以腹胀、双下肢水肿、气促为表现的POEMS综合征1例及文献复习

中南大学学报（医学版）J Cent South Univ (Med Sci)2019, 44(6) htt p://706POEMS syndrome presenting with abdominal distension, lower limb edema and shortness of breath: A case reportand literature reviewZ HANG Jiayi 1, OUYANG Zeying 1, LI Rong 2, LENG Aiming 1, LIU Ting 1( 1. Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008;2. Department of Gastroenterology, Second Xiangya Hospital, Central South University, Changsha 410011, China )ABSTRACTP OEMS syndrome is a rare paraneoplastic disorder. A 60-year-old female patient was admitt ed to the Department of Gastroenterology, Xiangya Hospital of Central South University (Changsha, China), complaining of abdominal distension, severe edema of both lower limbs and shortness of breath for more than 1 year. Aft er intensive and careful medical investigations, the patient manifested with polyneuropathy, M-proteinemia, splenomegaly, lymphadenopathy, hypothyroidism, extravascular volume overload, sclerotic bone lesions, elevated VEGF and pulmonary hypertension. According to the latest diagnostic criteria of POEMS syndrome, this patient met two mandatory major criteria, two other major criteria and three minor criteria, the diagnosis was clear aft er ruling out differential diagnosis. The patient was treated with dexamethasone and lenalidomide, which relieved her clinical symptoms. The pathogenesis of POEMS syndrome is not fully understood; however, increased levels of vascular endothelial growth factor may contribute to most of the clinical manifestations. This patient had been in physical discomfort for more than 14 months, which seriously aff ected her quality of life. Clinically, the awareness of early diagnosis and treatment of POEMS syndrome should be improved.KEY WORDSP OEMS syndrome; vascular endothelial growth factor; pulmonary hypertension; edema; Castleman’s diseaseDate of reception: 2018-11-13First author: ZHANG Jiayi, Email: 168112161@, ORCID: 0000-0002-3776-4683Corresponding author: LIU Ting, Email: liuting818@, ORCID: 0000-0001-7083-1238Foundation item: Th is work was supported by the fund from Changsha Science and T echnology Bureau (1701090) and Hunan Provincial Natural Science Foundation (2018JJ2664), China.DOI:10.11817/j.issn.1672-7347.2019.06.015htt p:///xbwk/fileup/PDF/201906706.pdf·CASE ANALYSES · ·临床病例讨论·POEMS syndrome presenting with abdominal distension, lower limb edema and shortness of breath: A case report and literature review ZHANG Jiayi , et al 707POEMS syndrome is a rare paraneoplastic disorder which involve multiple symptoms, including polyneuropathy, organomegaly, endocrinopathy, M-proteinemia and skin changes. Not all patients have all of these symptoms [1]. POEMS syndrome is associated with an underlying clonal plasma cell dyscrasia [2], but the mechanism by which plasma cells cause POEMS syndrome is not fully understood. Vascular endothelial growth factor (VEGF) is a major diagnostic criterion for POEMS syndrome, and may be responsible for many clinical presentations of the syndrome. The incidence of POEMS syndrome is low, but the misdiagnosis rate and mortality rate are high. It takes an average of 18 months from the onset of symptoms to a definitive diagnosis [3], and by the time the diagnosis is made, patients have developed multiple systemic impairments, and common causes of death include cardiopulmonary failure, coagulation disorders, long-term use of glucocorticoids and infections caused by immunosuppressive agents [1]. Therefore, early identification of this disease is very important due to its distinctive manifestations, difficult diagnosis and high mortality rate. We report a successful diagnosis of POEMS syndrome in a female patient. Lenalidomide and dexamethasone therapy was initiated after diagnosis. The patient had a good prognosis and was subsequently discharged from hospital.以腹胀、双下肢水肿、气促为表现的POEMS 综合征1例及文献复习张嘉怡1，欧阳泽颖1，李荣2，冷爱民1，刘霆1(中南大学 1. 湘雅医院消化内科，长沙 410008；2. 湘雅二医院消化内科，长沙 410011)[摘要] POEMS 综合征是一种少见的副肿瘤性疾病。

中南大学湘雅医院消化内科收治1例60岁女性POEMS 综合征患者，其腹胀病史超过1年，并伴有严重的双下肢水肿及气促；检查结果提示多发性周围神经病变、M 蛋白血症、脾肿大、淋巴结肿大、甲状腺功能减退、血管外容量负荷超载、硬化性骨病变、VEGF 升高和肺动脉高压。

