Meng Li ,Ying Zuo*

1Department of Clinical Medicine,North Sichuan Medical College,Nanchong 637000,China.

Abstract POEMS (Polyneuropathy,Organomegaly,Endocrinopathy,M-Protein and Skin Changes)syndrome is a rare multi-system disease associated with plasma cell abnormality.The etiology and pathogenesis of POEMS syndrome are unclear.Up to 11%-30% of POEMS patients have documented clonal plasma cell disorder with idiopathic multicentric Castleman disease (iMCD) histology.We report a case of POEMS syndrome characterized by plasma cell iMCD in a 64-year-old Asian woman.She was admitted with complaints of numbness and pain in both legs for the last one year.Over the last two months,she developed symptoms associated with respiratory,digestive,and endocrine system disorders.Finally,the POEMS syndrome was diagnosed by lymph node biopsy,electromyography,vascular endothelial growth factor,serum immunofixation electrophoresis,and other auxiliary examinations.POEMS syndrome lacks a standard treatment.This study contributes to providing a reference value for the diagnosis and treatment of this rare disease.

Keywords: Castleman disease;POEMS syndrome;hypothyroidism;peripheral neuropathy

Introduction

POEMS syndrome is a rare paraneoplastic syndrome associated with plasma cell dyscrasia,characterized by polyneuropathy,organomegaly,endocrinopathy,abnormal proliferation of monoclonal plasma cells,and skin changes [1].The rate of incidence is about 0.3/100,000 [2].The pathogenesis of this disease is still unclear.The association of the pro-inflammatory cytokine,vascular endothelial growth factor (VEGF) in POEMS is well documented.The overexpression of cytokines such as IL-6 and VEGF in Castleman disease (CD) is believed to cause abnormal proliferation of plasma cells,leading to the occurrence of POEMS syndrome,meanwhile,VEGF is related to the disease activity [3].Between 11% and 30% of POEMS patients show CD-like histology [4].Here,we will report a typical POEMS syndrome that can be used as a guide for identifying and treating this rare disease.

Case report

A 64-year-old female patient with a prior one-year history of numbness and tingling of the lower limbs was hospitalized in the Endocrinology Department of Affiliated Hospital of North Sichuan Medical College.Loss of appetite,edema,and skin pigmentation were the concomitant symptoms.Since the beginning of the illness,there was no improvement even after repeated medical treatments.Two months before admission,her symptoms worsened,accompanied by hypothyroidism and dyspnea,low fever,cough,sputum,constipation,nausea,and vomiting.The patient’s medical history revealed that she had non-atrophic chronic gastritis for two months and denied a history of having rashes,joint pains,or repeated mouth or vulva ulcers.The patient signed informed consent form.The study was approved by Medical Ethics Committee of Affiliated Hospital of North Sichuan Medical College (2022ER426-1).

The physical examination revealed that she had acute dyspnea and was emaciated with skin and mucous membrane pigmentation,and severe edema in the chest wall,lumbosacral junction,back,and lower limbs.There were several swollen lymph nodes of sizes ranging from 0.5 to 3.9 cm on the neck,armpit,and on both sides of the groin that were firm,not painful,not adhering,and movable.Jugular venous distention and hepatojugular reflux sign were positive.Wet rales could be heard in both lungs.

Due to hypothyroidism,the patient was admitted to the endocrinology department.Due to poor cardiopulmonary function,we first treated hypothyroidism and improved clinical symptoms.The patient took levothyroxine sodium tablet (50 μg daily) following admission.However,despite receiving medication for two weeks,the patient's condition did not improve.After improving the examination,we ruled out autoimmune diseases,tumors or infectious diseases.Subsequently,we had to do a lymph node biopsy,and the results confirmed plasma cell Castleman disease (Figure 1).The patient was therefore transferred to the hematology department.We further examined supplementary auxiliary examination (Table 1 and Figure 2).Based on the diagnostic criteria in 2021 [5],the diagnosis must fulfill at least two mandatory criteria,and at least one major and one minor criterion.The patient was diagnosed with classic POEMS syndrome (Table 2) [6].From December 2021 to April 2022,this patient underwent R-BCD chemotherapy (rituximab 600 mg D1,bortezomib 1.7 mg D1,4,8,11,cyclophosphamide 0.6 g D1,8,and dexamethasone 30 mg D1-2,D4-5,D8-9,D11-12) in the Hematology Department every four weeks.The patient received four courses of chemotherapy.Her dyspnea,edema,and skin condition have been significantly relieved.However,there was no significant improvement in the numbness of her lower limbs.Biochemical indicators improved significantly (Table 3).As the VEGF levels improved to normal,serum immobilization electrophoresis indicated a suspicious positive for the monoclonal protein.Currently,the patient is in remission and her chemotherapy regimen has been changed to rituximab,lenalidomide and dexamethasone since May 2022.

