Reactive lymphoid hyperplasia of the liver: A rare case report

1 Introduction

Reactive lymphoid hyperplasia (RLH), also known as pseudolymphoma or nodular lymphoid disease, occurs mostly in the lungs, skin, ocular adnexal, thyroid gland, breast, gastrointestinal tract, pancreas, and rarely in the liver [1–6]. Liver RLH patients are mostly middle-aged and elderly women, often found by chance. The imaging findings are similar to those of liver malignant tumors, and preoperative diagnosis is quite difficult [7]. The pathological features of RLH are significant proliferation of non-neoplastic polyclonal lymphocytes with a germinal center in the center and no cell atypia [8]. Here, we report a case of hepatic RLH in a patient who was misdiagnosed with metastatic liver cancer before surgery and underwent laparoscopic resection.

2 Case presentation

A 69-year-old female with no special discomfort was found a mass in the upper left external lobe of the liver after re-examination of the ground glass nodule of the lung. Serological data showed that tumor markers (AFP, CEA and CA199) were normal. Blood routine, liver function and coagulation tests were within the normal range, and hepatitis virus markers were negative. To confirm the diagnosis, the patient underwent further tests. Conventional ultrasound showed a background of fatty liver with a low-echo mass about 1.5×1.2 cm near the top of the diaphragm in the left external lobe of the liver. Ultrasonic elastography showed that the elastic hardness of the right lobe of liver was normal. Contrast-enhanced ultrasound showed that after SonoVue injection, the S2 lesions began to enhance at 19 s and earlier than the surrounding hepatic parenchyma. Then showed high enhancement and peaked at 22 s, followed by equal-enhancement in 30 s, and finally low-enhancement in 35 s. The contrast agent further subsided in the portal and the delayed phase, and there were no other abnormal regression areas in the remaining liver during the delayed phase, indicating that the diagnosis of metastatic liver cancer was highly likely (Fig. 1). Upper abdominal plain scan + enhancement + DWI + MRCP showed that the liver surface was uneven and the opposed phase signal was slightly reduced. There was a circular-like abnormal signal focus in the S2 segment of liver with a diameter of about 1.7 cm and clear boundary. T1-weighted images (T1WI) showed low signal, while T2-weighted images (T2WI) showed slightly high signal. The lesion showed high signal on diffusion-weighted images (DWI) and low apparent diffusion coefficient (ADC) signal. In the early stage of enhancement, the lesion showed obvious enhancement, relatively low signal in the portal and delayed stages, and annular envelope enhancement was observed in the later stage, indicating a suspected metastatic liver cancer (Fig. 2). Since all imaging studies indicated metastatic liver cancer, the patient underwent a laparoscopic partial hepatectomy (left external lobe). Intraoperative exploration showed no abdominal adhesion, liver sclerosis, or ascites. The tumor was about 1.5×1.5×1.5 cm in size and located in the S2 segment. It had clear boundary and without a tumor capsule. There was no hilar lymph node enlargement or cancer embolus in the portal vein. Postoperative pathology showed that the size of the surgically removed part of the liver was about 11×7.5×4.5 cm, and the size of the mass was about 1.6×1.4×1.3 cm. The cross-section of the mass was sallow and tough, and the surrounding liver tissue was delicate and earthy yellow. Low-power microscopic examination of HE stained sections showed that the boundary between the lesion and the surrounding normal liver tissue was clear, showing a pushing growth, and the suspected fibrous envelope was segmented from the surrounding liver tissue in some areas. A large number of proliferative polyclonal lymphoid tissues were found in the lesion. The cells were diffusely distributed, mainly reactive lymphoid follicles, and the center was the germinal center. High magnification showed that the cell size was consistent, the nuclei had no obvious atypia, and no clear mitotic image was observed. Eosinophilic fibrillary gel was deposited in the lesion, a small amount of bile duct structure and lymphoid tissue embedding growth were observed at the junction between the lesion and the surrounding liver, and lymphocyte infiltration was observed in some adjacent sink areas. Fatty changes were observed in the perihepatic tissues, but there was no pseudolobular structure or inflammatory cell infiltration in the sink area. Immunohistochemistry revealed: BCL-2 (germinal center –), BCL-6 (germinal center +), CD10 (germinal center +), CD20 (+), CD21 (+), CD3 (Lymphocyte +), Ckpan (–), Cyclin-D1 (–), Ki67 (germinal center 80% positive), IgG (+), IgG4 (small amount +), Kappa (part +), Lambda (part +), and reticular fiber staining of peripheral liver tissue were positive (Fig. 3). The diagnosis of hepatic RLH is clear.