根据POEMS 综合征的最新诊断标准，患者满足2个强制性主要标准、2个其他主要标准和3个次要标准，排除鉴别诊断后POEMS 综合征诊断明确。

患者接受地塞米松及来那度胺治疗，临床症状得到明显改善。

POEMS 综合征的发病机制尚不完全清楚，VEGF 水平的升高可能与上述临床表现有关。

该患者病史超过14个月，严重影响其生活质量，临床上应提高对POEMS 综合征早期诊断和早期治疗的意识。

[关键词] POEMS 综合征；血管内皮生长因子；肺动脉高压；水肿；Castleman 病1 Case reportOn November 9, 2017, a 60-year-old female patient was admitted to the Department of Gastroenterology, Xiangya Hospital of Central South University (Changsha, China), complaining of abdominal distension, severe edema of both lower limbs and shortness of breath. Her past medical history showed that she had type 2 diabetes for more than 4 years. She had no history of coronary heart disease, hypertension, hypercholesterolemia, alcohol consumption, cigarette smoking or drug abuse, and her family history was unremarkable.On admission, body temperature was 36.6 ℃; respiration rate, 14 min –1; heart rate, 86 min –1; and blood pressure, 15.7/10.4 kPa. Physical examination revealed severe edema of both lower limbs, and soft lymph nodes were palpable in the supraclavicular fossa, infraclavicular fossa and axillary fossa. Abdominal examination identified generalized tenderness without rebound tenderness. The patient’s body mass had decreased by 2 kg in the past year.Laboratory data on admission demonstrated a decrease in red blood cells (3.05×1012/L),hemoglobin (85 g/L) and platelets (116×109/L), which suggested moderate anemia. However, liver function, serum tumor markers, NT-proBNP, blood glucose, markers of viral hepatitis, and cardiac enzymes were within normal中南大学学报(医学版), 2019, 44(6) 708limits. Renal function test indicated increased uric acid. The HIV antibody was negative. Blood coagulation tests showed increased activated partial thromboplastin time and increased plasma D-dimer. Analysis of endocrine hormones revealed decreased free triiodothyronine, free tetraiodothyronine and increased thyroid stimulating hormone, which was suggestive of hypothyroidism. Serum VEGF was significantly increased (660.41 pg/mL, normal range: 0–142 pg/mL), which supported the diagnosis of POEMS syndrome and indicated the disease activity[4-6]. Serum immunofixation electrophoresis revealed increased production of M-protein, λ light chains and IgA.An electromyogram revealed motor and sensory polyneuropathy, with typical demyelination at the proximal and distal ends of peripheral nerves in all four limbs. Electrocardiography was normal. An abdominal color Doppler ultrasonography scan showed splenomegaly, ascites and multiple enlarged lymph nodes in the abdominal cavity. Echocardiography showed enlarged left atria, moderate tricuspid regurgitation, mild mitral regurgitation, pulmonary hypertension (systolic pulmonary artery pressure≈7.2 kPa), and pericardial effusion. Right heart catheterization showed moderate pulmonary hypertension(pulmonary arterial pressure = 6.0 kPa). Bone scanning revealed bone metabolism abnormality in the right sixth rib. CT scanning showed the signs of infection in the lungs, pulmonary hypertension, abdominal cavity, pelvic cavity and pericardial effusions, abdominal wall edema, and splenomegaly. Ventilation/ perfusion lung scanning, spirometry results and arterial blood gas analysis were normal. The patient also exhibited lymphadenopathy in the retroperitoneal, abdominal cavity and bilateral inguinal regions. The patient’s lymph node next to the right external iliac artery was obtained by biopsy (Figure 1) and immunohistochemistry revealed dysplasia of plasma cells which were positive for CD38, CD138, Ki-67 and kappa light chain, and negative for CD20 and CD21.According to the 2017 update on the diagnosis of POEMS syndrome[7], the patient was diagnosed with POEMS syndrome. Most studies have showed that in patients with POEMS syndrome, autologous stem cell transplantation and long-term thalidomide therapy can cause underlying connective tissue disease and neurological complications. However, lenalidomide is effective and safe and has some neurological benefit in patients with POEMS syndrome, as it can alleviate neurological symptoms and decrease plasma