Figure 2 Bone marrow tissue.(A) Hematoxylin-eosin staining showed Hematopoietic component accounted for about 40% and megakaryocytes proliferation;(B) Immunohistochemical showed the proportion of megakaryocytes and granuloids increased,and the proportion of erythroids decreased.

Table 1 Supplementary auxiliary examination

Table 2 POEMS syndrome diagnostic criteria and presentation of this patient

Table 3 Biochemical indicators and computed tomography changes before and after four chemotherapy sessions

Figure 1 Right inguinal lymph node.(A) Hematoxylin-eosin staining showed those lymphoproliferative lesions.(B) Immunohistochemical CD38 and CD138 showed plasma cell proliferation;CD3,CD5,CD19,CD20,CD21,CD123,CD68,CD43 and CD23 were positive;BCL-6 (Germinal center atrophy),HHV-8(-),IgG4 (30 positive cells/HFP),and were not restricted by light chain expression;Ki67 was about 20% in the follicular stroma;it was consistent with Castleman disease of plasma cell type.

Discussion

Pathological biopsy of the patient showed CD,accompanied by typical peripheral polyneuropathy,organ enlargement,skin changes,hypothyroidism,and the monoclonal protein;hence it was diagnosed as POEMS.The patient's symptoms were typical and the diagnosis was not difficult,but in most cases presentations and multisystem involvement vary widely,making POEMS syndrome extremely difficult to diagnose.It is important to differentiate POEMS syndrome and a monoclonal gammopathy of unknown significance (MGUS),multiple myeloma,solitary plasmacytoma,or systemic mastocytosis(SM) since the treatment and supportive care are quite different [5].For example,it is extremely difficult to distinguish between SM and POEMS as their signs and symptoms are similar.They all present with skin changes,limb numbness,extravascular volume overload,organomegaly,and lymphadenopathy.Finally,the two diseases can be identified by histopathological and immunohistochemical examination [7].

According to the reports,multicentric Castleman disease and POEMS syndrome were closely related [8-10],especially the CD variant of POEMS.The difference between them is the presence or absence of monoclonal protein [5].When compared with POEMS syndrome,the neuropathy of MCD is similar but less severe [11].Hence,when a biopsy suggests CD and merges peripheral polyneuropathy,POEMS syndrome should be suspected,and diseases with CD-like adenopathy such as autoimmune disorders like rheumatoid arthritis or systemic lupus erythematosus must be excluded [10].

The treatment of POEMS focuses on the management of plasma cell proliferative diseases.There is no standardized treatment [5,12].According to the current investigation,radiation therapy is often efficient for localized manifestation and can be used as a primary treatment for disseminated disease.Autologous stem cell transplant and chemotherapy are included for systemic affection treatment.Lenalidomide,thalidomide,and bortezomib have anti-VEGF and anti-TNF effects [13].In this case,after four courses of R-BCD treatment,the VEGF and monoclonal protein of the patient changed apparently.

Conclusion

POEMS is prone to misdiagnosis as it is rare,and the presence of diseases such as rheumatoid arthritis and Lupus can mimic its clinical manifestations.Herein,we describe the clinical manifestations,laboratory examination and treatment of POEMS.By reporting this case,clinicians can improve the understanding of the disease,and raise vigilance and diagnosis and treatment thinking for the future diagnosis and treatment of POEMS.