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Fig. 1

Ultrasound image of the lesion. (A) The lesion was hypoechoic on gray-scale ultrasound. (B–D) Contrast-enhanced ultrasonography of the lesions showed rapid hyperenhancement in the arterial phase (B), washout in portal phase (C), and low enhancement in the delayed phase (D).

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Fig. 2

Magnetic resonance imaging of the lesion. (A) Lesions presented as low signal on T1-weighted images. (B) lesions presented as high signal on T2-weighted images. (C) lesions presented as high signal on diffusion-weighted images. (D) The lesion showed significant enhancement in the arterial phase. (E-F) The lesion showed relatively low signal in the portal phase and perinodular enhancemen in delayed stage.

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Fig. 3

The hematoxylin-eosin (HE) and immunohistochemical findings (EnVision method) of the lesions. (A) A large number of proliferative polyclonal lymphoid tissue was found in the lesion. The cells were diffusely distributed, mainly reactive lymphoid follicles, and the center was the germinal center. (B) The lesion showed deposition of eosinophilic fibrils. (C) The lesion is Ckpan (–). Around the lesion, a small bile duct can be seen embedded and growing, forming a pushing boundary between it and the surrounding liver tissue. (D–F) There were reactive lymphoid follicles in the lesion and Bcl2 (D), Bcl6 (E), Ki67 (F) was expressed in the germinal center. (F) The Ki67 proliferation index in the germinal center is about 80%, and the Ki67 proliferation index around the germinal center is about 10%.

Hepatic RLH is a rare benign nonspecific disease. Most patients were middle-aged and elderly women, and most tumors were single and <2 cm in size [7]. Although the etiology and pathogenesis of hepatic RLH are not fully understood, many cases have been reported to be associated with chronic inflammation, autoimmune diseases and malignancies. Hepatic RLH has previously been reported in patients with primary biliary cirrhosis and autoimmune hepatitis, suggesting that it is associated with autoimmune and chronic inflammatory liver disease [9, 10]. In our case, the patient had concurrent fatty liver disease, and lymphocyte infiltration was seen in some adjacent sinks, suggesting a similar mechanism. Although hepatic RLH is a rare benign tumor, malignant transformation has also been reported [4, 11]. Therefore, we consider surgical resection as a necessary diagnostic and therapeutic tool.

The current EFSUMB guidelines indicated that most benign liver lesions show iso-enhancement or hyper-enhancement in the portal venous and late phases of CEUS, while a few very rare solid benign liver lesions show hypo-enhancement and early washout, such as inflammatory pseudotumors, bile duct adenomas, and hepatic epithelioid hemangioendotheliomas (HEHE) [12]. So they can usually only be clearly diagnosed during surgery. The imaging findings of hepatic RLH are not specific. It is usually appear as low echo with regular shape and clear boundary on gray scale ultrasound, and may easily misdiagnosed as malignant tumors (such as primary hepatic carcinoma, primary hepatic lymphoma, metastatic tumors, etc.) based on the enhanced imaging features of “wash-in and wash-out”. Some studies have shown that completely homogeneous hyperenhancement in arterial phase and donutlike enhancement when the lesion showed wash-out may be the CEUS features of HRLH. In this case, this features have be seen in enhanced MRI, but whether this feature has diagnostic value needs to be further studied [1, 2]. In addition, some scholars reported that the ADC value of hepatic RLH was significantly lower than that of spleen, and the difference was statistically significant with the average ADC value of other malignant tumors[1, 3]. In this case, the ADC signal was indeed significantly reduced. The possible pathological mechanism is limited diffusion of water molecules due to a large number of proliferative lymphoid follicles and the replacement of normal liver parenchyma by lymphocytes. It also has been reported that continuous linear high signals along the sink area in DWI have been shown to be helpful in the diagnosis of hepatic RLH, which consistented with lymphocyte infiltration in the sink area [13]. Furthermore, new techniques such as HiFR-CEUS technology (high frame rate contrast-enhanced ultrasound) might further improve the characteristics of peri-tumoral microvascularization, thereby improving the diagnostic accuracy of CEUS [14, 15]. And elastography plays an important role in the diagnosis of many diseases [16, 17], but it has not been reported to be applied to hepatic RLH at present. So if a certain number of cases are accumulated in the later stage, relevant studies can be conducted.

