The lymphocyte-depleted subtype “B” symptoms (fever >38°C, weight loss >10 percent of body weight,
presents in older patients with symptomatic, extensive disease, and may or drenching night sweats). Extranodal disease, representing extracap-
be associated with fever of unknown origin, jaundice, hepatosplenomeg- sular extension of lymph node disease that could be incorporated in a
aly, or pancytopenia. Peripheral and mediastinal adenopathy is much standard radiotherapy field, is distinguished from disseminated, stage
less common than in other subtypes. Cases of cHL developing in the IV disease. The correlation of this staging classification system with
setting of HIV typically exhibit the lymphocyte-depleted morphology. prognosis was extensively verified when radiotherapy served as the

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