胰腺炎可以表现的像癌症一样：一例胃癌的患者发生了淋巴浆细胞硬化性胰腺炎

Title：Pancreatitis Can Present Like Cancer: Lymphoplasmacytic Sclerosing Pancreatitis in a Patient with a History of Gastric Carcinoma
题目：胰腺炎可以表现的像癌症一样：一例胃癌的患者发生了淋巴浆细胞硬化性胰腺炎
 
Authors:
Susana Rocha Amaral1, Luís Elvas2, Tatiana Pereira1, Paula Jacinto1, Gabriela Sousa1 1Medical Oncology Department, Instituto Português de Oncologia de Coimbra, Coimbra, Portugal 2Gastroenterology Department, Instituto Português de Oncologia de Coimbra, Coimbra, Portugal
作者：
Susana Rocha Amaral1, Luís Elvas2, Tatiana Pereira1, Paula Jacinto1, Gabriela Sousa1 1Medical Oncology Department, Instituto Português de Oncologia de Coimbra, Coimbra, Portugal 2Gastroenterology Department, Instituto Português de Oncologia de Coimbra, Coimbra, Portugal
Received: 09/07/2019 Accepted: 25/07/2019 Published: 06/08/2019
接收：09/07/2019  接受：09/07/2019 发表：06/08/2019
 
翻译：张卫   审校：张立超 侯森林
 
ABSTRACT
Autoimmune pancreatitis has been associated with many syndromes in the presence of increased immunoglobulin levels. IgG4 antibodies are elevated in the context of lymphoplasmacytic sclerosing pancreatitis associated with IgG4-related disease. We present the case of a 74-year-old man diagnosed with autoimmune pancreatitis on a cancer background. Awareness of this condition in the cancer patient is crucial for timely diagnosis. Infectious complications might have implications for the choice of immunosuppressant.
摘要
自身免疫性胰腺炎与许多因免疫球蛋白水平升高引起的疾病综合症表现相关。在淋巴浆细胞硬化性胰腺炎的IgG4相关疾病中，IgG4自身抗体表达水平是升高的。我们列举了一位74岁的癌症老年患者，他被诊断为自身免疫性胰腺炎。对于癌症的患者，预知自身免疫性胰腺炎，对于做出及时的诊断是非常重要的。这样的病人出现感染的并发症，可能会影响免疫抑制剂的选择。
LEARNING POINTS

• Autoimmune pancreatitis can mimic pancreatic cancer, thus delaying diagnosis in patients with cancer. 

• It is important to rule out malignancy and distinguish autoimmune pancreatitis from pancreatic cancer, but obtaining a sample of pancreatic tissue can be diffcult. 

• Steroids are the mainstay of initial treatment, but there is growing evidence for the use of other immunomodulators, such as rituximab, 
for induction and maintenance or as an option for patients at high risk of relapse. 


学习要点：
1.自身免疫性胰腺炎可以表现的像胰腺癌一样，因此会把病人误诊为胰腺癌。
2.从胰腺癌中排除恶性肿瘤和鉴别自身免疫性胰腺炎这是非常重要的，但是得到胰腺组织的样本是非常困难。
3.类固醇激素是目前主要的治疗方案，但是越来越多的证据表明用其他的免疫调节剂，例如：利妥昔单抗用于诱导和维持，或者作为复发高风险的病人的一种治疗选择。
INTRODUCTION 

Autoimmune pancreatitis (AIP) is a chronic fibroinflammatory disease of the pancreas that belongs to the spectrum of immunoglobulin G-subclass 4-related diseases (IgG4-RD). Lymphoplasmacytic sclerosing pancreatitis (LPSP) typically presents with painless obstructive jaundice. Pancreatic imaging, measurement of serum IgG4 levels, and determination of other organ involvement are all helpful for distinguishing AIP from pancreatic cancer. LPSP is highly responsive to steroids, but immunomodulators should be included in induction therapy in patients who fulfil the severity criteria.
介绍
自身免疫性胰腺炎（AIP）是一种慢性纤维化的疾病，属于IgG4相关疾病（IgG4-RD）中的一种。淋巴浆细胞硬化性胰腺炎（LPSP）的典型变现为无痛性黄疸。胰腺的影像学表现以及实验室血清的IgG4水平，以及其他器官有无累及，对于鉴别胰腺癌和AIP都是有帮助的。LPSP对于类固醇激素是非常敏感的，但是对于符合标准的病人，应该考虑免疫调节剂作为诱导性的治疗。
CASE DESCRIPTION 

