Abstract
Heavy chain diseases (HCDs) are rare B-cell lymphoproliferative neoplasias characterized by the production of a monoclonal component consisting of a truncated monoclonal Ig heavy chain without the associated light chain. Among them, patients with gamma-HCD are so rare that no more than 150 cases can be found in the literature. In this paper, we report one additional case: an 83-year-old man with a gamma-HCD, in whom a kappa light chain component was detected in the serum by using the serum free light-chain assessment and in addition monoclonal kappa cytoplasmic expression was detected in bone marrow plasma cells by flow cytometric analysis. In the work-up of the patient, the underlying anatomopathological lymphoproliferative disease corresponded to a lymphoplasmacytic lymphoma, as it is stated in the current World Health Organization classification (2008), with both lymphadenopathic and bone marrow infiltration. As in other cases, several autoimmune manifestations (antiphospholipidic syndrome and immune thrombocytopenia) were present during the course of the disease in this patient. This case report illustrates a new case of gamma-HCD, in which serum free light-chain analysis and flow cytometry represented a valuable tool for diagnosis, a finding that could be very important for the future management of these patients.
Introduction
Heavy chain diseases (HCDs) are rare B-cell lymphoproliferative disorders characterized by production of truncated monoclonal Ig heavy chains without associated light chains. 1 HCDs involving the three main Ig classes have been described: alpha-HCD (Seligman's disease) is the most common and uniform while gamma-HCD (Franklin disease) and mu-HCD are clinically and histologically heterogeneous. 2 HCDs can be associated with non-Hodgkin's lymphomas (NHLs): alpha-HCD with extranodal marginal zone lymphoma of mucosa-associated lymph-node tissue, gamma-HCD with lymphoplasmacytic NHL and mu-HCD with chronic lymphocytic leukaemia. Although isolated cases with Bence-Jones proteinuria have been described, 3,4 HCD has usually been thought to lack monoclonal light chains. To investigate this possibility in depth, a new test to evaluate the presence of free light chains (FLCs) in the serum has been developed, which can be backed up by the results of immunophenotypic and molecular tests performed in samples containing the neoplastic cells responsible for M-component production.
We hereby report the case of an 83-year-old man with a gamma-HCD, in whom kappa-free light chains, highly probably monoclonal, were detected in the serum using the free light-chain assessment method. 5
Case report
An 83-year-old man was admitted to the Neurology Unit with acute delirium and deteriorated neurological symptoms persisting from a stroke in the left brain hemisphere five months earlier. A brain computed tomography (CT) scan showed an old, low-intensity frontoparietal lesion without mass effect. Days later, he developed progressive dyspnoea, hypoxaemia and right-sided chest pain and was moved to the Internal Medicine Unit for assessment. A CT angiograph showed pulmonary bullae and areas of ground-glass pattern with no evidence of pulmonary embolism. Incidentally, enlarged bilateral axillary and mediastinal (supracarinal) lymph nodes were seen.
On examination, he was found to have an enlarged spleen, right cervical and bilateral axillary lymphadenopathies. A CT scan of the chest, abdomen and pelvis confirmed splenomegaly (16 cm) and bilateral axillary (six in total, 1–2 cm in size), mediastinal (four, 10–13 mm in size) and retroperitoneal (periaortic, 2 cm) lymph nodes. There was a right pleural effusion, pulmonary bullae and areas of ground-glass pattern, as seen in the previous CT angiograph. There were no pulmonary nodules or masses. Routine laboratory monitoring revealed anaemia (haemoglobin: 98 g/L), monocytosis (1.1 × 109/L) and thrombocytopaenia (47 × 109/L) with a normal peripheral-blood smear; HIV test results, and hepatitis A, B and C virus serologies were negative; biochemistry showed normal electrolytes, proteins, albumin, liver and renal function; and the erythrocyte sedimentation rate was high (53 mm/h). His past medical history included hypertension, diabetes mellitus, gastritis with anti-intrinsic factor antibodies and an antiphospholipid syndrome. The patient was referred to a haemato-oncologist with the clinical suspicion of a lymphoproliferative disorder.
Examination of a fine-needle aspirate from a cervical lymph node showed a diffuse, polymorphous proliferation of small- to medium-sized lymphoid cells, some with plasmacytic differentiation, plasma cells and scattered large immunoblasts. Flow cytometric analysis with standard methods 6 revealed 7% of monoclonal plasma cells to be CD19-positive, CD56-negative, CD38-weakly positive, cytoplasmic-IgG positive and cytoplasmic-kappa-positive. A bone marrow aspirate showed normal cellularity with 12% infiltration of plasma cells of identical immunophenotype; the same percentage of plasma cells had a chromosome 14 translocation with no known partner. The bone marrow biopsy exhibited decreased cellularity and infiltration with lymphoplasmacytic aggregates, being CD20-positive, CD79-positive, CD38-positive (focal), CD3-negative, CD5-negative and with Ig expression (IgG) with kappa light chain restriction. Serum protein electrophoresis showed a spike in the gamma region, consistent with the presence of a monoclonal Ig (M-protein [IgG] = 19.1 g/L). Serum immunofixation (and immunosubstraction) revealed the presence of a monoclonal band in the gamma heavy chain lane without the corresponding band in either of the two light chain lanes, which is the defining feature of HCDs. Using the new serum FLC assessment method, 5 an abnormal ratio was detected in the serum (FLC ratio kappa/lambda = 27.44) with a notably greater quantity of kappa FLC (1070 mg/L). Molecular characterization of Ig genes 7 detected weak monoclonal polymerase chain reaction (PCR) amplification of the heavy chain in region 3 of the framework. The presence of presumably heavily mutated Ig genes prevented the amplification of the Ig-kappa rearrangement as well as the sequencing of any monoclonal rearrangement. The radiological skeletal survey revealed a normal skull without osteolytic lesions in the rest of the skeleton.
