POEMS Syndrome with Extensive Calciphylaxis: A Case Report and Literature Review.

POEMS syndrome, a paraneoplastic disorder, caused by plasma cell dyscrasia, is characterized by polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes. Calciphylaxis is a vasculopathy of subcutaneous arteries with calcification and skin ulceration, most commonly associated with end-stage renal disease. Calciphylaxis occurring in patients with POEMS syndrome is very rare; only 8 cases have been reported to date. We report the 9th case. A middle-aged woman with chronic inflammatory demyelinating polyneuropathy and monoclonal plasma cell proliferative disorder with IgA gammopathy presented with a 3-month history of multiple painful violaceous plaques with gangrenous necrosis and ulceration on the abdomen and extremities. The skin lesions worsened after surgical debridement and fasciotomy but improved with weekly intravenous bortezomib combined with thalidomide and dexamethasone for POEMS syndrome. The present case illustrates that effective control of the disease activity of POEMS syndrome may improve the surgical outcome of extensive skin necrosis in POEMS syndrome-associated calciphylaxis. Copyright:

Introduction

POEMS syndrome, a rare paraneoplastic syndrome, caused by underlying plasma cell dyscrasia, is characterized by polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes.[1234] Elevated serum levels of proinflammatory cytokines (IL-1α, IL-6 and TNF-γ) and vascular endothelial growth factor (VEGF) have been implicated in the pathogenesis of POEMS syndrome.[2] Calciphylaxis is also a rare, life-threatening vasculopathy mainly affecting patients with end-stage kidney disease[5] and manifesting skin necrosis with thrombosis and calcification of small- and medium-sized subcutaneous arteries.

To our knowledge, only 8 cases of POEMS syndrome with calciphylaxis have been reported to date.[134678910] Herein, we report a new case with severe calciphylaxis.

Case Report

A middle-aged female presented for dermatology consultation in September 2015 with a 3-month history of purpuric and necrotic skin lesions. The rash beginning as a coin-sized erythematous patch on the right thigh rapidly progressed to painful indurated plaques with central necrosis and bullae in a few days. Her medical history was significant for chronic inflammatory demyelinating polyneuropathy (CIDP) with IgA lambda monoclonal gammopathy that was diagnosed 2.5 years prior to the onset of skin lesions. She was taking prednisolone 25 mg/day, azathioprine 50 mg/day, and antihypertensive medications. The worsening of the skin lesions was followed by numbness on all the limbs with progressive muscle weakness of the lower limbs one month later. POEMS syndrome was suspected, and she was admitted to Neurology ward in November 2015 for further evaluation. Significant laboratory findings included white blood cells 22.5 × 103/μL with 87.5% of segmented neutrophils, hemoglobin 10.3 g/dL, platelets 700 × 103/μL, creatinine 1.38 mg/dL, serum calcium 9.2 mg/dL, phosphate 3.9 mg/dL, C-reactive protein 12.8 mg/L, IgA lambda monoclonal gammopathy (582 mg/dL), splenomegaly, lymphadenopathy, pleural effusion, and hypothyroidism. A bone marrow biopsy showed osteosclerotic myeloma. Parathyroid hormone was not checked, and the test for VEGF was not available in our hospital.

Dermatology examination revealed extensive violaceous plaques and ecchymoses with ulceration covered by hemorrhagic crusts on the upper extremities, abdomen, flanks, thighs, legs, and feet [Figure 1]. Additional findings were facial swelling with flushing, hypertrichosis, acrocyanosis, and pitting edema of legs. Biopsy from a skin lesion revealed extensive skin necrosis with either necrosis or thrombosis of nearly all small blood vessels in the dermis, and calcification in the intima of larger subcutaneous blood vessels [Figure 2]. Direct immunofluorescence study showed negative finding. The overall findings were consistent with POEMS syndrome with calciphylaxis.