VEGF level[7]. Considering the patient’s physical condition, we opted for low-dose steroid treatment (oral dexamethasone, 10 mg/d) and oral lenalidomide treatment (10 mg/d). Her condition was stable, and the symptoms of abdominal distension, lower limb edema and shortness of breath improved after treatment.Dispenzieri proposed widely accepted diagnostic criteria in 2017 in an attempt to standardise the various features and investigation findings necessary to make a diagnosis of POEMS syndrome[7]. The diagnosis is definite when both the polyneuropathy and monoclonal gammopathy are present in combination with one of the other three major criteria (Castleman’s disease, sclerotic bone lesions and increased levels of VEGF), and one of the six minor criteria (organomegaly, endocrinopathy, extravascular volume overload, skin changes, papilloedema, thrombocytosis/polycythemia). The clinical features of this patient included splenomegaly, lymphadenopathy, hypothyroidism, extravascular volume overload, sclerotic bone lesions, and pulmonary hypertension. Her laboratory examination presented a λ-type IgA monoclonal gammopathy and elevated VEGF; electromyogram manifested motor and sensory polyneuropathy, with typical demyelination at the proximal and distal ends of peripheral nerves in all four limbs. Our patient fulfilled two mandatory major criteria, two other major criteria and three minor criteria. The diagnosis was confirmed after excluding other differential diagnoses. Liver cirrhosis can be characterized by hepatosplenomegaly and ascites, our patient’s liver function is normal and there is no history of hepatitis B virus infection or other causes of cirrhosis. Therefore, the above symptoms caused by liver cirrhosis are not considered. Although Guillain Barre Syndrome has the characteristics of symmetrical lower limb motor neuron paralysis and separation of cerebrospinal fluid protein cells, it should not be accompanied by organomegaly and skin changes, and the determination of serum M protein can be helpful for identification. In addition, connective tissue disease also has urinary protein, hematologic disorder and dysimmunity, but accompanied by peripheral nerve damage and organomegaly is uncommon.POEMS syndrome presenting with abdominal distension, lower limb edema and shortness of breath: A case report and literature review ZHANG Jiayi, et al709 Figure 1 HE staining showing the lymph node next to the right external iliac artery with abnormal proliferation of plasma cellsA: ×100; B: ×2002 DiscussionPOEMS syndrome can be traced back to 1958 when it was described by Crow for the first time. In 1980, the first systematic study of POEMS syndrome was reported by Bardwick et al[8], who suggested that the main characteristics of POEMS syndrome were polyneuropathy, organomegaly, endocrinopathy, M-proteinemia and skin changes. He used acronyms of these characteristics and named them the POEMS syndrome. POEMS syndrome is also called Crow-Fukase syndrome[9] or Takatsuki syndrome[10]. Most studies[9-10] have been carried out in Japan; however, over the past decades, the incidence of POEMS syndrome has increased worldwide, including the United States, C hina, India and France[3, 11-12]. Although the pathogenesis of POEMS syndrome is not completely understood, many scholars hold the view that abnormal cytokine hyperproduction may be responsible for this disease, such as interleukin (IL)-6, IL-8, tumor necrosis factor-α (TNF-α) and VEGF[13-14]. The clinical manifestations of POEMS syndrome are extremely variable and nonspecific; therefore it is difficult to establish an accurate diagnosis quickly. However, detailed history and physical examination combined with appropriate laboratory tests can help differentiate this syndrome from other diseases.POEMS syndrome is believed to be related to a number of clinical symptoms. Several clinical studies have shown that almost all patients have multiple peripheral neuropathy (PN), and the incidence rates of other manifestations are: organomegaly (45%–85%), Castleman’s disease (11%–25%), endocrinopathy (67%–84%), diabetes (3%–36%), hypothyroidism (9%–67%), abnormal proliferation of monoclonal plasma cells (100%), M-proteinemia (24%–54%) and skin changes (68%–89%)[7, 15].In this case, severe edema in patient’s both lower limbs was one of the classic symptoms, and the possibility of nephrogenic, hepatogenic, cardiogenic, endocrine and autoimmune edema should be also considered. In addition, the patient had mild hypothyroidism, which could explain her severe edema of the lower limbs, but it was difficult to explain the patient’s accompanying multiple serous cavity hydrops, organomegaly and multiple lymphadenopathies. Our patient did not have a history of heart disease or hepatic disease. Since there are no sufficient diagnostic criteria for nephrotic syndrome or nephritis, lower limb edema was unlikely to be due to cardiac, hepatogenic, or nephrogenic diseases. Following thyroid hormone replacement therapy, the patient's edema did not significantly improve, and the diagnosis of POEMS syndrome was confirmed by lymph node biopsy and immunohistochemistry. Some studies have shown that increased VEGF and decreased serum erythropoietin induced functional alterations in the vessel wall that lead to increased permeability and edema[6, 16-17].Pulmonary arterial hypertension (PAH) is an interesting clinical manifestation in this case. PAH is characterized by an elevated mean pulmonary artery pressure of ≥3.3 kPa, with a normal pulmonary artery wedge pressure. This serious disease results in progressive right-sided heart failure and ultimately death[18]. Our patient had no evidence of portal hypertension on liver ultrasound, biologic data on renal and hepatic functionsA B中南大学学报(医学版), 2019, 44(6) 710were within normal limits, and chronic thromboembolic pulmonary hypertension was excluded after ventilation/ perfusion lung scan. Pulmonary hypertension caused by lung diseases or hypoxia were also excluded based on spirometric results and arterial blood gas analysis. No specific PAH gene mutations were identified. The patient had obvious chest tightness and shortness of breath, and right heart catheterization showed moderate pulmonary hypertension, and serum VEGF was markedly increased which may explain the occurrence of PAH. According to a retrospective study of 137 patients with POEMS syndrome carried out in the United States, 25% of patients also had pulmonary disease[19], in particular, pulmonary hypertension, and severe pulmonary hypertension could cause right heart failure or death. The pathogenesis of POEMS syndrome-associated pulmonary hypertension is currently unclear; however, excessive production of immune mediators in POEMS syndrome with pulmonary hypertension has been reported by Feinberg et al[20]. Increased baseline levels of VEGF, TNF-α, IL-6, abnormally low levels of sIL-6R and HHV-8 infection appear to be associated with the pathogenic manifestations of POEMS syndrome with PAH[21-23].Overproduction of serum VEGF was another meaningful presentation in this patient. Data from several reports have identified increased VEGF level as a useful biomarker for POEMS syndrome, which may also assess disease activity and correlate with therapeutic response[14, 24-25]. Fulfillment of the diagnostic criteria together with other findings prompted the diagnosis of POEMS syndrome in this patient. VEGF is expressed by osteoblasts, macrophages, tumor cells[14], plasma cells[26-27], and megakaryocytes/platelets[28]. VEGF targets endothelial cells, leads to a fast and irreversible increase in neovascularization and vasopermeability which may trigger symptoms of POEMS syndrome, such as angiomata, pleural effusion, edema, polyneuropathy, and organomegaly. Plasma cells and platelets both release VEGF in POEMS syndrome, and due to the secretion of VEGF from platelets in vitro during serum processing, serum VEGF level is higher than plasma VEGF level. The plasma VEGF critical value is 200 pg/mL (specificity: 95%; sensitivity: 68%)[6], the serum VEGF critical value is 1 920 pg/mL (specificity: 98%; sensitivity: 73%)[29]. However, overexpression of VEGF in