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Hepatic reactive lymphoid hyperplasia-associated primary biliary cholangitis masquerading as a neoplastic liver lesion
  1. Kwang Kiat Sim1,
  2. Tarini Fernando2,
  3. Lorenzo Tarquinio3 and
  4. Suresh Navadgi4
  1. 1General Surgery, Fiona Stanley Hospital, Murdoch, Western Australia, Australia
  2. 2Anatomical Pathology, Australian Clinical Labs, Clayton, Victoria, Australia
  3. 3School of Medicine, The University of Notre Dame Australia, Fremantle, Western Australia, Australia
  4. 4Upper GI-HPB Surgery, Royal Perth Hospital, Perth, Western Australia, Australia
  1. Correspondence to Dr Kwang Kiat Sim; kwang.sim{at}


Hepatic reactive lymphoid hyperplasia is an uncommon benign condition, often found incidentally as a solitary liver lesion. The chronic inflammatory reaction associated with autoimmune conditions and malignancies has been postulated as a possible aetiology. The diagnosis is challenging as it often mimics various malignancies radiologically and histologically, hence the diagnosis being made only after surgical resection. Lymphadenopathy is common with primary biliary cholangitis, though rarely reported with reactive lymphoid hyperplasia. We report a case of hepatic reactive lymphoid hyperplasia associated with portacaval lymphadenopathy in a patient with primary biliary cholangitis, diagnosed after surgical resection. We propose lesional biopsy be considered in patients with primary biliary cholangitis found to have a solitary lesion with supporting low-risk clinical and radiological features.

  • hepatic cancer
  • liver disease
  • gastrointestinal surgery

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Hepatic reactive lymphoid hyperplasia (RLH), also known as pseudolymphoma, or nodular lymphoid hyperplasia, is an uncommon benign condition characterised by localised proliferation of non-neoplastic, polyclonal lymphocytes forming reactive lymphoid follicles in germinal centres.1–3 Various organs including the skin, lungs, orbit, thyroid, stomach, breast, intestine, spleen and pancreas have been implicated; however, hepatic involvement is rare.2–4 The aetiology is likely a response to chronic inflammation, as hepatic RLH has been associated with autoimmune conditions, chronic disease, as well as various malignancies.2 3 Diagnosis is difficult, and the majority of cases are diagnosed after resection.2 To our knowledge, there have been 15 reported cases of hepatic RLH associated with primary biliary cholangitis (PBC).2 5 We report another case of hepatic reactive lymphoid hyperplasia with portacaval nodal involvement associated with PBC mimicking neoplasia.

Case presentation

A woman in her 70s with a background of alcohol consumption of up to six units per day was referred for assessment of deranged liver function tests, which persisted despite abstinence for 5 months. She had no other significant medical history and was asymptomatic of liver disease. Her physical examination was unremarkable. There were no peripheral stigmata of chronic liver disease or hepatosplenomegaly. Blood work revealed an elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma glutamyl transferase (GGT) of 49 u/L, 46 u/L and 52 u/L, respectively, with normal bilirubin and alkaline phosphatase (ALP) levels. She was negative for active or past hepatitis B and C infections. Her iron studies, ceruloplasmin and alpha-1-antritrypsin levels were normal. The liver-specific auto-antibody testing showed a positive anti-mitochondrial and anti-M2 antibody, with a normal immunoglobulin profile. Her antinuclear and anti-smooth muscle antibodies were negative. Assessment with a serum fibrosis marker (Hepascore 0.27) suggested the absence of significant fibrosis. Tumour markers including AFP, CEA and CA 19–9 were normal.

An abdominal ultrasound revealed a normal-appearing liver with no obvious features of cirrhosis or portal hypertension. An incidental 13 mm hypoechoic lesion with internal septation was identified in segment IVb. Multiphase contrast-enhanced abdominal CT showed a solitary 8 mm cystic lesion in segment V (figure 1). Contrast-enhanced abdominal MRI similarly revealed an ill-defined hypoechoic 13 mm lesion in segment V and additionally, a prominent portacaval lymph node measuring 8×21 mm (figure 2). The findings were concerning for a primary liver neoplasm with local metastatic disease.

Figure 1

CT demonstrating hypodense lesion on precontrast (A); hyperdense on arterial phase (B); and hypodense on portovenous and delayed phase, with no solid enhancing component (C).

Figure 2

MRI demonstrating an ill-defined hypoechoic 13 mm lesion in segment five with peripheral re-enhancement (A); a large surrounding zone of ill-defined T2 high signal (B); and a prominent portacaval lymph node measuring 8×21 mm (C).

