An unusual presentation of paraproteinemia: Call for a new entity

CASE HISTORY

A 41-year-old female patient presented to our hospital with a 2-month history of generalized weakness, loss of appetite, and body ache. On investigation, her hemoglobin was found to be 5.1 g/dL. Examination of the peripheral smear revealed normocytic normochromic anemia with rouleaux formation. The white blood cell count (WBC) was normal, with relative lymphocytosis on the differential count. The platelet count was adequate. The rest of the laboratory investigations are summarized in Table 1. The noteworthy findings included hypergammaglobulinemia with hypocalcemia and normal renal function. Radiologic imaging revealed hepatomegaly (14.4 cm), splenomegaly (12 cm), and multicentric lymph node enlargements in the bilateral axillary, cervical, para-aortic, aortocaval, paracaval, mesenteric, and bilateral iliac regions. In addition to this, on the positron emission tomography (PET) scan, there was evidence of diffuse osteosclerosis and a metabolically inactive lucent lesion in L1-L2 vertebrae. No osteolytic lesion was identified. Serum protein electrophoresis with immunofixation and free light chain assay revealed a monoclonal band of immunoglobulin G (IgG) showing kappa light chain restriction in the gamma region quantifying to 5.69 g/dL with a serum free kappa-to-lamda light chain ratio of 19.6:1 [Figure 1a]. For further evaluation, bone marrow examination was performed, but aspiration yielded a dry tap. Bone marrow biopsy was hypercellular for age and revealed diffuse infiltration by a population of monomorphic round cells having abundant clear cytoplasm, orthochromatic nuclei with inconspicuous nucleoli. Background revealed marked fibrosis. Trilineage hematopoiesis was suppressed [Figure 2a and b].

Table 1: Hematological and biochemical findings of the patient

Figure 1: Graph of serum protein electrophoresis showing the monoclonal (M) band (a) at the time of presentation, and (b) after treatment

Figure 2: (a) Low power view of bone marrow biopsy showing a diffuse pattern of infiltration in a fibrotic background (100x, H&E). (b) High power view of the infiltrating plasma cells (400x, H&E)

What is the diagnosis, and what should be done next? Once you have finalized your answer, please read on.

DIFFERENTIAL DIAGNOSIS AND FURTHER MANAGEMENT

The three main differential diagnoses in this case were multiple myeloma, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal band, and skin changes), and MGUS (monoclonal gammopathy of undetermined significance). POEMS differs from multiple myeloma in having predominantly neuropathic symptoms along with endocrine dysfunction, volume overload, elevated vascular endothelial growth factor levels, focal or multiple sclerotic bone lesions, and the presence of a monoclonal lymphoproliferative disorder showing lambda light chain restriction.^[1,2] The plasma cell percentage in the bone marrow is usually <5% and the size of the monoclonal band is <3.5 g/dL. The symptoms in POEMS are not related to the pattern or degree of plasma cell infiltration in the bone marrow, unlike multiple myeloma where there is end organ damage attributable to the load of plasma cells. The size of the monoclonal band and the proportion of malignant plasma cells in the bone marrow determine the risk of progression from asymptomatic to symptomatic disease in multiple myeloma.^[3] The development of symptoms and the need to initiate treatment depend on the extent of replacement of normal hematopoiesis, and the degree of sclerosis. Patients diagnosed before the onset of symptoms are designated as having “asymptomatic” or “smoldering” multiple myeloma and are differentiated from those whose disease is at an earlier stage (i.e., MGUS), by a minimum threshold of tumor mass.^[3] MGUS is a plasma cell dyscrasia showing a monoclonal band quantifying to <3 g/dL and a plasma cell percentage of <10% in the bone marrow along with the absence of end organ damage evidenced by the lack of CRAB features (hyperCalcemia, Renal insufficiency, Anemia, Bony lytic lesion). Approximately 20% of patients with MGUS progress to active multiple myeloma. Smoldering myeloma is an asymptomatic intermediate stage between MGUS and active myeloma with a higher level of monoclonal protein and more abnormal plasma cells in the bone marrow than MGUS (10-60%) with absent CRAB features. There are also certain histomorphological differences among them. In POEMS, the plasma cells infiltrate the bone marrow spaces in groups of less than 5 cells and there is hyperplasia of the megakaryocytes, whereas multiple myeloma is characterized by a diffuse, nodular or interstitial pattern of plasma cell infiltration with variably suppressed trilineage hematopoiesis.^[4–6] In the case described here, the size of the monoclonal band exceeded the defined value for POEMS and MGUS, and the plasma cell count in the bone marrow was >60%. These findings were consistent with the myeloma defining events put forward by the International Myeloma Working Group in 2014 based on which, it could have been labeled as multiple myeloma. However, the absence of any osteolytic focus and the presence of lymphadenopathy were against this diagnosis. Additionally, there was no neuropathy or hematological abnormalities (thrombocytosis/erythrocytosis) characteristic of osteosclerotic myeloma/POEMS. Notably, the monoclonal protein associated with POEMS is almost always lambda restricted (91%), whereas our case showed kappa light chain restriction.^[6] As the clinical scenario had overlapping findings and did not fit exclusively into any of the categories of POEMS, multiple myeloma, or MGUS, and considering the presence of diffuse osteosclerosis, diffuse bone marrow plasma cell infiltration along with a huge non-lambda monoclonal band, a diagnosis of Osteosclerotic Myeloma-non POEMS type was made. Immunohistochemistry findings were concordant with multiple myeloma and revealed infiltration by CD20 negative, CD138 positive, and CD56 positive plasma cells showing kappa light chain restriction. No lymphocytic population was identified. Systemic therapy with corticosteroids and lenalidomide was started. However, the patient soon developed lenalidomide-induced hepatotoxicity. Hence, lenalidomide was tapered off and steroids alone were continued. The patient responded very well and was discharged with a hemoglobin of 12.4 g/dL. After 5 months of treatment, the patient’s symptoms had resolved and the complete hemogram was normal. The size of the monoclonal band had decreased significantly to 0.73 g/dL with normal free light chain levels (kappa = 17.32 mg/L, lambda = 15.17 mg/L) [Figure 1b]. The treatment administered was slightly different from that for osteosclerotic myeloma-POEMS type where a solitary sclerotic plasmacytoma is first irradiated. This was omitted in our case because of the presence of disseminated sclerotic lesions. In patients with multiple myeloma who are eligible for a transplant, induction therapy with three to four cycles of bortezomib, lenalidomide, and dexamethasone (VRd) are given followed by autologous stem cell transplantation. On the other hand, patients ineligible for transplant are treated with VRd for approximately 8 to 12 cycles followed by lenalidomide.^[7] After autologous stem cell transplantation, maintenance lenalidomide is given to patients at standard risk, while maintenance bortezomib is given to patients at high risk.^[8,9]

