healthmedicinet

A 78-year-old woman with a history of tremors for several years presented to the Department
of Neurology in our hospital. She was admitted to our hospital, and she underwent
computed tomography (CT) for screening. The CT scan incidentally revealed multiple
lesions in the liver; therefore, a qualitative diagnosis was required.

The results of laboratory examinations, including liver function tests, were all within
normal limits. The results were as follows: white blood cell count, 6940/mm
³
; hemoglobin level, 14.1 g/dL; platelet count, 20.8?×?10
⁴
/mm
³
; serum aspartate aminotransferase level, 21 IU/L; serum alanine aminotransferase
level, 19 IU/L; alkaline phosphatase level, 204 IU/L; ?-glutamyl transpeptidase level,
37 IU/L; and total bilirubin level, 1.0 mg/dL. The levels of tumor markers, including
alpha-fetoprotein, a protein induced by vitamin K absence, carcinoembryonic antigen,
carbohydrate antigen 19-9, and soluble interleukin-2 receptor, were all within normal
limits. Viral markers for hepatitis B and C were negative. Levels of immunoglobulin
(Ig) G, including IgG4, IgA, and IgM were normal. Tests for antinuclear antibody,
anti-DNA antibody, and anti-smooth muscle antibody were negative.

Imaging revealed four nodules measuring up to 13 mm in diameter in segments 2, 3,
4, and 8 of the liver. Ultrasonography revealed low echoic lesions in segments 2 (13 mm
in diameter) and 3 (8 mm in diameter) of the liver. On contrast-enhanced ultrasonography
using perflubutane, these lesions showed enhancement in the arterial phase, subsequent
washout in the portal phase, and defects in the Kupffer phase. On contrast-enhanced
CT, these nodules showed ring enhancement in the arterial phase and subsequent washout
in the portal phase. In addition, small nodules with the same enhancement pattern
were identified in segments 4 and 8 (Fig. 1). CT arterial portography revealed nodular perfusion defects, and CT hepatic arteriography
revealed strong enhancement in the early phase and ring enhancement in the late phase.
Magnetic resonance imaging (MRI) showed low intensity on T1 weighted images, slightly
high intensity on T2 weighted images, and high intensity on diffusion-weighted images.
On gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced
dynamic MRI, the nodules showed ring enhancement in the arterial phase and defects
in the hepatocyte phase (Fig. 2). The patient also underwent whole-body positron emission tomography-computed tomography,
and all lesions had standardized uptake values up to 4.6.

Fig. 1. Contrast-enhanced computed tomography showing a nodule with ring enhancement in the
arterial phase and subsequent washout in the portal phase in segments 2, 3 (arrow), 4, and 8 of the liver

Fig. 2. Magnetic resonance imaging (MRI) showing a nodule with slight high intensity on a
T2-weighted image and high intensity on a diffusion-weighted image. Gadolinium-ethoxybenzyl-diethylenetriamine
pentaacetic acid-enhanced dynamic MRI showing a nodule with defects in the hepatocyte
phase in segments 2, 3 (arrow), 4, and 8 of the liver

Because of atypical imaging findings, these tumors could not be definitively diagnosed.
The differential diagnosis included hepatocellular carcinoma (HCC), metastatic liver
tumor (unknown primary origin), malignant lymphoma, inflammatory pseudotumor, and
pseudolymphoma. We performed laparoscopic limited resection of segments 2, 3, 4, and
8 of the liver.

On visual examination of the resected liver specimens, the tumors appeared well circumscribed
and ash colored (Fig. 3). On histopathological examination of the tumors, many aggregated lymphoid follicles
were noted with germinal centers consisting of lymphocytic or plasmacytic cells without
atypia along with fibrocollagenous and hyalinized stroma. The lymphoid follicles varied
in size and shape, and the germinal centers included small or large lymphoid cells
and tingible body macrophages. On immunohistochemical examination of the tumors, CD3-positive
cells were mainly localized in the parafollicular area, and CD20 and 79a immunostaining
was positive in B follicles, while Bcl-2 staining was negative (Fig. 4). Thus, the possibility of well-defined follicular lymphoma was excluded, and pseudolymphoma
of the liver was finally diagnosed. The patient has had no signs of recurrence for
6 months after the surgery.

Fig. 3. Image of a resected liver specimen showing a well-circumscribed, ash-colored tumor
(a). On histological analysis, many aggregated lymphoid follicles are seen with germinal
centers consisting of lymphocytic or plasmacytic cells without atypia (b: scale bar, 25 ?m, c: scale bar 10 ?m)

Fig. 4. Immunohistochemical analysis of the tumor. CD3-positive cells are mainly localized
in the parafollicular area, and CD20 and CD79a immunostaining is positive in B follicles,
while Bcl-2 staining is negative (scale bar, 25 ?m)

Discussion

We reported the case of a patient with pseudolymphoma of the liver. Pseudolymphoma
is a nodular lesion considered to result from a reactive immunological response; however,
the etiology of pseudolymphoma is yet unknown 1]. It was first described in the lungs by Saltzstein et al. in 1963 as a lymphocytic
tumor associated with inflammation and with no evidence of systemic dissemination
12]. Pseudolymphoma of the liver is rare and was first reported by Snover et al. in 1981
13]. Pseudolymphoma is defined histologically as the aggregation of lymphoid follicles
typically with reactive hyperplasia of germinal centers showing proliferation of polyclonal
lymphocytes without atypia.