Further workup with 18F fluorodeoxyglucose positron emission tomography (FDG-PET) was performed, which showed a solitary lesion with peripheral enhancement and moderately increased FDG activity with a standardised uptake value (SUV) max of 4.4 (figure 3). The prominent portacaval node was also mildly FDG active with a SUV max of 3.4 (figure 3). This raised a high suspicion of a primary neoplastic process with regional nodal involvement. Gastroscopy and colonoscopy were performed, which excluded a primary gastric or colonic malignancy.

Figure 3

FDG-PET demonstrating segment five lesion (A) and prominent portacaval node (B).

Factoring the small size of the lesion, the patient’s good health and liver function, surgical resection was considered in favour of needle biopsy to mitigate the risk of malignant dissemination. The patient underwent laparotomy with resection of the segment V liver lesion, including portal lymphadenectomy.

Histopathological examination demonstrated a lymphoproliferative lesion with a nodular architecture (figure 4A), composed of collections of reactive lymphoid follicles, showing germinal centres with intact mantle and marginal zones. The germinal centres demonstrated polarisation with tingible body macrophages (figure 4B). No cytological atypia or lymphoepithelial lesions were seen. Immunohistochemistry within the lesion demonstrated a mixed population of B and T cell lymphocytes on CD20, CD3 and CD5 surrounding the follicles. The follicles were CD20 positive (figure 4C), bcl2 negative (figure 4D) and bcl6 (figure 4E) and CD10 positive, confirming a reactive follicular hyperplasia. Follicular dendritic meshwork was confirmed on CD21 (figure 4F) and CD23. CyclinD1 and immunohistochemistry for EBV was negative. Reactive CD30-positive immunoblasts were identified. Scattered CD138-positive plasma cells were seen.

Figure 4

Histology shows nodular architecture at low power (A). The follicles are composed of reactive lymphoid follicles with germinal centres (B). The follicles are CD20 positive (C). bcl2 negative (D). bcl6 positive (E). Follicular dendritic meshwork is confirmed on CD21 (F). Reactive CD5 positive T cells (G).

The background liver parenchyma was seen to be nodular with bile ductular proliferation, expansion of the portal tracts by a lymphoplasmacytic infiltrate with lymphoid follicle formation. Scattered eosinophils and collections of histiocytes with focal multinucleated giant cells and non-necrotising granuloma formation were seen, consistent with a diagnosis of Scheuer stage 2–3 PBC. The histopathological assessment of the portacaval nodes also demonstrated reactive lymphoid hyperplasia with germinal centres with a similar immunohistochemical profile.

Outcome and follow-up

In view of the elevated liver enzymes and histopathological findings, treatment with ursodeoxycholic acid (UDCA) was commenced at a dose of 750 mg per day postoperatively with normalisation of the liver function tests after 9 months. The patient also completely abstained from further alcohol consumption. Nine-month follow-up ultrasound only showed postsurgical changes in segment V.


Hepatic RLH is a benign condition that is challenging to diagnose preoperatively.2 3 There have been at least 121 cases described, with a female predominance of 92.5% and a median age of 56.6 years (range=15–81 years). 86.25% of the lesions were solitary, with an average size of 17.4 mm at the time of diagnosis, which were usually found incidentally during radiological investigation for other unrelated issues.2 5

The pathogenesis of hepatic RLH is unclear, although they have been found to be associated with chronic inflammatory conditions and also accompanying malignancies. Reported cases of hepatic RLH have been associated with autoimmune conditions, including Sjogren’s syndrome, autoimmune thyroiditis, Takayasu disease and CREST syndrome. Additionally, chronic liver diseases including PBC, chronic viral hepatitis infections and non-alcoholic steatohepatitis were also found in this reported population. Therefore, it has been speculated that a chronic inflammatory or immune dysregulation could be a contributing factor.1–4 6–8 Gastric, renal, ovarian and pancreatic cancers have also been implicated and an immune reaction to cancer antigens is theorised; however, this association could just reflect the increased use of radiological abdominal examinations in this patient population.6 7

Association with PBC has been reported in at least 15 previous cases, accounting for 50% of autoimmune-associated cases.2 5 PBC is a chronic autoimmune cholestatic liver disease that causes granulomatous destruction of small intrahepatic bile ducts, resulting in progressive biliary fibrosis and ultimately cirrhosis.9 10 Due to the chronic inflammatory state, lymphadenopathy is common in patients with chronic liver disease with Braden et al reporting perihepatic lymphadenopathy in 100% of their PBC population with a correlation found between lymph node volume and histological stage.11 12 Interestingly, none of the previous cases of hepatic RLH associated with PBC mentioned radiological findings of lymphadenopathy, although Dominquez-Perez et al reported involvement of a perihepatic lymph node on biopsy.1–3 7 13–19 In our case, the involvement of portacaval nodes was likely due to the PBC.

