Pulmonary amyloidosis and multiple myeloma mimicking lymphoma in a patient with Sjogren’s syndrome: A case report

INTRODUCTION

We diagnosed the patient with pulmonary amyloidosis and multiple myeloma involving extramedullary organs (stomach, lymph nodes) associated with SS.

CASE PRESENTATION

Chief complaints

A 46-year-old male patient was admitted for treatment of an incidental gastric plasmacytoma.

History of present illness

根据一份针对大学生二手物品市场的调查报告，得知83.4%的大学生拥有闲置物品，并且多达38.6%的大学生拥有2～3件，仅2.7%的大学生宿舍闲置物品只有一件。由此可以看出，大学生二手市场具有不可小觑的规模，而且学生属于一类特殊群体，其还没有收入渠道，同时学生之间有一定相同的兴趣爱好、具有类似的消费心理。共同的生活环境—宿舍，寝室-食堂-教室三点一线的生活起居使得大学生交易的商品具有共性(如：书本、生活用品、体育用品、代步工具等)，学生之间的交易也愈加频繁，这也是造成交易需求压力增大的原因之一。

而在“英印人”独特体验的书写上，研究者们更多地关注吉卜林在身份认同方面的焦虑与不安。殊不知，凭借独特的人生经历及智慧，吉卜林在主人公基姆身上实践了对自己理想的身份的认同。

History of past illness

为便于验证“千聊”对于MOOC结课率的影响，笔者将网络公选课班级分为2个小组，其中，A组学生为60人，B组学生为58人。A组学生使用“千聊”进行自主学习，B组学生使用超星学习通APP进行学习，两个平台的课程的课件、习题、预习资料、微课资源完全一致。

第一，往大处想——定义一个更加宽泛的问题，不断地问“这个问题背后更大的问题是什么？”和“我们要达到的更好的效果是什么？”让思维获得更多的自由，从而想出更多的解决方案。第二，换位思考——进入你想模仿的人或公司的思维模式，重新审视遇到的问题，放开平常的限制，会发掘出新的、未想到过的解决方法。第三，强加约束——给现状引入一个强有力的限制，探索这样做能带来什么样的好处。第四，选择构架——怎么创造一种环境，让人们在这种环境中选择我们想要他们采取的行动。

Personal and family history

The patient had been diagnosed with SS four years ago due to dry eyes and dry mouth, and his symptoms improved after treatment with methotrexate, hydroxychloroquine. However, prednisolone was added two months ago due to swelling of the parotid glands and enlargement of lymph nodes.

Physical examination

A physical examination revealed painless lymph nodes of variable size in both inguinal areas and both neck areas.

他拖着胶鞋，啪哒啪哒走向外屋，又摸索着抓起几粒盐，把指头伸到嘴里，用上个月才安的门牙咬破水泡，在伤口撒上盐。他的整张脸痛得纠在一起，两根手指紧紧捏着那根受伤的指头。疼痛慢慢消减了，他又爬到床上，关掉电筒。

The patient was checked by a positron emission tomography (PET) scan due to enlargement of both inguinal lymph nodes more than two months ago. The PET scan revealed hypermetabolic activity in the gastric body, both inguinal lymph nodes(Figure 1A). A gastroscopic biopsy of the stomach lesion was performed and diagnosed with plasmacytoma (Figure 2).

Laboratory examinations

Although SS is typically known as an autoimmune disorder, it can also present as lymphoproliferative disease. The form of lymphoproliferative disease can present as polyclonal lymphocytic infiltration of the salivary glands, oligo- or monoclonal B cell proliferation resulting in clonally derived lymphoproliferative disorders such as monoclonal gammopathy, light-chain amyloidosis, and malignant lymphoma[3,4,6-9].SS often involves interstitial lung disease, sometimes primary pulmonary lymphoma,pleuritis, but occurrence of pulmonary amyloidosis is very rare[14].

Imaging examinations

The PET-computed tomography (CT) revealed hypermetabolic activity in the gastric body, a mild increase in metabolic activity in both inguinal areas, and ground glass opacities (GGO) and centrilobular nodules in both lung fields (Figure 1A). A chest CT showed patch GGO and multiple nodules in both lung fields (Figure 1C) and an abdominal CT showed multiple enlarged lymph nodes in the bilateral inguinal area(Figure 1D).

