Abstract
An uncommon association between multiple myeloma and Hodgkin lymphoma (HL) was observed in some case reports, while an association with monoclonal gammopathy of uncertain significance (MGUS) is exceedingly rare. We have diagnosed 110 HL cases from 2008 to 2018; here we report 4 HL cases associated with MGUS. MGUS was diagnosed before HL (1 case), together with HL (1 case) or after HL (2 cases). M-component was IgG/k (3 cases) and IgG/k and IgG/λ (1 case), MGUS was not influenced by HL treatment (2 cases), raised after therapy (1 case), while in the last case MGUS appeared after ASCT while HL was in complete remission. We suggest to further study a possible link between MGUS and HL and to perform serum immunofixation if protein electrophoresis shows a suspected discrete band. The comprehension of pathophysiology of this association and a possible role of cytokines such as IL-6 and antilymphoma therapies such as nivolumab or ASCT to MGUS development could represent an interesting research field that requires further investigations.
Keywords: MGUS, Hodgkin lymphoma, Diagnosis, Interleukins
Introduction
Hodgkin lymphoma (HL) is a hematological malignancy in which neoplastic Reed-Sternberg cells are surrounded by a reactive microenvironment including lymphocytes, eosinophils, macrophages and plasma cells; reactive bone marrow (BM) plasmacytosis is common in HL patients [1, 2]. An uncommon association between multiple myeloma (MM) and HL was observed in some case reports, while an association with monoclonal gammopathy of uncertain significance (MGUS) is exceedingly rare [3]. HL is less frequently associated with M-component compared to non-Hodgkin lymphomas [1].
A recently published experience showed the onset of pure red cell aplasia (PRCA) in a patient with MGUS since 3 years. Interestingly, after MGUS eradication with bortezomib in association with dexamethasone, the patient became transfusion independent, suggesting MGUS could represent a potential driver for PRCA, after excluding other causes [4].
In another paper, Le Clech and colleagues demonstrated the presence of MGUS in 667 patients with Ph-negative myeloproliferative disorders was associated with reduced survival, higher risk of secondary myelofibrosis, myelodysplastic syndrome and solid cancer. The authors suggest the pro-inflammatory cytokine IL-6 could influence both myeloid and plasma cells growth and survival by promoting anti-apoptotic proteins [5].
Case Report
According to this background, at our Institution, we have diagnosed 110 HL cases from 2008 to 2018; here we report 4 HL cases associated with MGUS, pointing out the importance to perform serum electrophoresis in the diagnostic work-up before therapy. All patients signed informed consent. MGUS can arise before or after HL diagnosis, as illustrated in Table 1.
Table 1.
Characteristics of patients
| Age | Histological subtype | Stage | M-component | BJ proteinuria | BMB | Relation between MGUS and HL diagnosis | M-component after HL treatment | |
|---|---|---|---|---|---|---|---|---|
| Patient 1 | 70 | Nodular sclerosis | IIA | IgG/k | No | Mild plasmacytosis, | Concurrent | Stable |
| Patient 2 | 69 | Mixed cellularity | IIIA | IgG/k | No | Mild plasmacytosis | MGUS before HL | Stable |
| Patient 3 | 52 | Mixed cellularity | IVB | IgG/k and IgG/λ | No | Positive for HL | MGUS after HL | Raised |
| Patient 4 | 20 | Nodular sclerosis | IIA | IgG/k | No | Not done | MGUS after HL | n.e.a |
BJ Bence-Jones, BMB bone marrow biopsy, MGUS monoclonal gammopathy of uncertain significance, HL Hodgkin lymphoma, n.e. not evaluable
aMGUS appeared after ASCT while HL was in complete remission
The first case was a 70-year-old man that was referred to our hospital because of enlarged supraclavicular lymph node. Laboratory data showed a small serum IgG/k M-component (total IgG count 1390 mg/dl) without Bence Jones (BJ) proteinuria. Lymph node biopsy was performed, histological diagnosis was nodular sclerosis HL; BM biopsy (BMB) showed mild plasmacytosis, clinical staging was IIA unfavourable. The patient received 4 ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) cycles followed by radiotherapy (30 Gy total dose), achieving a durable CR. M-component was not influenced by HL therapy and remained stable since last follow-up 8 years after treatment.
