Preliminary findings suggest that abnormal HLC ratios are found in a significant percentage of lymphoma patients, particularly those with indolent types (follicular lymphoma [FL], marginal zone lymphoma [MZL] and WM). In a study of 145 patients with indolent and aggressive lymphomas, 64/145 (44%) had an abnormal HLC ratio (Table 30.2 and Figure 30.1) [679] . By comparison, a monoclonal protein was detected in the serum of 38/145 (26%) patients by SPE and 45/145 (31%) patients by immunofixation electrophoresis (IFE) [679]. This suggests that HLC assays provide a more sensitive means of detecting monoclonal protein production in lymphoproliferative malignancies than conventional electrophoretic techniques. HLC analysis may also be useful in situations where the monoclonal protein concentration is low and accurate quantitation by SPE is difficult (Section 32.4.1). In addition, evidence suggests that HLC analysis is useful for monitoring WM (Section 32.4.2).

In lymphoma patients, the most frequent HLC ratio abnormality was IgM, detected in approximately two-thirds of cases [679]. Approximately one quarter of patients had abnormal HLC ratios for more than one immunoglobulin class.

Disease HLC at diagnosis Prognosis Monitoring
HLC ratio
IFE positive
HLunknown unknown unknown unknown
NHLDLBCL [657][663][679]24 - 44% 0 - 24% IgMκ/IgMλ HLC ratio
predicts PFS
FL[657][679]17% 8 - 24% unknown unknown
MZL[657][679]44% 36 - 37% unknown unknown
MCL [657][679]11% 20 - 22% unknown unknown
BL[657]unknown 12% unknown unknown
WM[679][680][681]97 - 100% 100% Initial data
supports use
Initial data
supports use
CLL [673]unknown 17% unknown unknown

Table 30.2. Summary of the incidence of HLC and IFE abnormalities, and the role of HLC measurements in HL, NHL and CLL. PFS: progression-free survival; other abbreviations defined in Table 30.1.

To date, only one study has investigated the prognostic value of HLC measurements in lymphoma. In a preliminary investigation following patients with DLBCL, multivariate analysis indicated that the IgMκ/IgMλ HLC ratio was predictive of progression free survival (Section 31.3.2) [663].

The concentration of the uninvolved HLC-pair (e.g. IgGλ in a patient with monoclonal IgGκ) provides information on polyclonal immunosuppression. This is prognostic in a number of plasma cell disorders, including monoclonal gammopathy of undetermined significance (MGUS; Chapter 13) and multiple myeloma (Chapter 20). Emerging evidence suggests that HLC-pair suppression may be present in a significant number of lymphoma patients. For example in WM, HLC-pair suppression was present in a quarter of individuals (Section 32.4.3). Further studies on the prognostic utility of HLC-pair suppression in lymphoproliferative disorders are warranted.

Heavy chain disease (HCD) is characterised by the production of a monoclonal immunoglobulin heavy chain with no associated light chains (Section 34.3). As HLC assays do not recognise the monoclonal heavy chain protein, they allow quantitation of the intact immunoglobulins and provide an indirect estimate of the heavy chain production (by subtraction of summated HLC values from total immunoglobulin measurements). In a study of 15 γ-HCD patients, Kaleta et al. [682] found that 20% of patients also had monoclonal sFLC production.