Various studies have attempted to radiologically characterise hepatic RLHs; however, CT and MRI findings can be similar to those found with hepatocellular carcinoma (HCC) and liver metastases, making differentiation difficult.1 18 Some unique characteristics have however been identified, including a homogenous parenchymal pattern without necrosis or calcification and vessel penetrating sign suggesting preservation of intratumorous portal tracts.1 Another study by Zhou et al found similar MRI characteristics. They noted that the apparent diffusion coefficient (ADC) of RLH was lower than the spleen, as opposed to a higher ADC seen with HCC.20 On FDG-PET, Suzumura et al found that 78% of hepatic RLH showed FDG uptake, with a median SUV max of 4.3 and a range of 3.4–7.2, similar to the median SUV max of 2.64, 5.20 and 4.38 in seen HCC, cholangiocarcinoma (CCC) and metastatic liver cancer, respectively.21

Due to these similar radiological findings, hepatic RLH was often misdiagnosed preoperatively as a malignancy.2 4 8 Surgical resection is usually undertaken, and needle biopsies were rarely performed mainly due to the potential risk of peritoneal dissemination.4 In cases of PBC, HCC can be a rare complication with an incidence of 2.4%, with cholangiocarcinoma being even rarer.2 22 This risk of HCC increases with advanced disease, hepatic decompensation and male gender.23 Tumour markers could be used to further risk stratify patients if they return negative.

Few cases have been diagnosed on biopsy and followed up with close surveillance. These mostly demonstrated a reduction in the size of the lesion despite receiving no treatment.1 7 However, an enlargement of the lesion was reported in some cases, with one reported transformation into hepatic non-Hodgkin’s B cell lymphoma.2 4 21 The actual frequency of malignant transformation, though well documented in other organs such as lung, stomach and skin, is unclear as most cases were surgically resected for suspicion of malignancy.13 24

As hepatic RLH is suggested to be a reaction to chronic inflammatory or immune dysregulation, treatment of the known underlying disease could possibly result in regression of the lesion. In the case of PBC, first-line treatment is with UDCA. It improves liver biochemical function and slows disease progression, reducing the risk of death or liver transplantation, and improving transplant-free survival.9 A double-blinded controlled trial by Pares demonstrated UDCA resulted in the reduction of histological staging, decreasing periportal inflammation, and lobular or piecemeal necrosis.25 In addition, UDCA started at Scheuer stage 1 results in a significantly better prognosis, as compared with in stages 3 and 4, with patients in stages 1–3 of the disease being more likely to respond to treatment.26 It should, however, be noted that patients with biochemical non-response to UDCA are at a significant risk of developing HCC, including those in early stages of the disease.23

In patients with PBC who have low-risk features, such as a small solitary liver lesion, young age, female gender, negative tumour markers, in the absence of cirrhosis on the basis of serum fibrosis score and/or liver elastography or early Scheuer stage (if biopsy performed of the ‘normal’ liver), the diagnosis of hepatic RLH should be considered.1–8 22 23 Lesional biopsy may be considered in preference to surgical resection to confirm a diagnosis. First-line therapy with UDCA should also be considered for the underlying PBC to reduce the background chronic inflammatory state.9 25 26

Learning points

  • Reactive lymphoid hyperplasia (RLH) is a rare benign lesion of uncertain aetiology associated with a number of chronic inflammatory conditions.

  • RLH has been reported to also occur in patients with primary biliary cholangitis (PBC).

  • RLH is diagnostically challenging as malignant lesions share similar radiological features.

  • Ursodeoxycholic acid has been shown to improve histological grading of PBC and reduce periportal inflammation, thereby slowing progression of the disease and improving transplant-free survival.

  • For non-cirrhotic PBC patients with a liver lesion associated with low-risk features for malignancy, lesional biopsy may be considered in preference to surgical resection, to make a diagnosis.

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  • Contributors The following authors were responsible for drafting of the text, sourcing and editing of clinical images, investigation of results, drawing original diagrams and algorithms and critical revision for important intellectual content: KKS, TF, LT and SN. The following authors gave final approval of the manuscript: KKS, TF, LT and SN.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.