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An aggressive intrasinusoidal lymphoma presenting with marked systemic disturbance but normal imaging studies


A patient with an aggressive intrasinusoidal non-Hodgkins lymphoma, presenting with marked systemic disturbance but only a mildly raised alkaline phosphatase as a localising sign is described. All imaging studies of the liver were normal and the diagnosis was delayed until a percutaneous liver biopsy was performed. Once diagnosed, the patient responded extremely well to conventional anti-lymphoma chemotherapy.

  • lymphoma
  • fever of unknown origin

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Mildly abnormal liver function tests detected during the investigation of a pyrexia of unknown origin (PUO) are often disregarded in the presence of normal imaging studies of the liver. However, such results are not always epiphenomena. Similarly, the finding of a normal appearing hepatic parenchyma on ultrasound or computed tomography (CT) scanning does not necessarily exclude significant pathology. Here we report the case of an aggressive intrasinusoidal lymphoma of the liver, presenting as a PUO, with only a mildly raised alkaline phosphatase as an initial localising feature.

Case report

A previously well 62-year-old Caucasian man was referred to the Infectious Diseases Unit, Newcastle General Hospital, with a PUO. He reported 3 months of general malaise, recurrent drenching sweats, rigors and 15 kg weight loss. Apart from evidence of recent weight loss and temperatures spiking up to 39°C several times a day, there were no other abnormalities on physical examination.

Autoimmune and extensive microbiological investigations including serology for HIV, hepatitis A, B and C were negative. A bone marrow biopsy showed only reactive plasma cells. Cerebrospinal fluid analysis including cytology was unremarkable. A bone scan, an abdominal ultrasound scan and a CT scan of the thorax and abdomen all appeared normal.

Inflammatory markers on admission revealed a normal white cell count of 4.9 × 10 9/l (normal differential) but an erythrocyte sedimentation rate of 137 mm/h and a C-reactive protein of 347 mg/l (normal < 10). Immunoglobulin levels and clotting times were unremarkable. Liver function tests showed a low albumin at 25 g/l (normal 34–50) with normal levels of bilirubin, alanine transaminase and gamma-glutamyl transferase. A mildly raised alkaline phosphatase at 169 U/l (normal 65–100) was felt to be ‘reactive’.

The patient deteriorated rapidly, losing weight, becoming extremely weak and intermittently confused. He developed oral ulceration, a normochromic, normocytic anaemia (haemoglobin 8.1 g/dl) and thrombocytopenia (26 × 109/l). By the third week of his hospital admission the patient had become moribund. His alkaline phosphatase had risen to 293 U/l and his lactate dehydrogenase to 1025 U/l (normal < 430).

Following platelet infusion pre-procedure, a percutaneous liver biopsy revealed an intra-sinusoidal high-grade centroblastic B-cell non-Hodgkins lymphoma (figure 1). With the already available imaging information this was designated stage 1E non-Hodgkins lymphoma with B symptoms.

Figure 1

Liver biopsy (periodic acid–Schiff stain). Note presence of abundant large pleomorphic lymphoid cells in the hepatic sinusoids. Immunostaining showed the cells to be CD20 and CD45 positive. A 25-μm scale marker is shown

Initial therapy with high-dose intravenous (iv) dexamethasone (4 mg qid) produced a dramatic fall in temperature (figure 2). Urgent combination chemotherapy was then commenced using 3-week cycles of CHOP (cyclophosphamide 750 mg/m2 iv, adriamycin 50 mg/m2 iv, vincristine 2 mg iv, with oral prednisolone 40 mg daily for 5 days). A reduced dose (75%) was used in the first course and full doses thereafter. By the sixth and final course he was apyrexial, had gained 18 kg in weight and his liver function tests had normalised. A repeat liver biopsy performed one month after his last course of chemotherapy showed no evidence of persistent lymphoma. Six months later he remains clinically and biochemically disease-free. A CT scan of the abdomen, pelvis and thorax performed during follow-up appeared normal, as had all previous imaging modalities.

Figure 2

Temperature chart showing lysis of patient's pyrexia following commencement of high dose dexamethasone (arrow). Intervals of 24 hours (at midnight) are marked


Primary non-Hodgkins lymphoma of the liver (stage 1E) is rare.1 A 4:1 male to female preponderance with a mean age of onset in the 5th decade has been described.2 In 50% of cases B symptoms, particularly weight loss, appear prominent. Biochemically, 80% of cases show an elevated alkaline phosphatase, and 100% show an elevated lactate dehydrogenase.3 4 The majority are diffuse large cell lymphomas of B-cell lineage.3 The prognosis with treatment appears variable, ranging from 14% to 56% survival 4 years after diagnosis.1 2 In the present case, thrombocytopenia was a prominent feature, previously noted commonly only in Chinese patients.1 The lack of hepatomegaly was unusual, being present in the majority (63–100%) of previously reported cases.1-5 The unique feature in this patient was the normal appearance of the liver on ultrasound and CT scanning. In all other recorded cases, imaging studies of the liver have shown either a diffuse abnormality or a uni-/multi-nodular pattern,1-5directly precipitating biopsy.

Learning points

  • primary lymphoma of the liver can present with severe systemic disturbance but few localising signs

  • normal ultrasound or CT imaging studies of the liver do not exclude significant hepatic pathology

  • mild elevation of alkaline phosphatase levels occurring during PUO is not always nonspecific

This case demonstrates that mildly abnormal liver function tests in a patient with a PUO should not necessarily be dismissed as non-specific findings. The case also demonstrates that a normal liver ultrasound or CT scan in this situation does not exclude relevant hepatic pathology. Percutaneous liver biopsy proved to be diagnostic. We recommend a low threshold for liver biopsy in the investigation of PUOs in a similar clinical setting, having ensured an adequate platelet count and clotting beforehand.