FURTHER DIAGNOSTIC WORK-UP

An excisional lymph node biopsy was performed for differential diagnosis of pulmonary tuberculosis with tuberculous lymphadenitis from lymphoma. Biopsy of the right inguinal lymph node revealed diffuse infiltration of plasma cells, which were positive for CD 138, Kappa, and lambda chain immunohistochemical staining(Figure 3). The results of a bone marrow biopsy showed that plasmas cells were increased to 34% and immunostain of IgG, IgA, kappa, and lambda was positive.

突出表现为生态系统产出下降，特别是渔业资源显著下降，长江干流的年捕捞产量由20世纪50年代的40多万t下降到现今的不足10万t，且鱼类资源小型化趋势明显。水生态系统结构受损，环境承载力和对污染的处理能力下降，局部江段和湖泊污染严重、水华时有发生，影响饮用水安全。

Systemic chemotherapy was planned for the multiple myeloma, however the patient was transferred to a larger hospital.

FINAL DIAGNOSIS

Primary Sjogren’s syndrome (SS) is a chronic systemic autoimmune disease characterized by decreased organ function by lymphocyte infiltration, not only exocrine gland but also extraglandular organ[1]. Major B cell activation is the main pathogenesis of SS and continuous activation of B cells can lead to clonal proliferation and malignant lymphoma[2-4]. Clonal proliferation of B cells may lead to both monoclonal gammopathy of undetermined significance, a benign monoclonal gammopathy, and multiple myeloma (MM), a hematologic malignancy[5-9]. However,in practice, multiple myeloma is very rare[6,7,10]. Amyloidosis is a heterogeneous group of disorders characterized by deposits in the extracellular matrix of abnormal protein material. The incidence of amyloidosis is low and that of amyloidosis with involvement of only the respiratory system is extremely low[11,12]. In particular,amyloidosis is a rare cause of pulmonary infiltration in SS[13]. Simultaneous occurrence of pulmonary amyloidosis and multiple myeloma associated with SS is extremely rare.

TREATMENT

A lung biopsy was also performed to rule out pulmonary tuberculosis, interstitial lung disease, or lung involvement of multiple myeloma. Lung biopsy revealed chronic inflammation showing multinucleated giant cells and deposition of amorphous proteinaceous material (Figure 4A). Infiltration of lymphoplasmacytes was observed in the interstitium and perivascular area (Figure 4B). In addition, Congo-red stain for amorphous proteinaceous material revealed apple green birefringence under a polarized microscope. Mycobacterium tuberculosis nested polymerase chain reaction to exclude pulmonary tuberculosis was negative.

OUTCOME AND FOLLOW-UP

The patient was transferred to another hospital and underwent chemotherapy. He is on regular follow up for SS to our rheumatology department and is on medication.

DISCUSSION

The complete blood count results, with normal ranges in parentheses, were as follows:white blood cells, 5160 × 10/μL (4.0–10.0 × 10/μL); hemoglobin, 13.3 g/dL (12–16 g/dL); platelets, 305 × 10/μL (150–400 × 10/μL). Blood biochemistry results were as follows: total protein 9.03 g/dL (5.3-7.4 g/dL); albumin 3.74g/dL (3.5-5.2 g/dL), A/G ratio 0.71 (1.0-2.0); C-reactive protein, 0.49 mg/dL (0–0.3 mg/dL). The results of serum protein electrophoresis showed an increase in the total protein amount, a decrease of albumin, and a slightly sharp increase of gamma-globulin. The results of serum immunofixation electrophoresis revealed oligoclonal gammopathy; multiple dense bands were observed in IgG, IgA, kappa, and lambda antisera. The results of Ig quantification showed IgG 2540 mg/dL (700-1600); IgM 18.3 mg/dL (40-230 mg/dL);IgA 1220 mg/dL (70-400 mg/dL). B2-microglobulin level was increased to 2.8 mg/L(0.0-2.4 mg/L). The results of a serum free light chain assay revealed increased kappa light chain (420.60 mg/L, normal 3.3-19.40 mg/L) and an increased kappa/lambda light chain ratio (34.9, normal 0.26-1.65). Alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenase, calcium, and creatinine were all within normal limits.