serum can also be observed in other diseases, such as rheumatoid arthritis, systemic lupus erythematosus and multiple myeloma. Wang et al revealed a correlation between N-terminal propeptide of type I collagen and POEMS syndrome. They demonstrated that N-terminal propeptide of type I collagen was a new biomarker for the diagnosis of POEMS syndrome and the best threshold of this biomarker in the diagnosis of POEMS syndrome is 70 ng/mL (specificity: 91.5%; sensitivity: 80%)[29].Castleman’s disease is currently considered to be an unexplained reactive lymphoproliferative disorder[30], and is one of three other major criteria in the diagnosis of POEMS syndrome[7]. Castleman’s disease or Castleman-like histology occurs in 11%–30% patients with POEMS syndrome[31]. Castleman’s disease is classified into two major types: unicentric CD (UCD) and multicentric CD (MCD). A subset of multicentric CD (MCD) is caused by human herpesvirus-8 (HHV-8) (HHV-8-associated MCD), while HHV-8-negative MCD cases remain idiopathic (iMCD)[32]. Castleman’s disease and HIV also have strong relationships[33]. Castleman’s disease is a diagnosis of exclusion, and the ultimate investigation is a pathological diagnosis made by excisional biopsy of affected lymph node tissue, it can be classified into three types based on pathological characteristics: hyaline vascular type (HV), plasma cell type (PC) and mixed type[34]. In the hyaline-vascular subtype, the centers of the huge folliculus lymphaticus are atrophied, numerous hyalinized blood vessels are increased, and a portion have an “onion-skinning” appearance[35-36]. In the plasmacytic subtype, the lymphoid follicles are variably characterized by germinal centers which are hyperplastic or regressive[34], and the plasma cells are mainly spread throughout the interfollicular areas[37]. In the mixed type, it has the typical histology of the mixed form, and there are numerous immunoblasts. In this case, our patient without any pathological features of increased numbers of hyalinized blood vessels, hyperplastic or regressive changes in the follicles of involved lymph nodes, or obvious “onion-like skin” appearance, and the patient’s laboratory examinations showed that the HIV antibody was negative. So our patient could not be diagnosed as Castleman’s disease. VEGF is the most consistently elevated cytokine of POEMS syndrome, in contrast to POEMS syndrome, IL-6 is the major abnormally overexpressed cytokine of Castleman’s disease[7]. In CD, the PN is less frequent, more subtle, and more sensory than that of POEMS patients. Only patientsPOEMS syndrome presenting with abdominal distension, lower limb edema and shortness of breath: A case report and literature review ZHANG Jiayi , et al 711(ASCT) and the use of drugs, such as alkylators, corticosteroids, bevacizumab, rituximab, bortezomib, and thalidomide [55-56]. Radiotherapy doses in patients with fewer than three bone lesions, no bone-marrow involvement and no medullar infiltration, should be 40 Gy or more [57-58]. ASCT is effective in POEMS syndrome [59-60], although it seems to be accompanied by a worrying number of complications [61]. Dexamethasone, thalidomide and lenalidomide are also beneficial in patients with POEMS syndrome [62-63].In conclusion, POEMS syndrome is rare, delayed diagnosis combined with advanced stage lead to a poor prognosis; therefore, recognition and early diagnosis of this syndrome are crucial. This case will contribute to an improved understanding of the clinical presentation and laboratory indicators of POEMS syndrome. With further research, a more comprehensive recognition and scientific basis of the disease will provide the best treatment strategies in the future.References[1]Dispenzieri A, Kyle RA, Lacy MQ, et al. POEMS syndrome: definitions and long-term outcome[J]. Blood, 2003, 101(7): 2496-2506.[2]Dispenzieri A. POEMS syndrome: update on diagnosis, risk-stratification, and management[J]. Am J hematol, 2015, 90(10): 951-962.[3]Li J, Zhou DB, Huang Z, et al. Clinical characteristics and long-term outcome of patients with POEMS syndrome in China[J]. Ann Hematol, 2011, 90(7): 819-826.