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CHAPTER 110 ETIOLOGY AND PATHOGENESIS

HEAVY-CHAIN DISEASE The etiology of γ-HCD is unknown.

CLINICAL FEATURES

Dietlind L. Wahner-Roedler and Robert A. Kyle Originally, γ-HCD was considered to be a lymphomatous illness. How-
ever, γ-HCD has various clinical and pathologic features that can be
divided into three broad categories, as described below.
SUMMARY
DISSEMINATED LYMPHOPROLIFERATIVE
The heavy-chain diseases (HCDs) are B-cell lymphoplasmacytic proliferative DISEASE
disorders in which neoplastic cells produce monoclonal immunoglobulins
(Ig) consisting of truncated heavy chains (HCs) without attached light chains. Disseminated lymphoproliferative disease is present in most patients at
The complex abnormalities of HCD proteins and the usual lack of normal light the time of diagnosis, and various series have reported it in 57 percent
to 66 percent of patients. In two different series, lymphadenopathy
4–6
4,5
chains are a result of several distinct gene alterations, including somatic muta- was present in 56 percent and 62 percent of patients, splenomegaly in 38
tions, deletions, and insertions. HCDs involving the three main immunoglobu- percent and 52 percent, and hepatomegaly in 8 percent and 37 percent
lin classes have been described: α-HCD is the most common and has the most at the time of diagnosis.
uniform presentation; γ- and μ-HCDs have variable clinical presentations and
histopathologic features. The diagnosis is established from immunofixation of LOCALIZED PROLIFERATIVE DISEASE
serum, urine, or secretory fluids in the case of α-HCD or by immunohistologic
analysis of the proliferating lymphoplasmacytic cells in nonsecretory disease. In approximately 25 percent of patients, the lymphoproliferative pro-
cess is localized, which may be extramedullary or may involve only
Treatment of α-HCD consists of antibiotics. If there is no response to antibiotics the marrow. Cutaneous involvement is the most frequently reported
4,5
or if aggressive lymphoma is diagnosed, chemotherapy is indicated. Treatment extramedullary presentation. Patients may present with extramedul-
4,5
of γ- and μ-HCDs depends on the underlying clinicopathologic features rather lary plasmacytoma of the thyroid or parotid gland or an oropharyngeal
than on the presence of the abnormal protein. Table 110–1 summarizes the mass and hypertrophic spinal pachymeningitis. 7
5
features of the HCDs.
NO APPARENT PROLIFERATIVE DISEASE
A proliferative lymphoplasmacytic disease is not apparent in 9 percent
γ-HEAVY-CHAIN DISEASE DEFINITION to 17 percent of patients. In most of these patients, an underlying auto-

AND HISTORY immune disorder has been reported. Autoimmune disorders with or
without underlying lymphoid proliferation include rheumatoid arthri-
γ-Heavy-chain disease (HCD) is not a specific cytopathologic process; tis, autoimmune cytopenias, systemic lupus erythematosus, Sjögren
rather, it is a biochemical expression of a mutant B-cell clone. The disease syndrome, myasthenia gravis, thyroiditis, and vasculitis. 5
should be considered a serologically determined entity with a variety of
clinical and histopathologic features. It is defined by the recognition of LABORATORY FEATURES
monoclonal deleted gamma (γ) chains devoid of light chains. 1
The first case of γ-HCD was described in 1964 by Franklin and MOLECULAR BIOLOGY AND GENETICS
colleagues, who observed a homogeneous band between γ- and
2
β-globulin in an African American patient with generalized lymph- Most γ-HCD proteins are dimers of truncated HCs devoid of light
adenopathy. Comparison of the proteins in the urine to those in the chains. The molecular weight of the monomeric unit varies from 27,000
serum showed that they were the same, a suggestion of the presence of to 49,000. The length of the truncated γ chain varies, but usually it is
a low-molecular-weight serum γ-globulin, which then was shown to be one-half to three-fourths the length of the normal γ chain. Structural
a fragment of a γ-heavy chain (HC). Since this first description, more analysis of the defective monoclonal γ-HC of 23 patients with γ-HCD
than 130 patients with γ-HCD have been described in the literature. 3–5 showed several characteristic features (Fig. 110–1). The proteins usu-
ally begin with a normal variable region. In most cases, this sequence is
short and interrupted by a large deletion encompassing the remainder
EPIDEMIOLOGY of the variable region, although four of the HCs shown in Fig. 110–1
appear to have retained most or all of their variable (V), diversity (D),
γ-HCD has been described throughout the world. Although initially γ- and joining (J) sequences. In all γ-HCD proteins, the entire constant
HCD was reported to occur equally in men and women, there was a region 1 (C 1) domain is also deleted, with normal sequence beginning
4
H
clear predominance of women in a more recent series of 23 patients. at the hinge or occasionally at the C 2 domain. C 1 is responsible for
5
The median age at diagnosis in that series was 68 years (range: 42 to 87 light-chain binding. In the absence of an associated light chain, the C 1
H
H
years). domain binds to heat shock protein 78 (HC binding protein), and the
H
HC undergoes proteasomal degradation rather than secretion.
In two cases of γ-HCD (OMM and RIV), genomic sequence data
Acronyms and Abbreviations: C 1 (2, 3, 4), constant region 1 (2, 3, 4); D, diversity; are available (Fig. 110–2). The presence of large deletions in the switch/
H
HC, heavy chain; HCD, heavy-chain disease; Ig, immunoglobulin; IPSID, immunopro- C 1 regions of these two γ-HCD genes explains why the corresponding
H
liferative small intestinal disease; J, joining; V, variable. HCD proteins lack C 1. Because the normal C 1 acceptor splice site is
H
H
deleted, the donor splice of the leader, or the J region, is spliced directly
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