The patient was started on cyclophosphamide (50 mg/24 h) and prednisone (20 mg/24 h) but the latter had to be stopped early due to side-effects. A 25% reduction in the monoclonal spike after the first course was observed. Three months later, the patient developed a respiratory infection, and amoxicillin plus ciprofloxacin was started. A few days later he was admitted with gastrointestinal bleeding and peripheral thrombocytopenia (platelet count of 1 × 109/L and immature platelet fraction of 18%), for which he received high-dose Igs, which produced a favourable response. Due to respiratory deterioration and persistent fever, initial therapy was switched to piperacyllin–tazobactam. In spite of some improvement, the patient finally died due to respiratory insufficiency.
Discussion
Around 120 patients with gamma-HCD throughout the world have been described in the literature since the first report by Franklin et al. in 1964. 1 Although gamma-HCD has previously been found to occur equally in men and women, there is a predominance of women in the most recently described series, 2 in which the median age at diagnosis was 68 years (range 42–87 y). We report one additional case, an 83-year-old man with gamma-HCD, in whom a kappa light chain component, probably monoclonal, was also detected in the serum by using serum FLC assessment, 5 which was also supported by the detection of plasma cells with kappa restriction by flow cytometry in the bone marrow.
Most gamma-HCD proteins are dimers of truncated heavy chains devoid of light chains. The length of the truncated gamma chains varies, but is usually one-half to three-quarters of the length of the normal gamma chain. The proteins usually start with a normal variable region. In most cases, this sequence is short and interrupted by a large deletion encompassing the remainder of the V region. In all gamma-HCD proteins, the entire CHI domain is also deleted, with the normal sequence beginning at the hinge or occasionally at the CH2 domain. 8,9
Gamma-HCD can be divided into two categories: lymphoproliferative (disseminated or localized) and not associated with any lymphoproliferative disease. 2 Our patient presented with lymphadenopathies and splenomegaly and would therefore be included in the first group. His underlying lymphoproliferative disease morphologically and immunophenotypically matched the diagnosis of lymphoplasmacytic lymphoma, which has usually been associated with gamma-HCD in the past. Autoimmune manifestations have frequently been reported. 2 The present case was known to have antiphospholipid syndrome and developed thrombocytopenic purpura during the course of the disease.
The presence of an abnormal serum Ig composed of only gamma heavy chains is the fundamental feature of a gamma-HCD. The diagnosis is established by immunofixation or immunoelectrophoresis of the serum or a concentrated urine specimen. A monoclonal peak can be detected in 60–80% of patients. 4,10 When present, it is most commonly found in the β1 or β2 region. The median value of the monoclonal spike at diagnosis was 15.9 g/L (range 4–39.1 g/L) in 19 patients reported by Wahner-Roedler et al. 4 In our case, immunofixation showed an IgG heavy chain without a bound light chain and the concentration of the monoclonal spike was 19.1 g/L.
Flow cytometry evaluation of the tumour cells demonstrated that they were CD38w+, CD138+, CD19+, CD56−, CD20+, CD79+, CD3−, CD5−, Cytoplasmic-IgG+ and featured kappa restriction. Interestingly, this abnormal immunophenotype overlaps with plasma cells from Waldenström disease 11 and myelomatous plasma cells. 12 In addition, in the current case, tumour cells were slightly positive for CD38 and had a high proliferative rate. Cytogenetic studies have seldom been reported 10 and no single abnormalities have been found. Our patient presented cytogenetic abnormalities in chromosome 14 of plasma cells, a typical but not exclusive characteristic of multiple myeloma plasma cells.
The presence of traits of highly probable monoclonal light chains is an intriguing finding of the present case, although some similar features have been observed in isolated cases of multiple myeloma. 13 An elevated kappa FLC was detected in the serum of this patient by the serum FLC assessment method, 5 and cytoplasmic light chains with kappa restriction were identified in tumour cells by both flow cytometry and immunohistochemistry. HCD has usually been thought to lack the presence of light chains, but these findings suggest that this could be a misunderstanding arising from the lack of suitable tests (for example, in this case, no light-chain monoclonality could be demonstrated by PCR amplification). In addition, after excluding a laboratory error, this could be attributed to an antibody failure to recognize this particular monoclonal light chain. Although this is always possible, it is not probable in the current case because this phenomenon has been usually associated to IgA-lambda clones. 14 Moreover, the absence of a kappa light chain in the monoclonal Ig peak was assessed by two different methodologies (immunofixation and immunosubstration) with different anti-kappa antibodies. Accordingly, all these findings suggest that monoclonal FLCs could be found in HCD, so their assessment should be considered as a complementary examination in these patients in the future.
In summary, we present here a new gamma-HCD patient characterized by lymphadenopathy, splenomegaly and abnormal monoclonal gamma-chain secretion. The pathological substrate in this case seemed to be an atypical lymphoplasmacytic lymphoma. Although no light chain was joined to the monoclonal heavy chain, free monoclonal chain secretion was observed. This finding draws attention to the importance of specifically examining for this in patients in the future.
DECLARATIONS