In order to distinguish from liver malignancies, the clinical characteristics of the patient are also important. Serum levels of tumor markers (such as AFP, CEA, etc.) are significantly increased in most primary hepatic carcinoma (HCC) and metastatic HCC patients, while they are basically normal in patients with hepatic RLH and primary hepatic lymphoma (PHL). However, patients with primary lymphoma usually have abnormal liver function tests (including aminotransferase, alkaline phosphatase, lactate dehydrogenase, etc.). Although the mean age at diagnosis of PHL is 50–62 years, which is also similar to hepatic RLH, it is most commonly reported in men [18]. Therefore, suspected malignant nodules in the liver found in women without cirrhosis or chronic viral hepatitis infection, especially when tumor markers are normal, need to be considered for differential diagnosis of hepatic RLH.

Pathologically, the boundary between liver RLH lesions and liver tissue is clear, and most of them have fibrous envelope formation. The histological features of liver RLH are remarkable proliferation of polyclonal lymphocyte, germinal center in the center and no cell atypia. Immunohistochemical staining is positive for B cell markers (such as CD20 or CD21) and T cell markers (such as CD3), suggesting a polyclonal origin, which may be supplemented by gene rearrangement tests if available. In addition, a negative Bcl-2 also indicates non-neoplastic hyperplasia, and the Kappa/lambda (κ/λ) ratio is within the normal range. The pathological manifestations of this patient were similar to those reported in the literature, and it was worth noting that the deposition of eosinophil fibrils was also observed at high magnification in this case. PHL, which is easily confused with it, shows poor cell adhesion, obvious cell atypia, frequent mitotic images, and characteristic lymphoepithelial lesions, and monoclonal immunochemistry histologically. Moreover, it can be monoclonal in immunohistochemistry.

4 Conclusion

In summary, we report a case of hepatic RLH located in the left external lobe of the liver. If small, isolated nodules are found in the liver of middle-aged and elderly women with no risk factors for malignancy, the possibility of liver RLH should be considered. The author believes that enhanced imaging “wash-in and wash-out”, perinodal enhancement, and limited DWI diffusion are helpful in differentiating liver RLH from other malignant tumors of the liver before surgery.

Funding

This work was supported by National Natural Science Foundation of China (Grant No. 82272013) and Clinical Research Plan of SHDC (Grant No. SHDC2020CR1031B). All funding departments had no role in the collection, analysis, or interpretation of the data or in the decision to submit the manuscript for publication.

Data availability statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethics statement

The studies involving human participants were reviewed and approved by the Institutional Review Board of Zhongshan Hospital Affiliated to Fudan University (B2022-223R). Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

Author contributions

Keke Chen wrote the draft of the manuscript. Feihang Wang provided radiological figures and interpreted the data. Minying Deng wrote the pathologic findings of the resected specimen. Kai Yuan, Xi Wang and Qiannan Zhao provided ideas. Yi Dong and Wenping Wang revised the manuscript. All the authors read and approved the final version of the manuscript.