Figure 1

A middle-aged woman with POEMS and calciphylaxis presenting with extensive violaceous plaques and ecchymosis with ischemic hemorrhagic necrosis on the abdomen and thighs

Figure 2

The skin biopsy specimen reveals calcification in the intima of a subcutaneous thick-walled blood vessel (H and E, ×400)

The necrotic ulcerated wounds were debrided with regional fasciectomy. However, the wound worsened after surgery. After a combined treatment for POEMS syndrome (weekly intravenous bortezomib 1.3 mg/m2, thalidomide 50 mg daily, and biweekly dexamethasone 20 mg/day) and monthly zoledronic acid for hypercalcemia prevention, her condition began to improve 8 weeks later with reduction of serum free lambda protein from 151 mg/L to 36.2 mg/L in 3 months. The ulcer on the left thigh healed completely after a second surgical debridement with split-thickness skin graft. Bortezomib-based therapy was continued for 9 months, and she remained in complete remission on thalidomide 50 mg in a follow-up 30 month later.

Discussion

Diagnosis of POEMS syndrome is based on a constellation of clinical and laboratory features.[2] The major criteria are polyneuropathy, clonal plasma cell proliferative disorder (PCD), Castleman disease, sclerotic bone lesions, and an elevation of VEGF. The minor criteria include organomegaly, endocrinopathy, characteristic skin changes, papilledema, volume overload, and thrombocytosis/polycythemia. Diagnosis requires 3 major criteria (polyneuropathy and clonal PCD must be included), and at least one minor criteria.[2] Diagnosis of POEMS syndrome is often delayed because of its rarity and potential confusion with other neurologic disorders, most commonly demyelinating polyradiculoneuropathy.[2] In the present case, the delay was nearly 3 years after the initial diagnosis of polyneuropathy.

Calciphylaxis may occur in non-uremic settings, such as primary and secondary hyperparathyroidism, connective tissue diseases, and malignancies, especially, multiple myeloma (MM).[5] Corticosteroids, parathyroid hormones, and pro-inflammatory cytokines may be involved in the activation of nuclear factor κB (NF-κB) pathway, which ultimately causes vascular mineral deposition in calciphylaxis.[1] The mortality rate ranges from 52% to 80% with sepsis being the leading cause of death.[5]

Our case represents the 9th case of POEMS syndrome with calciphylaxis.[134678910] Calciphylaxis usually occur many years after the diagnosis of POEMS syndrome. Most such cases (89%) had no elevation of serum calcium, phosphate, and parathyroid hormone levels, suggesting that the mechanism for calciphylaxis in POEMS syndrome differs from that in end-stage kidney disease, and might be due to VEGF and/or pro-inflammatory cytokines-induced deregulation of calcium homeostasis.[7] In our patient, systemic corticosteroid therapy and the underlying POEMS syndrome might be the reasons for developing calciphylaxis.

Successful treatment outcome of POEMS syndrome has been associated with therapy targeted at the underlying clonal PCD,[2] specifically, irradiation for dominant sclerotic plasmacytoma and systemic therapy for diffuse sclerotic lesions or disseminated bone marrow involvement, or progression of disease 3-6 months post radiotherapy. Systemic therapy includes corticosteroids, alkylating agents, lenalidomide, thalidomide and bortezomib, and stem cell transplantation.

Optimal treatment for calciphylaxis in non-uremic patients has not been established, but a combined approach consisting of trigger-agent cessation, wound management, antibiotic therapy, intravenous sodium thiosulfate, and hyperbaric oxygen therapy have been suggested. Of the 9 cases of P0EMS syndrome with calciphylaxis, surgical debridement was performed in 7 without adverse effect. In our patient, the wound worsening after initial debridement might be due to the pre-existing severe vascular damage, resulting in poor local tissue perfusion and wound healing after surgery.

In conclusion, we reported the 9th case of calciphylaxis in association with POEMS syndrome. The association in these cases suggests that POEMS syndrome may be a risk factor for developing calciphylaxis in non-uremic setting. The present case illustrates as well that effective control of the disease activity of POEMS syndrome may improve surgical outcome of extensive skin necrosis in POEMS syndrome-associated calciphylaxis.

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Conflicts of interest

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