We reviewed the PubMed database from 1985 to 2014, using the keywords “liver,” “pseudolymphoma,”
and “lymphoid hyperplasia,” and we found 50 cases of pseudolymphoma of the liver.
These cases and our case are summarized in Table 1. The mean age of the patients was 58.9 years (range, 27–85; median, 60). Of the 51
cases, 5 (9.8 %) involved male patients and 46 involved female patients (90.2 %).
Among the 51 cases, 14 (27.4 %) had malignant diseases, including gastric cancer 14]–17], colon cancer 2], 18], 19], uterine/ovarian cancer 20], renal cell carcinoma 21], 22], pancreatic cancer 17], common bile duct cancer 23], and HCC 24]. Therefore, the pathogenesis of pseudolymphoma of the liver with an associated malignant
tumor may be related to an immunological abnormality caused by the malignant tumor
itself. However, we cannot confirm the relationship between the presence of a pseudolymphoma
of the liver and a malignant tumor. This association may be found frequently on incidental
image examinations in patients with malignant diseases.

Table 1. Clinical presentation of cases of pseudolymphoma of the liver

Because pseudolymphoma is a lymphoid reaction, it has been suggested that immunological
dysregulation is associated with pseudolymphoma 24]. Among the 51 cases reviewed, 11 (22.2 %) had extrahepatic autoimmune diseases, including
Sjogren’s syndrome in 4 cases 25], 26], autoimmune thyroiditis in 4 cases 24], 27]–29], Takayasu aortitis in 1 case 24], antiphospholipid syndrome in 1 case, and CREST syndrome (limited cutaneous form
of systemic scleroderma) in 1 case 1]. However, the present patient did not have any autoimmune disease.

Among the 51 cases reviewed, 14 (27.5 %) had chronic liver diseases, including primary
biliary cirrhosis in 6 cases 1], 16], 24], 26], 30], viral hepatitis in 6 cases 24], 31], 32], and nonalcoholic steatohepatitis in 2 cases 33], 34]. Pseudolymphoma has been reported to develop after interferon treatment for chronic
hepatitis 31], 35]. This finding supports the inflammatory nature of the lesion. Moreover, lymphoid
follicles are generally not identified in the portal area of a normal liver but are
found in a liver with chronic hepatitis. Therefore, pseudolymphoma of the liver has
been reported to be associated with hepatitis 24], 32]. However, the present patient did not have any liver disease, including chronic hepatitis.

Imaging findings of pseudolymphoma resemble those of other vascular tumors of the
liver, such as HCC, cholangiocarcinoma, and metastatic liver tumor; therefore, preoperative
diagnosis of pseudolymphoma of the liver is extremely difficult with imaging studies
alone. In terms of preoperative imaging findings, it has been reported that most pseudolymphomas
appear as low echoic lesions with or without well-defined margins on ultrasonography
and as lesions having a low density on plain CT 36]. In this case, the lesions showed defects in the Kupffer phase on contrast-enhanced
ultrasonography using perflubutane. Perflubutane is phagocytosed by macrophages, including
Kupffer cells. A pseudolymphoma is a non-malignant tumor and lymphoid hyperplasia,
but pseudolymphoma lesions in the liver replace normal liver tissue. Therefore, these
lesions have fewer macrophages, including Kupffer cells, than normal liver tissue,
and these lesions may demonstrate a defect in the Kupffer phase. Additionally, the
lesions have variable density on contrast CT, and many show enhancement in the early
phase and wash out in the late phase 32], 37]. On MRI, most of the lesions show low intensity on T1-weighted images, high intensity
on T2-weighted images, hyperintensity on diffusion-weighted images, and hypointensity
on T1-weighted images in the hepatocyte phase with Gd-EOB-DTPA enhancement 37]. Pseudolymphoma of the liver may mimic a primary or metastatic hepatic malignancy
radiologically, especially in patients with chronic hepatitis or internal malignancies.
Among the 51 reviewed cases, 19 had been misdiagnosed with HCC preoperatively. Our
patient did not have any risk factors for HCC. Additionally, the patient’s liver was
not cirrhotic and the levels of tumor markers were within normal limits. However,
CT and MRI revealed multiple tumors with ring enhancement. Therefore, malignancy could
not be excluded. We considered hepatic biopsy; however, we believed that it would
be insufficient to obtain an accurate diagnosis and there was a possibility of needle
implantation of malignant tumor cells. Therefore, we decided to perform hepatectomy
without biopsy.

Histologically, pseudolymphoma consists of hyperplastic lymphoid follicles, lymphocytes,
and other inflammatory cells, and an accurate diagnosis of pseudolymphoma relies on
immunohistochemical analysis 38]. Immunohistochemical staining shows positive results for CD3, CD4, and CD8 (T cell
markers) and CD20 and CD79a (B cell markers), indicating the polyclonality of the
tumor. Additionally, CD20 positive B cells are predominantly located within the lymphoid
follicles, and CD3 positive T cells are predominantly located in the peri and interfollicular
areas. However, the lymphocytes within the germinal centers are negative for Bcl-2,
indicating the reactive and nonneoplastic nature of the tumor 20].

The difference between pseudolymphoma and malignant lymphoma is significant. Although
the precise etiology and pathogenesis of pseudolymphoma remain unknown, its prognosis
is much better than that of malignant lymphoma, especially follicular lymphoma. Follicular
lymphoma includes atypical cells and shows monoclonal proliferation. Additionally,
Bcl-2 expression in lymphoid follicles is distinct for follicular lymphoma. Moreover,
in situ hybridization demonstrates intermixed kappa and lambda light chains within
interfollicular plasma cells. DNA analysis helps to distinguish these lesions from
those capable of malignant clonal lymphoproliferation by ruling out monoclonal rearrangements
of immunoglobulin heavy chains or T cell receptor beta and gamma genes 32].