[4]Scarlato M, Previtali SC, Carpo M, et al. Polyneuropathy in POEMS syndrome: role of angiogenic factors in the pathogenesis[J]. Brain, 2005, 128(Pt 8): 1911-1920.[5]Goto H, Nishio M, Kumano K, et al. Discrepancy between disease activity and levels of vascular endothelial growth factor in a patient with POEMS syndrome successfully treated with autologous stem-cell transplantation[J]. Bone Marrow Transplant, 2008, 42(9): 627-629.[6]D ’Souza A, Hayman SR, Buadi F, et al. The utility of plasma vascular endothelial growth factor levels in the diagnosis and follow-up of patients with POEMS syndrome[J]. Blood, 2011, 118(17): 4663-4665.[7]Dispenzieri A. POEMS syndrome: 2017 Update on diagnosis, risk stratification, and management[J]. Am J Hematol, 2017, 92(8): 814-829.[8]Bardwick PA, Zvaifler NJ, Gill GN, et al. Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, M protein, and skinwith PN and a plasma cell clone can be diagnosed with POEMS syndrome, and if a patient has other POEMS symptoms, but without these two features, the patient can be classified as having Castleman’s disease.PN is one of the mandatory major criteria, and it is normally depicted as a ascending, peripheral, symmetrical, and demyelinating on ner ve conduction studies (NCS)[38-39]. POEMS syndrome should be differentiated from other neuropathies associated with monoclonal gammopathies such as monoclonal gammopathy of undetermined significance (MGUS)[40-42]. The presence of a λ-type IgA or IgG monoclonal gammopathy is required for the diagnosis of the POEMS syndrome. In MGUS-associated neuropathy the paraprotein is IgM more generally [43-44]. The most typical presentation in IgM MGUS is distal acquired demyelinating symmetric neuropathy [45], which manifests slowly progressive sensory neuropathy with predominantly distal numbness, ataxia, and mild to no weakness. IgM isotype is also associated with Waldenström’s macroglobulinemia (WM), a lethal lymphoproliferative disease characterized by a monoclonal lymphoplasmacytosis within the bone marrow and/or the peripheral lymphatic tissue accompanied by an elevated serum IgM M protein [46-47], and most of patients have myelin-associated glycoprotein (MAG) antibodies on serologic testing [48]. Although WM and POEMS syndrome may both have neuropathy and papilloedema [49], a bone marrow biopsy is effective to distinguish the two diseases [50-51]. PN is a usual presentation of primary amyloidosis (AL), which is a multisystemic disease characterized by widespread amyloid deposition. The PN in AL is typically a progressive, distal, symmetric sensory neuropathy with autonomic dysfunction. The main clinical features of AL included loss of light touch and temperature sensation, painful dysesthesia, and marked autonomic involvement [52-53]. The diagnosis depends on the histological confirmation, which can be accomplished through Congo red staining or mass spectrometry of biopsied tissue. The histological examination demonstrates the amyloid deposits in tissue obtained from involved organs [53]. POEMS syndrome and AL can be differentiated by bone marrow findings and the plasma or serum VEGF level [7, 54].Due to the rarity of the disease, prospective therapeutic clinical trials are rare. To date, treatment strategies for POEMS syndrome include radiation, chemotherapy, autologous stem cell transplantation中南大学学报(医学版), 2019, 44(6) 712changes: the POEMS syndrome. Report on two cases and a review ofthe literature[J]. Medicine, 1980, 59(4): 311-322.[9] Nakanishi T, Sobue I, Toyokura Y, et al. The Crow-Fukase syndrome:a study of 102 cases in Japan[J]. Neurology, 1984, 34(6): 712-720.[10] Takatsuki K, Sanada I. Plasma cell dyscrasia with polyneuropathy andendocrine disorder: clinical and laboratory features of 109 reportedcases[J]. Jpn J Clin Oncol, 1983, 13(3): 543-555.[11] Kulkarni GB, Mahadevan A, Taly AB, et al. Clinicopathologicalprofile of polyneuropathy, organomegaly, endocrinopathy, M proteinand skin changes (POEMS) syndrome[J]. 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