Serum Ig Abnormalities in Mantle Cell Lymphoma

To the Editor:

Although the term mantle cell lymphoma (MCL) was coined only in 1982,1,2 it is now recognized as a distinct entity with accurate diagnostic criteria [characteristic cytologic and pathologic features; coexpression of CD5 and B-cell markers, including bright staining for monoclonal surface Ig generally without CD23 expression; and a t(11; 14)(q13; q32) that is found in approximately 40% of cases and juxtaposes the bcl-1 gene and the J region of the Ig heavy chain locus].3-5 In their recent thorough review of MCL, Weisenburger and Armitage3 briefly mentioned hypogammaglobulinemia and monoclonal gammopathy as being decidedly uncommon and serum Ig were not even alluded to in two other recent reviews.4,5 Our experience is different, because we have observed a high incidence of such serum Ig abnormalities.

Diagnosis of MCL in the 42 patients (33 men and 9 women; 32 to 88 years of age; mean, 62.5 years of age; 33 untreated and 9 having received chemotherapy) observed in our institution was based on histopathologic features of lymph node biopsies, cytologic studies of blood, bone marrow and/or lymph node prints (independently reviewed by two of us [G.F. and A.B.]), and immunophenotyping (performed in 35 cases) showing CD5⁺ (34 cases) B cells that strongly stained for monoclonal surface Ig and were negative for CD23 in 20 of 23 cases studied. Cytogenetic analysis showed a t(11; 14)(q13; q32) in 20 of the 40 cases studied (50%). Serum monoclonal Ig (moIg) were characterized by thin-layer agarose electrophoresis and immunoelectrophoretic (IEL) analysis and confirmed in some cases by a sensitive immunoblotting procedure.6 Only those moIg that were detectable by IEL were taken into account, because moIg evidenced by immunoblotting are common in elderly subjects and are mostly unrelated to the proliferating clone in chronic lymphocytic leukemia.6 Serum Ig class levels were measured by laser nephelometry. Normal levels determined in normal subjects of various age and sex groups are 6.9 to 14.0 mg/mL for IgG, 0.7 to 4.1 mg/mL for IgA, and 0.34 to 2.4 mg/mL for IgM in adults.

Serum moIg detectable by IEL were found in 10 patients (25.6%), including 8 men and 2 women and 44 to 84 years of age (mean, 63.7 years of age), which is not different from the age of patients without moIg. In 1 patient, the moIg was detected only when the disease relapsed after chemotherapy, whereas the first study of the other patients' serum evidenced the moIg in the other cases (at diagnosis in 7 cases). These moIg were 8 IgM, 5 κ and 3 λ, and 2 IgG, one of each light-chain type. They were present in moderate amounts, ie, less than 10 mg/mL, in all but 1 case (13 mg/mL). One of these patients' sera contained a type II mixed cryoglobulin made up of the monoclonal IgM λ and of polyclonal IgG. Data on surface Ig were available in 8 of the 10 patients with serum moIg. The isotypes of serum and surface moIg matched in the 6 cases with monoclonal serum IgM. In contrast, the patient with a serum IgG κ had surface IgM λ and the lymphoma cells from the patient with a serum IgG λ carried κ chains with a staining for heavy chains too dim to characterize them. High resolution electrophoresis showed one or, more often, several low abundance peaks, a pattern sometimes designed as oligoclonal, in 18 patients (16 men and 2 women). The latter patients tended to be older (45 to 88 years of age; mean, 64.7 years of age) than those without an oligoclonal pattern (32 to 84 years of age; mean, 59.3 years of age), but the difference was not statistically significant.

Immunochemical study of the patients' urine was performed in 3 cases only (including a patient with a serum moIg). A κ type Bence-Jones protein was found in a patient with surface IgM κ and no detectable serum moIg.

Serum polyclonal Ig levels (Table 1) were normal or increased in 15 of the 33 untreated patients (and 2 of 9 treated patients), whereas abnormally low levels of at least one Ig class were found in 18 and 7 cases, respectively, with the most commonly affected isotypes being IgM and IgG. Measurements of serum Ig levels were repeated in 6 cases. In 5 of them, Ig levels decreased with time.

Hence, serum Ig abnormalities appear to occur frequently in MCL with one in four patients having a serum moIg detectable by IEL and 55% of untreated patients having hypoimmunoglobulinemia. These moIg were present in moderate amounts, sometimes close to the limit of detection by IEL, and similar monoclonal components might have escaped routine analyses. Similarly, we systematically measured Ig class levels, even in patients without hypogammaglobulinemia. Serum monoclonal IgM might result from some degree of persistent plasma cell maturation or Ig secretion by lymphoma cells because their isotypes matched those of the corresponding surface Ig. The same hypothesis may apply to the case with monoclonal free light chains in urine. This is unlikely for the two serum monoclonal IgG, which might be a mere coincidence (due to aging, for instance, these patients being 67 and 68 years of age, respectively). Although both patients had normal IgA and IgM levels, the monoclonal IgG might also be linked to the existence of an immunodeficiency state secondary to the lymphoma, which is apparent in hypoimmunoglobulinemic patients. They might also be produced by a subclone derived from the original lymphoma clone by heavy-chain class switching and light-chain replacement. Such questions should be answered by molecular studies and by the evaluation of the immune status of MCL patients, which has not yet been performed systematically and appears to be warranted.