FINAL DIAGNOSIS

Osteosclerotic Myeloma-non-POEMS type.^[4]

DISCUSSION

The term osteosclerotic myeloma (OM) is used synonymously with POEMS. The major difference between patients with osteosclerotic myeloma and the one described here is the diffuse skeletal sclerosis seen on radiographic imaging. Most patients with osteosclerotic myeloma (POEMS) have one or a few small isolated sclerotic bone lesions which include scattered osteosclerotic spots, mixed sclerotic and lytic changes, tumor formation with sclerotic septa, periosteal calcium deposition, and a few purely lytic lesions. Multiple myeloma associated with widespread osteosclerotic lesions is very rare but has been documented. Lacy et al.^[10] described three cases of multiple myeloma associated with widespread osteosclerotic lesions, the presence of a monoclonal band and >10% plasma cells in the bone marrow. Apart from these three cases, they also studied and compared the clinical features of 11 other similar cases reported in the literature. The authors reported that the presenting symptoms in osteosclerotic myeloma-non-POEMS type included bone pain and anemia, in contrast to the neurological complaints in POEMS. The clinical course in such cases more closely resembles multiple myeloma than osteosclerotic myeloma. However, the prognosis is uncertain, with differing reports in the literature.^[11–13] The diagnostic criteria for multiple myeloma were updated by the International Myeloma Working Group in 2014 to identify high risk groups and to include cases with variable presentations to permit the initiation of therapy before serious organ damage ensued.^[14] They introduced three myeloma defining events as important biomarkers of the disease, which if present suggested an 80% higher risk for developing myeloma-related organ damage within two years. These myeloma defining events include: 1) 60% or greater clonal plasma cells on examination of the bone marrow; 2) serum involved/uninvolved free light chain ratio of 100 or greater, provided the absolute level of the involved light chain is at least 100 mg/L; and 3) more than one focal lesion on magnetic resonance imaging that is at least 5 mm or greater in size. The presence of any one myeloma defining event is sufficient to diagnose an active case of multiple myeloma even in the absence of CRAB. Our patient had all three myeloma defining events. Hence, it was appropriate to label the disease as multiple myeloma but in view of the diffuse osteosclerosis and the absence of bony lytic lesions, we preferred to use the term ‘osteosclerotic myeloma-non-POEMS type’. Lymphadenopathy is one of the minor criteria for the diagnosis of POEMS but was observed in our case. This suggests an overlap between the spectra of these two diseases. In fact, it can be postulated that multiple myeloma and osteosclerotic myeloma-non-POEMS represent two extreme ends of the spectrum of plasma cell dyscrasias with entities like POEMS, MGUS, and smoldering myeloma oscillating between them. The histological findings in the lymph nodes are those of Castleman disease but clinically, both POEMS and osteosclerotic myeloma-non-POEMS are different from multicentric Castleman disease which shows polyclonal hypergammaglobulinemia and the absence of sclerosis with a worse prognosis.^[1,2] The suggested reason behind the osteosclerotic lesions is the uncoupling of osteoblastic and osteoclastic cell activities and synthesis of growth promoting cytokines like platelet-derived growth factor and transforming growth factor-beta which stimulate osteoblasts and fibroblasts.^[10]

CONCLUSION

Osteosclerotic lesions are usually seen in POEMS but there are rare situations in which the criteria for POEMS are not fulfilled. Because of overlapping findings with multiple myeloma and POEMS, it is preferable to assign a different category to such cases so that they are more extensively studied and followed up, enabling the appropriate course of treatment, and determining the prognosis, which is still under debate.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published, and due efforts will be made to conceal her identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.