Amyloidosis is a disease group; certain proteins such as amyloid fibrils are deposited in extracellular tissue. Amyloidosis can be classified as primary and secondary. Primary amyloidosis is caused by clonal plasma cell proliferation which appears in monoclonal gammopathy or myeloma and the associated abnormal proteins consist of fragments of immunoglobulin light chain such as kappa and lambda (light chain amyloidosis)[15]. Secondary amyloidosis is the reactive systemic amyloidosis usually associated with chronic inflammatory diseases or neoplasms and the associated fibrils are composed of fragments of the acute phase reactant serum amyloid A (reactive amyloidosis)[15]. These two types are the most common form of amyloidosis. Amyloid deposition is rare in SS patients, but when it does occur,multiple organs are affected, such as skin, kidney, breast, tongue, and lymph nodes, as well as the lung[16-21]. However, only about 50 cases related to primary SS and pulmonary amyloidosis have been reported so far[22]. Amyloidosis of the lungs has three different clinicopathologic forms: diffuse alveolar-septal amyloidosis (diffuse parenchymal amyloidosis), nodular pulmonary amyloidosis (nodular parenchymal amyloidosis), and tracheobronchial amyloidosis[23]. Diffuse alveolar-septal amyloidosis is characterized by amyloid deposition in the alveolar septa and vessel walls, and transbronchial amyloidosis is characterized by amyloid deposition in various segments of the tracheobronchial tree[23]. Nodular pulmonary amyloidosis can be defined as one or more tumor-like amyloid deposits involving the lungs[23].Pathologically, well circumscribed nodules with homogeneous and dense eosinophilic material, lymphocytes and plasma cells are generally found within or nearby nodules[23]. Other pathologic findings that may appear include foreign body giant cells,calcifications, and bony or cartilaginous areas[23]. Lung biopsy of our patient revealed chronic inflammatory nodules showing multinucleated giant cells and deposition of amorphous proteinaceous material (Figure 4A). Infiltration of lymphoplasmacytes was observed in the interstitium and perivascular area (Figure 4B). Congo-red stain for amorphous proteinaceous material revealed apple green birefringence under a polarized microscope.

In MM, monoclonal immunoglobulin is produced by plasma cell neoplastic proliferation of plasma cells. There are two categories of MM, according to diagnostic criteria for plasma cell proliferative disorders. The first is asymptomatic multiple myeloma (smoldering multiple myeloma), which is serum monoclonal protein more than 3 g/dL and/or clonal bone marrow plasma cells more than 10% but absence of end-organ damage[5]. Symptomatic multiple myeloma satisfies all of the following:more than 10% clonal bone marrow plasma cells and presence of serum and/or urinary monoclonal protein and evidence of end-organ damage[5].

This patient had increased serum protein IgG, IgA, and Kappa light chain, and plasma cells in the bone marrow were increased to 34%. Although there was no endorgan damage such as anemia, renal insufficiency, hypercalcemia, and bone lesions,plasmacytomas were observed in multiple lymph nodes and stomach as end-organ involvement. This patient was expressed as the type of extramedullary plasmacytoma in multiple myeloma.

Plasmacytomas, tumors composed of plasma cells, are histologically identical to those observed in MM[24]. Those that occur solely in the bone are designated solitary plasmacytoma of bone[25]. Those that arise outside bone in soft tissues are called solitary extramedullary plasmacytoma (EMP)[25]. EMP can arise anywhere in the body. The incidence of extramedullary disease with newly diagnosed MM is variable,ranging from 7%-13%[26]. EMP arise most commonly from direct extension of primary bone tumors, but rarely they may also result from hematogenous spread involving distant organs[26].

The incidence of benign monoclonal gammopathy in SS patients is relatively high and a prevalence of monoclonal gammopathy in primary SS patients of 7% to 22% was recently reported[6-8], however, the prevalence of MM is very rare[6,7,10]. IgG is the most common class associated with MM[7]. This report describes a patient with SS associated with IgG and IgA-kappa-type MM.

Amyloidosis and MM associated primary SS is rare but can occur respectively.However, no cases of simultaneous occurrence of MM and amyloidosis in patients with SS have been reported. Of course, there is a limitation which cannot rule out the occurrence of pulmonary amyloidosis caused by MM. However, abnormal proteins of pulmonary amyloidosis caused by MM consist of fragments of immunoglobulin light chains such as kappa and lambda. Pulmonary amyloidosis was diagnosed in our patient’s lung biopsy, but immunohistochemistry of kappa and lambda was negative.Therefore, we report a rare case diagnosed simultaneously with pulmonary amyloidosis and multiple myeloma associated with SS.

CONCLUSION

SS is a chronic inflammatory disease characterized by decreased organ function by lymphocyte infiltration, not only exocrine gland but also extraglandular organ.Interstitial lung disease is the most common pulmonary abnormality in primary SS,but pulmonary amyloidosis is rare. Monoclonal gammopathy can also occur, but progression to MM is rare in primary SS. To the best of our knowledge, simultaneous development of MM and pulmonary amyloidosis in primary SS patients has not been reported so far. Herein, we report the extremely rare case of pulmonary amyloidosis and multiple myeloma associated with SS.