The second case was a 69-year-old-woman with multiple comorbidities that was followed since many years for an IgG/k MGUS without BJ proteinuria or bone lesions (total IgG count 1025 mg/dl). On 2012, she presented with enlarged inguinal lymph nodes, lymph node biopsy made a diagnosis of mixed cellularity HL, Ann Arbor staging was IIIA, BMB demonstrated mild plasmacytosis. The patient received 6 VEPEMB (vinblastine, cyclophosphamide, procarbazine, prednisone, etoposide, mitoxantrone, bleomycin) cycles achieving a durable CR. M-component remained stable since last follow-up 7 years after treatment.
The third case was a 52-year-old man that was diagnosed with mixed cellularity stage IVB HL. At diagnosis, serum electrophoresis did not show M-component. The patient was refractory to ABVD, BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone) brentuximab and bendamustine. After 4th line therapy with bendamustine the patient had progressive disease and a biclonal IgG/k and IgG/λ gammopathy appeared, without BJ proteinuria; BMB was positive for HL. The patient received nivolumab and achieved durable CR; interestingly, M-component slightly raised during treatment, that is ongoing to date (total IgG value raised from 588 mg/dl to 1520 mg/dl).
The last patient was a 20-year-old woman that was diagnosed with IIA nodular sclerosis HL and received ABVD achieving a CR. An early relapse occurred, the patient received 2nd line therapy and autologous stem cell transplantation (ASCT) as consolidation, achieving CR. After ASCT a small IgG/k serum M-component appeared, that represented 4% of total proteins; BMB was not performed. Serum free light chain k/λ ratio was normal in all cases.
Discussion
Simultaneous occurrence of HL with serum monoclonal immunoglobulins is uncommon. In 2 reported cases, unlike our cases, the size of M-component diminished after HL treatment [6]. Interestingly, a concurrent diagnosis of HL and biclonal IgG/k and IgG/λ MM was reported, while in another case HL diagnosis was followed by a biclonal IgG/k and IgG/λ gammopathy with BJ proteinuria [7, 8]. These findings suggest to further study a possible link between MGUS and HL and to perform serum immunofixation if protein electrophoresis shows a suspected discrete band.
Given the known incidence of MGUS (3.2% in aged 50 years or more), the incidence in our cohort is comparable to general population [9, 10]. However, in 2 patients MGUS occurred after HL and 1 case was very young at MGUS diagnosis. In our opinion, both the immunological reconstitution following ABMT and the mechanism of action of new drugs such as checkpoint inhibitors could play a role in the appearance of a M-component. M-component was associated with PRCA and with poor prognosis in diffuse large B-cell lymphoma and Ph-negative myeloproliferative disorders; thus we argue the association may not be just by chance in HL cases and a possible clonal relationship should be investigated in future larger clinical trials [1, 2, 11].
A possible explanation is represented by the physiopathological IL-6 role, postulated for both MGUS and Ph-negative myeloproliferative disorders [5]. IL-6 is an anti-apoptotic protein and the binding to its receptor results in the activation of JAK-STAT pathway, that recently showed a critical role in HL pathogenesis [12]. Elevated serum IL-6 level and genotype collected before treatment showed a possible correlation with B symptoms, response rate and survival in younger HL patients, suggesting IL-6 could play a role in cases with coexistence of HL and MGUS [13].
In conclusion, the comprehension of pathophysiology of this association and a possible role of antilymphoma therapies such as nivolumab or ASCT to MGUS development could represent an interesting research field that requires further investigations.
Compliance with Ethical Standards
Conflict of interest
The authors report no conflict of interests.
Ethical Approval
All procedures performed in the study were in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed Consent
Informed consent was obtained from all individual participants included in the study.
Footnotes
Publisher's Note
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