Peripheral T-cell lymphoma presenting as fever of unknown origin in a man with deranged liver function tests and pancytopenia

Background

Peripheral T-cell lymphomas (PTCL) are relatively rare, differ widely in terms of how they present, and account for between 10% and 15% of all non-Hodgkin’s lymphomas.1 As a result of their heterogeneity, they are often difficult to diagnose, and treatment options remain associated with poor outcomes.2 The definitive method for diagnosing PTCL is through a haematopathological diagnosis based on a confirmatory biopsy.

In this case, this patient had a negative bronchoscopy and two negative bone marrow aspirate and trephines (BMAT), despite many clinical signs indicating disease, which delayed treatment as a result. We also review 15 previously reported cases in which diagnosis of PTCL, not otherwise specified (NOS) was delayed or difficult due to atypical presentation or negative initial biopsies.

The subject of this case study is fortunately still alive at time of writing, but the most recent update of his disease status indicated an ongoing aggressive progression of lymphoma despite multiagent chemotherapy.

It is essential for clinicians to remain vigilant with regard to confirming/excluding the diagnosis of this aggressive disease, with consideration of further invasive procedures if initial approaches are inconclusive.

Case presentation

A 57-year-old dairy farmer presented to his rural general practitioner (GP) in June 2017 with a 2-year history of night sweats and increasing shortness of breath, as well as new onset of anaemia. His prior medical history included chronic obstructive pulmonary disease (with a 40 pack-year smoking history), atrial fibrillation (controlled with flecainide) and postural hypotension for which no cause was ever identified. His mental health history was significant for anxiety, depression and bipolar disorder managed with venlafaxine, mirtazapine and diazepam. He had no allergies and had no significant family history.

A CT scan of his chest organised by his GP revealed bulky lymphadenopathy suspicious for lymphoma. He was referred to a local haematologist for investigation, however, several biopsies taken during endobronchial ultrasound did not reveal any malignant cells and a repeat CT done several months later showed shrinking lymph nodes. The patient’s symptoms were stable and attributed to a presumptive diagnosis of reactive lymphadenopathy.

Four months later, this patient presented to the emergency department (ED) of our rural hospital with a 1-week history of fevers, rigours, vague abdominal discomfort and multiple presyncopal episodes over the previous 24 hours. He had no localised infective symptoms. An initial workup in ED revealed pancytopenia with significantly elevated inflammatory markers, deranged liver function tests of a primarily cholestatic picture, an abdominal ultrasound scan (USS) showing mild hepatosplenomegaly without evidence of cirrhosis and an unremarkable chest X-ray. Repeated blood and faecal cultures did not grow any pathogens, nevertheless he was treated with 5 days of IV Tazocin for sepsis of unknown origin, which resulted in improving inflammatory markers. After also receiving a transfusion of packed red blood cells for persistent anaemia, he was discharged home on oral antibiotics.

One week after discharge, the patient represented to our hospital with ongoing febrile illness, involving multiple intermittent fevers throughout the day. Despite continuing oral antibiotics he had declined clinically, reporting further episodes of fevers and presyncope. On examination, he was tachycardic and hypotensive. Physical examination revealed hepatosplenomegaly but no palpable lymphadenopathy or abnormal respiratory sounds were present. He was readmitted for further elucidation of the cause of his symptoms and treatment with intravenous antibiotics in the interim.

Differential diagnosis

A man presented to our hospital with postural hypotension and over 2 years of intermittent fevers and night sweats. He had persistent mediastinal lymphadenopathy and hepatosplenomegaly on imaging, with pancytopenia and elevated liver enzymes. Further metabolic panel showed elevated LDH and positive IgG serology for Epstein-Barr virus. Serial blood cultures were all negative.

Our differential diagnoses were malignant lymphoma, sarcoidosis, intracellular infection (mycobacterium, legionella) and haemophagocytic lymphohistiocytosis. Our primary differentials for infectious causes included tuberculosis (for which serology was negative), histoplasmosis and coccidiomycosis, however, these conditions are rare in Australia and our patient had not visited any endemic areas. To arrive at a definitive diagnosis among the diseases considered, positive serology/blood cultures and tissue biopsy for pathology are essential; however, two biopsies performed at our centre were inconclusive. After transfer to a larger metropolitan centre, a diagnosis of PTCL (NOS) was made from the results of a mediastinoscopy and percutaneous liver biopsy.

Outcome and follow-up

At time of writing, this patient is alive and under the care of a local haematologist. He had his first cycle of multiagent cyclophosphamide, doxorubicin, etoposide, vincristine and prednisone chemotherapy in early May, and is scheduled to receive six cycles, followed by autologous stem-cell transplantation.

Shortly after his first chemotherapy cycle, he returned to our regional hospital with febrile neutropaenia complicated by Clostridium difficile colitis and oral candidiasis. On last review, 6 months postdiagnosis, he was continuing chemotherapy while living at home in the community.