A 74-year-old Caucasian man presented to the outpatient clinic in May 2018 with painless obstructive jaundice. He had a history of stage IIA gastric cancer in 2013 (submitted to perioperative chemotherapy with six cycles of cisplatin+5- fluorouracil and total gastrectomy with complete pathological response) and also of non-muscle-invasive bladder cancer in 2017 (submitted to trans-urethral resection). Colangio-MRI was performed and showed a mass measuring 40×30×40 mm in the head of the pancreas and causing obstruction of the main pancreatic and biliary duct leading to dilatation of the biliary tree。
2018年5月，一名74岁的白人男子因无痛性黄疸来到门诊。他在2013年确定为IIA期胃癌（接受了全胃切除术，组织学病理提示对顺铂+5-氟尿嘧啶化疗敏感，并进行了6周期的化疗）,并且在2017年被确诊为膀胱癌，但并未累及肌层（行经尿道膀胱癌切除术）。胆道核磁发现了一个位于胰头部大小约40x30x40mm的肿块，这个肿块造成了主胰管及胆管的扩张。
Tumour markers (CEA, CA19.9) were normal. IgG4 levels were not measured. A percutaneous pancreatic biopsy was performed since endoscopic ultrasonography was not feasible due to the surgical history. The specimen did not show any histological changes compatible with malignancy or inflammatory disease. A biliary stent was inserted. The patient was discharged with clinical and imaging re-evaluation scheduled within the following 3 months.
肿瘤标记物（CEA，CA199）是正常的，血清IgG4水平未检测。由于既往外科手术的病史，没有选择超声内镜穿刺活检，而是选择经皮胰腺组织穿刺活检。活检标本并没有发现肿瘤及全身性疾病的组织学病理表现，所以选择了放置胆管支架予以出院，并进行了3个月的临床随访及影像学的复查。
Shortly before the date of re-evaluation, the patient was admitted to hospital because of new-onset ascites, peripheral oedema and acute kidney injury. He was pale, thin and dehydrated, with a distended abdomen without palpable masses, and oedema below the knees. The laboratory work-up revealed normocytic/normochromic anaemia, hypoalbuminaemia, normal bilirubinaemia, increased alkaline phosphatase and aminotransferases, increased IgG4, acute kidney injury and hyponatraemia 。
 再进行复查前不久，这个病人因为新发的腹水，外周水肿和急性肾功能不全被收治入院，入院时患者面色苍白，消瘦和脱水的状态，腹胀，但腹部并未触及肿块,合并下肢的水肿。实验室检查显示，正常红细胞/非正常红细胞性贫血，低蛋白血症，胆红素正常，碱性磷酸酶及氨基转移酶是升高的，IgG4水平是升高的，并且合并急性肾损伤和低钠血症。
Diagnostic paracentesis showed no signs of infection or malignancy. The abdominal CT scan showed an increase in the size of the pancreatic mass and portal vein thrombosis. Percutaneous biopsy was repeated and showed lymphoplasmacytic foci, marked storiform fibrosis, CD138 positivity and IgG4 expression
诊断性穿刺并未提示感染征象，并没有找见肿瘤细胞。腹部增强CT显示胰腺肿块增大同时合并门脉血栓。再次行经皮穿刺活检，显示病灶淋巴细胞浸润，并伴有纤维样坏死，CD138及IgG4高表达。
The diagnosis of LPSP was established and the patient started treatment with steroids (40 mg/day) and anticoagulation for the portal vein thrombosis. During his hospital admission, the patient developed Escherichia coli bacteraemia that first manifested as cholangitis, which required intravenous antibiotics. The patient responded partially to the treatment (his IgG4 level dropped to 1379) and a first attempt at steroid tapering was made. However, the patient deteriorated clinically and had to be readmitted to hospital. The dose of steroids was increased to 40 mg/day with no improvement. The patient’s clinical situation rapidly declined due to severe sepsis which started as another episode of cholangitis. There was no response to broad-spectrum intravenous antibiotics and the patient died on day 12.
病历介绍
这个病人被确诊为LPSP，开始接受类固醇激素的治疗（40mg/天）并且针对门脉血栓选择应用抗凝药物。在病人住院期间，病人发生了菌血症，第一次表现为胆管炎，并应用抗生素治疗。患者对第一次使用类固醇激素治疗有部分反应（IgG4水平回降至1379）。然而，病人的情况恶化使他不得不再次住院。因为严重的败血症，再次发生胆管炎，同样的类固醇激素的剂量（40mg/天）并没有改善，病人的情况很快恶化。病人因为没有有效的广谱抗生素治疗在12天后而死亡。
DISCUSSION
LPSP is the pancreatic manifestation of systemic IgG4-RD. The typical patient with LPSP is over 60–70 years of age, with male predominance (3:1). Other clinical presentations include a pancreatic mass on imaging, focal or diffuse pancreatic enlargement, pancreatic ductal strictures and rarely, acute pancreatitis. The clinical presentation can mimic other types of pancreatitis and pancreatic cancer. The incidence of malignancy in patients with IgG4-RD is similar to that observed in the general population. However, the incidence of AIP in patients with cancer is unknown and hard to establish particularly because of the difficulties of diagnosis.
LPSP是IgG4相关疾病中胰腺受累及。绝大多数术LPSP病人发病年龄在60-70岁之间，男性为主（3：1），其他临床表现为：影像学提示胰腺肿块，胰腺局灶或者弥漫性肿大，胰管狭窄、急性胰腺炎。他的临床表现也可以像其他类型的胰腺炎或者胰腺癌。IgG4相关疾病的病人肿瘤的发生率与普通人群比是相似的。然而，对于肿瘤的病人来说，AIP的发生率是不明确的，也是很难确定的，因为它的诊断很困难。
 
Patients with LPSP most commonly present with a cholestatic pattern of liver enzyme elevation and raised IgG4 levels (>2 times the upper limit of normal). The diagnosis of LPSP is based on histological and imaging findings. The key histological finding is lymphoplasmacytic infiltration rich in IgG4-positive plasma cells combined with storiform fibrosis and obliterative phlebitis. Imaging studies show a diffusely enlarged gland with featureless borders and delayed enhancement with/without a capsule-like rim. In our case, the diagnosis was delayed mainly due to lack of awareness of this condition and the high probability of malignancy. Consequently, treatment with steroids was delayed for 3 months when there was decompensated cholestatic hepatic disease.
LPSP的病人大部分表现为胆管炎，肝酶和IgG4水平升高（超过正常上限的2倍）。LPSP的诊断是依靠组织学和影像学的表现。重要的组织学发现是淋巴细胞大量的浸润，IgG4浆细胞合并纤维样改变和闭塞性脉管炎。影像学表现为胰腺弥漫性改变，边界不清和有/无囊状边缘的延迟强化。在我们的这个病历中，AIP被延误诊断主要是由于缺少认识这种情况和高度怀疑肿瘤的可能。因此类固醇激素的治疗被延迟了3个月，这个时候病人已经出现了胆汁淤积性肝病。
 
Steroids are a cornerstone in the management of LPSP. Most patients show remarkable initial improvement with prednisone administration as shown by a decrease in liver enzymes. The recommended regimen is prednisone 40 mg/day for 4 weeks, and slow tapering by 5 mg/week after evaluation of clinical, radiological and serological response. Other immunosuppressant therapy, such as rituximab, might be considered for induction in patients with risk factors for relapse: proximal biliary involvement, younger age and high alkaline phosphatase. Our patient had two criteria for the use of rituximab and his disease was refractory to therapy with steroids. However, infectious complications precluded the use of this B-cell depletion therapy. 类固醇激素作为治疗LPSP的基石。大部分的病人在服用强的松后有明显的改善，表现为肝酶的下降。推荐的治疗方案是40mg/天，治疗4周，临床评估血清学及影像学的改变，缓慢减量5mg/周。其他免疫抑制剂治疗，例如利妥昔单抗，对于高风险复发的病人（胆管下端受累，年轻和高碱性磷酸酶的患者），可以考虑作为诱导性的治疗。我们的这个病人有两个使用利妥昔单抗的标准，他的疾病是难以用类固醇治疗的。然而感染的并发症使他难以应用B细胞耗竭这种治疗方案。
 
The diagnosis of LPSP is difficult, particularly in the cancer patient, where the diagnostic assessment is sometimes simplified and the therapeutic intervention tailored for symptom management. Higher awareness of the diagnosis could have resulted in earlier introduction of steroid therapy in our patient. Stratifying the risk for relapsing disease is mandatory. Infectious complications commonly limit therapeutic intervention in these patients.
讨论
LPSP的诊断是困难的，特别是对于伴有癌症的患者。诊断的评估有时是简单的，需个体化治疗。针对我们的这个病人，我们很缺乏AIP诊断的意识，使病人没有早期接受的类固醇激素治疗。必须对高风险复查的病人进行分类，出现感染的并发症后，对于AIP病人的治疗往往都是受限制的。